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Nanotechnology from lab to industry – a look at current trends
First published on 1st August 2022
Nanotechnology holds great promise and is hyped by many as the next industrial evolution. Medicine, food and cosmetics, agriculture and environmental health, and technology industries already profit from nanotechnology innovations and their influence is expected to increase drastically in the near future. However, there are also many challenges that need to be overcome to bring a nanotechnological product or business to the market. In this article we discuss current examples of nanotechnology that have been successfully introduced in the market and their relevance and geographical spread. We then discuss different partners for scientists and their role in the commercialization process. Finally, we review the different steps it takes to bring a nanotechnology to the market, highlight the many difficulties related to these steps, and provide a roadmap for the journey from lab to industry which can be beneficial to researchers.
2. nanotechnology developments.
All inhabited continents are represented among the top countries involved in scientific publishing; however, only Europe (14 countries), Asia (8 countries), North America (2 countries), and Oceania (1 country) are included among the top 25 countries involved in the patenting of nanotechnology developments. Seventeen countries were common factors among both publishing and patenting discoveries. It is also noteworthy that the two countries that had the highest investments in scientific research (China and The USA) produced highest numbers of publications and patents, respectively. Patents can be used as technological indicators as they provide an insight into the research and development activities that are intended for commercial gain. 12 The transfer of these nanotechnology advancements to commercialized end products is however a major challenge that the scientific community faces. However, it has to be noted here that there are also quite some differences in culture when it comes to patenting. There are differences between countries in how buerocratic the patent process is. Additionally, there are differences in how much is patented at all. In some cultures, it might be more common to keep innovation a secret than to patent. There are also differences in how patents are made. In some places there is a high number of smaller patents while in others there are a few more elaborate ones.
2.1. Nanotechnology industries worldwide
3. the business of ‘lab-to-industry’, 3.1. ideation.
These two approaches show how innovation relies on technology seeds and market needs. One might ponder which of the two approaches is better. There are both merits and challenges associated with each approach. While each can lead to innovation, a pairing of the two is recommended. When closely integrated, the potential impact of the innovation increases. This synchronization of the ‘seed’ and ‘need’ approaches is called accelerated innovation. It enables the restructuring of research and development, and innovation processes to make new product development dramatically faster and less costly. 15 Furthermore, it also facilitates functional thinking and exaptation where the latter refers to the discovery of unintended functions for technologies. Altogether creating the ideal conditions for researchers to make radical innovations and bridge the gap between academia and industry.
3.2. Business model
Breakthrough technologies, especially those incorporating the use of nanotechnology, are intended to create value. Value is created via this technology when there is meaningful performance improvement or when the cost of solving problems is significantly reduced. There is however a major challenge for nanotechnology innovations in terms of a business model, and that is, the challenge of taking the product to customers. Several factors can influence this (for example, having limited resources) and for this reason, a go-to-market strategy is critical.
A joint-development partnership is an agreement between two organizations to develop a new product or service. It is a strategic alliance that serves to leverage the assets of each company to create a new offering for commercialization that would be difficult to achieve individually. This type of partnership is commonly used for product development or beta testing. Typically, these agreements are not binding and one party can quit at any time. Profits, access, expenses, and losses are usually shared between the companies. With this type of business partnership, it is important to have a close business relationship with the company before engaging in this agreement. As is the case with licensing arrangements, the most ideal joint-development partnership can be determined with the assistance of an attorney. Matters relating to the ownership and access to intellectual property, responsibilities, disengagement, and termination are some of the issues to be discussed with a suitable attorney before engaging a potential partner.
In partnerships, securing intellectual property early remains crucial. In an innovative nanotechnology business, the science underpinning the technology is critical and must be protected. This can be achieved by engaging an intellectual property counsel. The services of a corporate counsel should also be acquired early to ensure the start-up is properly incorporated. These parties should be appointed at the early stages as they help with structuring the company. The technology transfer process which is discussed in Section 3.3 helps to get these counsels on board.
There are some key players that are needed to guarantee a good business model and these are outlined in Fig. 4 . To assure a diversity of skills that are necessary for success, an often overlooked group of individuals is needed. This is a company board. This can include a board of advisors and a board of directors. The functions of these two bodies bear some similarities and differences. The board of advisors is composed of business professionals who fill skill and expertise gaps and can offer guidance to the management team. This can include matters concerning business performance, market trends, long-term goals of the company, and financing to name a few. While the additional skill set required in a science-based industry might be in business management, it is not unusual for additional technical expertise to be warranted. This can include the skills of fellow scientists who have had prior success in transitioning science to the marketplace. These scientists, when recruited, could form a scientific or technical advisory board. Regardless of the composition of the advisory board, their core function is to provide non-binding strategic advice. Their role is not fiduciary. This means that the team of experts and community leaders has no legal responsibility to the company. Their role however remains critical as they can compensate for some of the weaknesses within the management team and bring different opinions, perspectives, and experiences to the table. The board of advisors is particularly helpful for start-ups. A board of directors, on the other hand, is essentially a panel of people elected or appointed to represent shareholders. They oversee the activities of the company and have a fiduciary responsibility to represent and protect the members' or investors' interests in the company. The management team however reports to the board of directors. Larger companies that will require significant funding need a board of directors. Both the boards of advisors and directors can assist with strategic planning, the development of new ideas, improvement of management structure, improving company image and reputation, reassuring stakeholders and investors, and overall, help to ensure the success of the company.
The management team and the company board can together decide on the most suitable business model for the company. In making this decision, special focus should be placed on the model that will create and deliver great value to customers while simultaneously delivering great margins. The model should also hedge against customer dissatisfaction or dissonance and issues securing adequate funding. While the team is now multifaceted, additional support to make the right decisions that will position the company for success can be sought. This can be achieved using accelerators and incubators (which might be available within the university or municipality), government agencies such as the local chamber of commerce, and small business and technology development centers. Start-ups are generally encouraged to not employ at the early stages and to instead contract personnel for specific functions if necessary.
3.3. Technology transfer process
The efficiency of the transfer of nanotechnology innovations from the lab to the industry is dependent on the efficacy of the technology transfer process. Countries that invest in improving nanotechnology transfer policies and practices have greater nanotechnology outputs. This is evident in the United States where the National Nanotechnology Initiative (NNI) was developed. It is a collaboration of federal departments and agencies with interests in nanotechnology research, development, and commercialization. 17 Within the NNI are agencies such as the Nano manufacturing and Small Business Innovation Research (SBIR) programs, and the NNI's National Nanotechnology Coordination Office (NNCO) that are concerned with the transfer of newly developed nanotechnologies into products for commercial use. In Asia, there has been an increase in expenditure towards nanotechnology research and deliberate efforts to transfer research findings to industries. While the production of nanotechnology publications in China is higher than in other countries ( Fig. 2a ), the transfer of these technologies to industries is not equivalent. 18 The National Steering Committee for Nanoscience and Nanotechnology (NSCNN) was established to oversee and coordinate nanotechnology policies and programs in China. Some key members of this group include the Chinese Academy of Sciences (CAS), the National Natural Science Foundation of China (NSFC), the National Development and Reform Commission (NDRC), and the Chinese Academy of Engineering. These agencies are expected to impact the technology transfer process within the country.
The success of the transfer of technology in The United States reveals that more favorable environments for nanotechnology transfer need to be created globally. This will create a stronger ecosystem for nanotechnology research and innovation, and in turn, result in greater success in the use of intellectual property to facilitate the creation of start-ups formed from the ground up or through partnerships. Some nanotechnology and nano-engineering associations across the world that can be modelled in other countries to positively impact the transfer of technology are outlined in Table 2 . These associations were selected from the Nanotechnology 2020 Market Analysis. 9
3.4. Readiness for commercialization
Technology readiness evaluates the technology itself and seeks to determine if the technology will maintain itself in the market. This is usually determined by performing a technology readiness assessment (TRA). It is recommended that this TRA is done at several points during the ‘life cycle’ of the new technology or system. Possible components of this assessment include an evaluation of the conceptual design, a clear protocol to facilitate a decision from among several competing design options, and similarly, a defined approach to decide when to begin full-scale development. These decisions might be made by the research team or they can be more complex and warrant an external, independent peer-review process. 20 Market readiness assesses how marketable the technology is; that is, how well the technology will be accepted by the target market. This is generally done by examining whether the technology offers meaningful identifiable and quantifiable benefits, has distinct advantages over competing products, has access to a market of a suitable size that is defined and is growing (demand-based), has immediate market uses, and has feasible manufacturing requirements. 21
The commercialization readiness assessment also evaluates the readiness of the technology's business model. This is done to verify the stability and readiness of the foundation upon which the technology will be delivered. Within this component, parameters for assessment include determining whether prospective licensees are identified, if industry contacts are available, and if further development or patenting is possible based on the availability of financial support for the licensee. Additionally, anticipated future royalty revenue of the license, access to venture capital, a profitable investment, and availability of government support for additional development for innovations resulting from universities are also crucial. 22 The last key area is management readiness which assesses the readiness of the management team that is responsible for the technology. It addresses matters such as the ability of the inventor to champion the innovation as a team player, whether the inventor's expectations for success are realistic, if the inventor is recognized and reputable in the field, if commercialization skills such as sales and marketing skills are available, whether management capabilities are available, and also whether the inventor is the patent holder for innovations resulting from government labs. 23
A method of quantifying the judgments made for each criterion of the four areas of the Cloverleaf framework to determine the degree to which each condition is met was suggested. 19 If all components of the criteria list for the four ‘leaves’ assessing readiness are satisfied, then the technology is ready for commercialization. If a partnership agreement is being utilized, some components should be completed before engaging a partner and others should be finalized with the partner. Regardless of the business model, if any area is found lacking, additional preparation is warranted to ensure the success of the venture when it enters the market.
Alternative to the Cloverleaf framework is the Technology Readiness Levels (TRL) model. This was developed by NASA and is a type of measurement system that is used to permit more effective assessment and communication regarding the maturity of new technologies. 20 The different levels of the framework are outlined in Fig. 6 . There are nine technology readiness levels. A project is evaluated against the parameters for each technology level and is then assigned a TRL rating based on its progress. TRL 1 is the lowest level and indicates that a technology requires further research and development, and testing. TRL 9 is the highest level and signifies a mature technology that is proven to work and may be put into use and commercialized.
Another type of capital provider is venture capitalists. These private investors provide funds to early-stage companies that are pursuing big opportunities with high growth potential. Venture capital firms exchange capital for equity ownership and can also provide strategic assistance, and an invaluable network. To capture the interest of a venture capitalist, a start-up should have a good “elevator pitch” and a strong investor pitch deck for their innovative product. This should therefore include the strength of the management team and clearly outline the large potential market for the nanotechnology innovation, and a unique product or service with a strong competitive advantage. Another entity that can provide financing and has a similar structure to a venture capital firm is a family office. This is a special investment firm that manages the wealth owned by individuals and families with a high net worth. 26 Family offices make optimal investors and are increasingly entering venture investment as a relatively new capital provider. They are comprised of qualified professionals with extensive experience and tend to offer more patient capital and expect lower returns than traditional investors.
4. The challenge of moving technology from lab to industry
Biological or environmental challenges are other factors that can impede the transfer of nanotechnology from the lab to the industry. Biological challenges include insufficient knowledge involving the interaction of nanomaterials in vitro and in vivo , inadequate information on their bioaccumulation in target organs, tissues, and cells, and also limited information on their biocompatibility. 30,31 Physical properties such as particle size, composition, surface area, surface charge, surface chemistry, and agglomeration state all influence the biocompatibility of nanomaterials and so more information is needed on their safety in vivo . 31 Environmental challenges include nanomaterials entering the environment either directly or indirectly (for example, via landfills). Nanomaterials can have potentially adverse effects on natural systems and can enter the environment at different stages of their life cycle. Three emission scenarios that are generally of relevance are (i) release during the production of various nanotechnology products or nano-enabled products; (ii) release during use; and (iii) release after disposal. 32 While present in the environment, nanomaterials can then undergo many transformations. These include chemical transformations (for example, photo-degradation), physical transformations (such as aggregation), biologically-mediated transformations (for instance, redox reactions in biological systems), and interactions with macromolecules (for example, flocculation). 30 The interplay between these transformations and the transport of the nanomaterial within the ecosystem ultimately determine their fate and ecotoxicity.
Possible biological and environmental impacts of nanotechnology innovations should be determined with in vitro and in vivo models, as well as within aquatic and terrestrial ecosystems. The production process from which the nanomaterial results should also be considered so that any such material emitted during this time or released from nano-enabled devices during their fabrication, use, recycling or disposal can be studied and minimized. Biological and environmental challenges can also be mitigated by providing employers and the extended workforce with information on the potential toxicity of nanomaterials at different stages of their life cycle. With the help of modelling, recent developments have been geared towards predicting the fate, behavior, and concentration of nanomaterials in the environment. 33 While these simulations can be helpful, more efficient and reliable analytical instruments and methods must be developed so that nanomaterials can be satisfactorily characterized and quantified, and the necessary tools developed to detect, monitor and track them in biological media and complex environmental matrixes.
The nanotechnology industry plays a major role in economic development; however, several economic challenges can hinder the transfer of innovations from the lab to the industry. Generally, these include limited investment in relevant research and development activities and a lack of appropriate mechanisms to secure these investments, lack of laboratory equipment and appropriate infrastructure to facilitate research and its commercialization, and insufficient funding opportunities to engage in research that has the potential for commercialization. Constraints imposed on the activities needed to commercialize nanotechnology outputs are also impacted by the socio-economic dynamics of innovation. While many believe the rapid growth in nanotechnology will have significant economic benefits, some advocate to reduce or halt its development. The backlash against nanotechnology by this group is based on the belief that it will exacerbate problems concerning existing socio-economic inequity and power imbalance caused by inequality. This, they suggest, will cause a nano-divide which refers to differing access to nanotechnology between low-, middle-, and high-income countries. 34,35 The ethical criticism is mainly concerned with inequity based on where knowledge is developed and retained and a country's capacity to engage in these processes. 35 An attempt to combat these challenges is outlined in the European Union's Framework Programs through the Responsible Research and Innovation (RRI) approach. This approach ‘anticipates and assesses potential implications and societal expectations concerning research and innovation, intending to foster the design of inclusive and sustainable research and innovation’ (https://ec.europa.eu). These measures which are intended to facilitate broader access to nano-technology and its innovations globally are critical in addressing a nano-divide.
The final category of challenges that can significantly impact the transfer of nanotechnology from the lab to the industry is regulatory challenges. These are concerned with a lack of clear regulatory guidelines for nanotechnology and nanotechnology-enabled products. Some regulatory challenges include inadequate policies to foster the development and operation of nanotechnology businesses or insufficient strategies implemented by governments to attract nanotechnology business initiatives. Additionally, a lack of technology transfer protocols, or requisites for regulatory approvals to facilitate the movement of innovation from the lab to commercial products are problematic. 36 The multidisciplinary nature of nanotechnology also presents regulatory challenges. With its cross-industry applications, policing and enforcement nanotechnology patents have proven to be prohibitively expensive (WIPO, 2011). New intellectual property practices and protocols are therefore required to simplify the pathway from lab to industry thereby reducing time and expense.
The technical, biological, environmental, economic, and regulatory challenges of nanotechnology need to be addressed urgently. Policies governing all aspects of nanotechnology research and subsequent commercialization must balance its potential benefits with its current challenges. Combatting these challenges will require considerable efforts to prevent any possible harmful effects of nanotechnology while also facilitating the awareness of its benefits to society. 37 The involvement of scientific, governmental, industry, and labor force representatives is therefore critical in decision making so the challenges associated with the commercialization of nanotechnology can be controlled, minimized or mitigated.
The necessary risk assessment to understand the potentially harmful effects of products resulting from nanotechnology have however not kept pace with their proliferation; and researchers are racing to address this knowledge gap. 38 Companies resulting from the transfer of nanotechnology innovations from the lab to the marketplace must therefore have rigorous risk management protocols where risks are identified, control measures are planned and implemented, and risks communication. 37 Identified regulatory impediments should also be addressed and technology transfer policies and practices implemented. Entrepreneurial education and training, and the establishment of business incubators should also be supported within the necessary departments or research institutes. Improvement in the understanding of nanotechnology within society would also help commercialization efforts. Overall, societal actors such as researchers, policymakers, investors, citizens etc. must work together during the research and commercialization stages so that the many benefits of nanotechnology outputs can be aligned with the needs and expectations of society.
Conflicts of interest
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- Open access
- Published: 02 November 2021
Cancer nanotechnology: current status and perspectives
- Jessica A. Kemp 1 &
- Young Jik Kwon ORCID: orcid.org/0000-0003-4086-6995 1 , 2 , 3 , 4
Nano Convergence volume 8 , Article number: 34 ( 2021 ) Cite this article
Modern medicine has been waging a war on cancer for nearly a century with no tangible end in sight. Cancer treatments have significantly progressed, but the need to increase specificity and decrease systemic toxicities remains. Early diagnosis holds a key to improving prognostic outlook and patient quality of life, and diagnostic tools are on the cusp of a technological revolution. Nanotechnology has steadily expanded into the reaches of cancer chemotherapy, radiotherapy, diagnostics, and imaging, demonstrating the capacity to augment each and advance patient care. Nanomaterials provide an abundance of versatility, functionality, and applications to engineer specifically targeted cancer medicine, accurate early-detection devices, robust imaging modalities, and enhanced radiotherapy adjuvants. This review provides insights into the current clinical and pre-clinical nanotechnological applications for cancer drug therapy, diagnostics, imaging, and radiation therapy.
Cancer devastates tens of millions of lives each year despite great advances in medicine and technology [ 1 , 2 ]. Decades of research continuously reveal the ever-dynamic nature of the disease, and although treatment options have improved, severe side effects from harsh chemotherapies persist [ 3 , 4 ]. Particularly, when aggressive cancers lie dormant then re-emerge, patients suffer when the need arises for more aggressive therapies [ 5 , 6 , 7 ]. One of the greatest challenges in finding a successful cancer treatment is the pervasive emergence of resistance mechanisms. Upon shutdown of initial oncogenic routes, resistance mechanisms are activated in parallel signaling pathways and re-route to allow for cancer to thrive [ 8 , 9 ]. Heterogeneity can be found within different tumor cells, between patient tumors, amongst genetic mutations, and epigenetic patterns, all of which can limit responses to therapeutics, further allowing for drug resistance [ 10 , 11 , 12 , 13 ]. Clonal heterogeneity affects overall tumor biology and is known to drive metastasis and cancer progression [ 14 ]. Although new targets and therapies can advance cancer treatments, the dynamic nature of cancer finds a way to survive.
The strategy against cancer needs to shift from finding new therapies to improving existing therapies and diagnostics in innovative, effective, and plausible ways. Pain is experienced by 55% of patients undergoing cancer treatment and 66% of patients with advanced stage cancer [ 15 ]. Chemotherapies without distinct targeting mechanisms kill cancerous and noncancerous cells alike, therefore the systemic toxicity will continue to deteriorate patient quality of life [ 16 , 17 ]. Furthermore, the benefits of early detection are clear. Cancer detected in early stages has a significantly higher 5-year survival rate, considerably lower overall cost to the patient, and typically less aggressive treatment course (Fig. 1 ) [ 18 , 19 , 20 ].
Late stage diagnoses for cancer results in significantly higher patient costs and decreased 5-year survival rates. The burden of cancer severely impacts patient quality of life with a majority experiencing pain directly from the disease and/or from treatment side effects. As the second leading cause of deaths worldwide, it is pertinent that new avenues are explored to improve cancer therapies and diagnostics
The solution may be found in nanotechnology: equipping existing therapies with better targeting capability, increasing localized drug efficacy, limiting systemic toxicity, improving diagnostic sensitivity, enhancing imaging, and refining radiation therapy [ 21 , 22 , 23 , 24 ]. Clinical translation of cancer nanomedicine dates back several decades, and the number of nano-based therapies and components for imaging, diagnostics, and radiation therapy in clinical use has steadily increased (Table 1 ) [ 25 , 26 ]. For example, the CellSearch® system is the first FDA-approved diagnostic blood test which utilizes magnetic nanoparticles (NPs) targeting EpCAM and cell staining to identify circulating tumor cells [ 27 ]. Nano-based imaging contrast agents such as superparamagnetic iron oxide NPs (SPIONs) and Gadolinium (Gd)-based contrast agents enhance detection of tumor and imaging in vivo when using conventional scanning devices, such as magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography (CT) [ 28 ].
Nanoformulations can counter resistance mechanisms by targeting multiple components with dual-drug loading, increasing specificity with triggered release, and utilizing physical modalities to eradicate cancerous cells [ 29 , 30 ]. Nanoscale carriers can cross a tumor endothelium and passively accumulate in tumors owing to the leaky blood vessels and poor lymphatic drainage [ 31 ]. Furthermore, nanomaterials have unique physico-chemical properties which are employed in highly sensitive diagnostic tests, allowing for early detection of cancer and better patient prognosis [ 32 , 33 ]. Cancer diagnostics are steadily moving away from invasive, complicated procedures to the direction of highly sensitive point-of-care liquid biopsies, where nanomaterials have demonstrated high utility for biomarker detection [ 34 , 35 , 36 ]. Certain properties also enable vast improvement of imaging techniques used for surgical guidance and tumor surveillance, enabling highly specific surgical resection and enhanced treatment monitoring [ 37 ]. Nanomaterials can function as radiosensitizers, creating highly specific and uniform radiation dosing to tumors while sparing healthy tissue [ 38 ]. The versatility and functionality of nanomaterials provide a multitude of applications for cancer drug treatments, diagnostics, imaging, and radiotherapy. Early detection, decreased radiation dosage, and improved therapeutic specificity can help eliminate the systemic toxicities associated with traditional methods and improve prognosis and patient quality of life [ 39 , 40 , 41 ].
2 Principles of nanotechnology
Use of nanotechnology to improve therapeutics is no longer novel, in fact, there has been a steady increase in nanotechnology research as the benefits become more apparent [ 24 , 26 ]. Currently approved cancer nanomedicines are predominantly liposomal formulations and drug conjugates (protein, polymer, and/or antibody) focused on improving pharmacokinetics and pharmacodynamics (PK/PD) of the free drug and utilizing passive targeting. There are many clinical studies currently investigating nanomaterials for therapeutic and diagnostic applications, including imaging modalities (Fig. 2 ) [ 43 , 44 ]. Passive targeting for tumors is based upon the enhanced permeation and retention (EPR) effect, where NPs can preferentially accumulate within tumor vasculature [ 45 ]. Many tumors have leaky blood vessels with apertures suitable for NPs to pass through and accumulate within the tumor tissue [ 46 ]. However, the EPR effect is not the end-all solution: passive targeting does not eliminate drug action in healthy tissues nor the side effects that accompany systemic distribution [ 47 ]. There are physiological obstacles that prevent NPs from reaching their target, even without a diseased state, and can become even more complex to navigate for cancer patients [ 48 ]. Protein and lipid adsorption, blood flow rate, coronas, and phagocytic cells can reduce stability and delivery capability [ 49 , 50 , 51 , 52 ]. Interstitial pressure and extracellular matrices can also limit access to a tumor [ 53 , 54 ]. Differences in cancer types can further complicate these issues, presenting a need to optimize formulation according to each kind [ 55 ]. First-generation nanomedicines have greatly improved pharmacokinetic (PK) profiles, solubility, bioavailability, and stability of major cancer therapeutics [ 56 ]. With the growing availability of technology and information, nanomaterials can broaden into new territory to incorporate highly specialized design and function. This enables the next generation of nanomedicine to incorporate combination therapies, specific targeting, triggered drug release, gene therapy, novel immunotherapy approaches, radiation, and multi-modal therapies. Furthermore, as scientific insights elucidate cancer initiation and survival mechanisms, nanotechnology will be a critical asset for improving diagnostics and bioimaging to halt metastasis.
Examples of nanomaterials currently being investigated in clinical trials for various applications to improve therapeutic delivery, diagnostics, radiation therapy, and imaging modalities
Drugs can have vastly different biodistributive properties and relative concentrations, so it can be difficult to optimize dose coordination for combination therapies, and is further complicated by vast physiological variations in different types of cancer and amongst individual patients [ 44 , 57 ]. Co-delivery of synergistic drugs within a single carrier can greatly improve synergistic potential as complementary action can occur in a coordinated fashion [ 30 ]. Nanomaterials such as lipid-based, polymeric, inorganic, carbon-based, biomacromolecular, and hydrogel can properly formulate multiple therapeutics with highly different chemical properties [ 58 , 59 , 60 , 61 ]. Multiple drugs may be engineered to be released simultaneously or in specific sequence depending on kinetics and mechanism of action, with drug release occuring through degradation of the carrier, drug desorption, diffusion through the nanoparticle matrix, or by triggered release [ 62 , 63 ]. Specific targeting utilizes a nanocarrier or drug conjugate tethered with specific molecules that have high affinity for cancerous cells and lower affinity for healthy cells, lowering the likelihood of systemic toxicity [ 64 , 65 ]. Antibody drug conjugates currently improve targeting, but targeted delivery of a nanocarrier may incorporate a higher dosage of drug and typically have more versatility for targeting modes using dynamic nanomaterials [ 66 , 67 ]. For example, doxorubicin (DOX)-loaded immunoliposomes decorated with epidermal growth factor (EGF) to target EGF receptors (EGFR) are currently in clinical trials (ClinicalTrials.gov Identifier: NCT03603379). Specific targeting can also be utilized for tumor imaging, for example, probes targeting somatostatin receptors overexpressed in neuroendocrine tumors and activated only within the tumor microenvironment (TME) [ 68 ].
Nanocarriers must be able to protect the cargo from degradation, achieve prolonged circulation, avoid the reticuloendothelial system uptake, and efficiently deliver to the target cells [ 69 , 70 ]. Therefore, engineering of the nanoformulation requires proper selection of carrier materials, choice of ligand, and optimal density of ligand on the nanocarrier’s surface (Fig. 3 ) [ 71 ]. Certain therapies require intracellular delivery and while others utilize cellular membrane diffusion, so specific mechanism of action further plays a critical role in optimizing nanoformulation. Under particular circumstances, targeting constituents of the TME can be sufficient to see improved drug efficacy and specificity [ 72 , 73 ]. In addition to specific targeting, nanotechnology can improve therapeutic specificity through stimuli-responsive activation. Release of drugs occurs under precise chemical, biological, or physical conditions found within tumor environment or cancerous cells to limit off-target effects [ 24 , 26 ]. Nanocarriers may be designed to release drugs under specific pH, glucose levels, specific enzymes, oxidative/reductive conditions, and ion concentration, or by external stimulation such as radiation, electric and magnetic fields, and hyperthermia [ 32 , 74 , 75 , 76 , 77 ]. These same modalities may be exploited for imaging and diagnostic purposes as well, such as utilizing magnetic particles for MRI tumor imaging or theranostic applications [ 78 , 79 ]. pH-responsive peptide-based NPs were recently engineered to morph into fibrils within the TME where they exhibited strong fluorescent signals and enhanced photodynamic therapy [ 80 ].
Schematic representation of versatile nanoformulations employed in cancer therapy and diagnostics, including specific physical formulation and surface chemistry for improved targeting. Reprinted with permission, [ 71 ] https://doi.org/10.1186/s40580-019-0193-2
Intrinsic properties of certain nanomaterials are ideal for bioimaging, multi-modal therapies, and molecular detection for diagnostics [ 81 , 82 ]. Fluorescent NPs have shown to be effective alternatives to traditional dyes, demonstrating high stability and decreased photobleaching [ 36 ]. Gd-based NPs have shown great utility as MRI and CT contrast agents and as radiosensitizers due to their paramagnetic property and high X-ray attenuation coefficient [ 83 ]. Gold NPs are ideal for creating highly selective, versatile, and sensitive biosensors, capable of optical and electrical detection, surface plasmon resonance, and fluorescence resonance energy transfer [ 84 , 85 ]. Nanomaterials can enable early detection of circulating tumor cells (CTCs) from peripheral blood, as was shown using magnetic NPs functionalized with polyethyleneimine/protein corona or in a separate study, tannic acid [ 86 , 87 ]. The vast range of nanotechnology applications can drastically improve cancer therapies and diagnostics, and this review provides an overview of current clinical applications and forthcoming technologies (Fig. 4 ).
Nanotechnology provides many advantages over conventional anti-cancer drugs, radiation therapy, diagnostics, and imaging. Utilizing targeted delivery, nanomedicines can alleviate systemic toxicities while increasing therapeutic efficacy at the target site. Certain nanomaterials have intrinsic physico-chemical properties that enhance bioimaging, localize radiation therapy, facilitate early diagnoses, circumvent drug resistance, and enable multi-modal treatments
3 Applications of nanotechnology in cancer therapeutics
3.1 conventional cancer therapies.
Chemotherapy remains the first-line treatment for most cancers, and drug discovery is constantly evolving and shifting toward cancer-specific targets [ 88 ]. Traditional chemotherapy drugs include alkylating agents and antibiotics to induce DNA damage, antimetabolites, mitotic inhibitors, and topoisomerase inhibitors to interfere with cellular replication [ 89 ]. Despite the high efficacy of traditional chemotherapies, patients suffer because of their non-specificity. Traditional chemotherapies are highly toxic to cancerous cells, but systemically affect healthy cells and induce harsh side effects for patients [ 90 , 91 ].
There are specific signaling networks known to promote and sustain cancer, and a multitude of inhibitors currently exist and are under development to target enzymes within these pathways [ 92 , 93 ]. Various inhibitors of tyrosine kinases, cyclin-dependent kinases, poly ADP-ribose polymerases, and proteasomes comprise the majority small-molecule drugs currently used in the clinic as targeted therapies [ 94 ]. Tumor growth and proliferation is fueled by components found in the TME such as immune and inflammatory cells, blood and lymphatic endothelial cells, cancer associated fibroblasts (CAFs), and bone marrow-derived mesenchymal stem cells [ 95 , 96 , 97 , 98 , 99 ]. Protein synthesis, glucose metabolism, and other key components of cell survival are often hyper-activated in the PI3K/Akt/mTOR pathways, often re-routing signals in response to initial therapies [ 100 ]. The RAS/RAF/MEK/ERK pathway initiates cell proliferation, differentiation, and development, thus multiple mutations are commonly found here across many cancer types [ 101 , 102 ]. Mutation in RAS proteins is the one of the most commonly found in human cancers, and Sotorasib is the first KRAS targeting drug to receive FDA approval [ 103 , 104 ]. Mutations in in EGFRs also contribute to oncogenesis, and there are approximately 14 EGFR-tyrosine kinase inhibitors (TKIs) on the market and/or in clinical trials [ 105 , 106 ]. Targeting these pathways and factors responsible for cancer progression has become a focal point in developing new drug therapies, but new drug development costs billions of dollars and takes over a decade from development to FDA approval [ 107 , 108 ].
Cytotoxic and targeted therapies can select for drug resistance, therefore making complete eradication nearly impossible [ 109 ]. Drug resistance may develop through alterations in drug metabolism, changes in efflux/influx, hyper-activated repair pathways, signal transduction re-routing, and mutated drug targets [ 110 , 111 ]. Methods for overcoming drug resistance include multiple therapeutics, combination chemoradiotherapy, and personalized medicine [ 112 ]. Co-administration of drugs with different molecular targets can help modulate cancer cell mutations and possibly halt the cancer adaptation process [ 113 ]. Effective combinations have been found where a drug can heighten or re-introduce sensitivity of the cancer cells to an existing therapy, and new combinatorial treatments are consistently being investigated in clinical trials. However, limitations exist for combination treatments largely due to different PK/PD properties and disjointed uptake of the complementary drugs, which reduces their efficacy and synergistic action. Co-delivery of anti-cancer therapies within a single nanocarrier can alleviate these issues and increase the therapeutic index [ 56 , 114 ]. In 2017, the U.S. Food and Drug Administration (FDA) approved VYXEOS, a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML [ 115 ]. The synergistic molar ratio of daunorubicin and cytarabine has been shown to enhance the killing of leukemia cells in vitro and in murine models. In preclinical studies, VYXEOS liposomes were preferentially taken up by leukemia cells than by normal bone marrow cells in a murine model [ 116 ]. Furthermore, the liposomes were strategically engineered to interact with receptors overexpressed in leukemic cells compared to the expression in normal bone marrow cells. This is a promising treatment option, but the need persists for more innovative technologies to combat drug resistance and therapy-related toxicities.
3.2 Current clinical testing of nanoformulated therapeutics
Nanotechnology presents a unique set of tools to overcome both intrinsic and acquired drug resistance through various mechanisms and enabling the use of novel immunotherapies such as mRNA vaccines and specific targeting [ 117 , 118 ]. Tumoral genetic diversity is accompanied by induced mutagenesis or differential sensitivity, and both can result in drug resistance and prolonged illness (Fig. 5 ) [ 119 ]. Various nanoformulations for cancer therapeutics are in clinical use including liposomes, polymer microspheres, protein conjugates, and polymer conjugates, and novel nanomaterials are being investigated for improved drug efficacy and targeting [ 118 ]. As aforementioned, targeted delivery is the pinnacle for cancer therapy since it can significantly lower toxicity associated with non-specific action. There are several new developments that incorporate targeting moieties which are currently being tested in clinical trials (Table 2 ).
Multiple types of heterogeneity require consideration when treating cancer patients including patient tumors, multi-focal disease, intra-tumor cellular heterogeneity, genomic heterogeneity, and epigenetic heterogeneity. Reprinted with permission, [ 119 ] https://doi.org/10.20517/2394-4722.2017.34
3.2.1 Formulations for enhanced PK and specific targeting
Liposomes are a particularly advantageous class of nanomaterial for drug delivery applications, because of their ease of fabrication and drug loading, capacity for surface modification, and biocompatible components [ 44 , 120 , 121 ]. Liposomes are vesicles consisting of a lipid bilayer primarily composed of amphipathic phospholipids that encompass an aqueous interior. Properties of the liposome can be tuned depending on the phospholipid polar headgroup, length and hydrophobicity of the fatty acid tails, additional components in the membrane or on the surface, and type of synthetic or natural lipid [ 122 ]. Owing to the versatility and relative ease of manufacturing, liposomes are one of the most investigated nanomedicines for the treatment of many diseases. Doxil, a liposomal formulation of the highly toxic chemotherapy DOX, was the first of its kind approved by the FDA in 1995. One year later, another liposomal formulation of daunorubicin was approved, DaunoXome®, to treat advanced HIV-associated Kaposi sarcoma [ 44 ]. Marqibo®, a sphingomyelin/cholesterol liposomal formulation of vincristine sulfate, FDA approved in 2012, demonstrated enhanced PK/PD properties over vincristine as well as enhanced concentration in solid tumors. Depocyt® (Cytarabine/Ara-C), Myocet®(DOX), Mepact® (Mifamurtide), and Onivyde® (Irinotecan) are also liposomal therapeutics clinically approved for cancer treatment, making a total of only 7 currently on the market today. It should be noted, however, that Depocyt was on microscale, and has been discontinued in its use.
Cisplatin is one of the most widely used chemotherapies due to its efficacy against multiple cancer types but has severe side effects, demonstrating the critical need for specificity and re-formulation [ 123 ]. LiPlaCis is the first liposomal formulation with a triggered release mechanism to undergo clinical development in oncology, where selective hydrolysis occurs by tumor-expressed phospholipase A2–IIA isoenzyme, highly expressed in a multitude of human solid tumors including prostatic, pancreatic, colorectal, gastric, and breast cancers [ 124 , 125 ]. LiPlaCis has an enhanced therapeutic window compared to cisplatin, with superior PK properties, greater potency, and an increased maximum tolerated dose (ClinicalTrials.gov Identifier: NCT01861496). Drug Response Prediction (DRP®) is used to significantly increase the probability of success in clinical trials. Patients undergo genetic screening of tumors, then are selected for the trial based upon those most likely to respond to treatment, providing a highly-defined patient group and subsequently lowering costs and risks [ 126 ]. DRP® has provided statistically significant prediction of drug treatment clinical outcome for cancer patients in 29 out of 37 clinical studies that were examined.
High grade gliomas are the most common brain tumor in adults, and median survival of 9–12 months for patients with newly diagnosed glioblastoma multiforme and 24–36 months for patients with anaplastic astrocytoma [ 127 , 128 , 129 ]. The currently available treatments for malignant gliomas are limited by low activity, drug resistance, brain damage from therapeutic modalities, and limited access to privileged intracranial sites [ 130 ]. A current Phase 1 clinical study is underway to investigate liposomal irinotecan and Gd administered with convection enhanced delivery (CED) (ClinicalTrials.gov Identifier: NCT02022644). Liposomal formulation enables for delivery across the blood brain barrier, and the Gd will provide capability for real-time delivery imaging. CED improves chemotherapeutic delivery to brain tumors intraparenchymally by utilizing fluid convection [ 131 ]. Through the maintenance of a pressure gradient from the delivery cannula tip to the surrounding tissues, CED is able to distribute small and large molecules, including liposomes, to clinically significant target volumes [ 131 ].
E7389-LF is a liposomal formulation of eribulin, a halichondrin-class microtubule dynamics inhibitor approved for treatment of advanced/metastatic breast cancer, and previously treated, unresected liposarcoma (ClinicalTrials.gov Identifier: NCT04078295) [ 132 ]. This nanomedicine is currently undergoing a Phase 1/2 clinical trial to evaluate safety and tolerability and to determine recommended Phase 2 dose of E7389-LF in combination with nivolumab in Phase 1b part, and to evaluate objective response rate of E7389-LF and nivolumab using RP2D in Phase 2 part in each tumor type. ThermoDox is a heat-activated lysolipid formulation of DOX designed to release the drug when heated to 40–45 °C [ 133 ]. It is currently in multiple clinical trials, including a completed Phase 3 trial, after initial trials showed a 2.1-year improvement in overall survival in liver cancer patients with single lesion (ClinicalTrials.gov Identifiers: NCT02181075, NCT04852367, NCT02112656, NCT04791228). Compared to I.V. administration of DOX, ThermoDox delivers up to 25 × more therapeutic to tumors and 5 × more than Doxil, the standard liposomal formulation of DOX. The majority of clinical trials currently investigating liposomal drugs for cancer therapy involve combination treatments with Doxil or DaunoXome, but not within a single carrier. Several clinical studies underway are utilizing liposomes for nucleic acid delivery, discussed in further detail in Sects. 3.2.2 and 3.2.3 .
Paclitaxel (PTX), a naturally derived compound used against many types of cancer, has a unique mechanism to block cell cycle progression, prevent mitosis, and subsequently inhibit the growth of cancer cells. However, neuropathy, cardiotoxicity, and hepatotoxicity are potential side effects of PTX, posing a major downside to using the highly effective drug. Particularly, peripheral neuropathy includes shooting/burning pain (especially in hands and feet), sensory loss, numbness, and tingling [ 134 ]. Several nanoformulations have been developed to decrease the adverse effects of PTX and improve aqueous solubility without the use of Cremophor® EL, a common excipient in PTX formulation in solution, also known to cause toxicity [ 135 ]. Genexol-PM® is a PEG-b-poly(D,L-lactic acid) (PEG-PLA) micellar formulation of PTX approved in South Korea in 2007 for the treatment of breast cancer and NSCLC. It has shown lower toxicity than Taxol (PTX formulated with Cremophor® EL), with its maximum tolerated dose identified as 2 to 3 times that of Taxol. Nanoxel® is a polymeric amphiphilic micelle formulation approved for clinical use in India in 2006 and is currently undergoing clinical trials for FDA approval (ClinicalTrials.gov Identifier: NCT04066335), and Apealea, approved for use in the European Union in 2018, utilizes poly‐(l‐glutamic acid) conjugated to PTX. Unfortunately, peripheral neuropathy remains a clinical challenge despite improved formulations, further necessitating continued optimization [ 136 ].
Two major advantages of polymeric micelles are a desirable sub-50 nm hydrodynamic size and their relative ease of large-scale manufacturing. However, despite the utility of polymeric micelles, there are limitations in stability and drug retention once administered into the bloodstream [ 137 ]. Partial micellar dissolution occurs after micelles drop below the critical micelle forming concentration (CMC) in the blood, and certain blood components such as albumin and apolipoproteins can also initiate micelle dissociation and premature drug loss [ 138 ]. Formulations can be optimized to enhance stability and drug retention using strategies such as covalent core and/or shell crosslinking, drug conjugation via reversible bonds, zwitterionic polymer micelles, unimolecular micelle formulation, hydrogen-bond core complexation, and macrocylclic complexation [ 139 ]. But as with all drug formulations, with further complexity comes greater manufacturing and scale-up considerations. Hence, there are limited clinical trials on novel micellar formulations. A clinical trial (ClinicalTrials.gov Identifier: NCT01644890) for poly(ethylene glycol)-block-poly(aspartic acid) (PEG-b-pAsp) loaded PTX micelles (NK105) was recently completed where incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥ Grade 3) for NK105 and PTX, respectively. NC-6300 is a micellar formulation of DOX, which is covalently conjugated to the carboxylic acid groups of PEG-b-p(b-Asp) via a a hydrazone bond, to enable drug release upon pH stimuli (pH < 5), and is undergoing a Phase 2 clinical investigation (ClinicalTrials.gov Identifier: NCT03168061). A poly(ethylene glycol)-block-poly(glutamic acid) (PEG-b-pGlu) micelle containing cisplatin (NC-6004) has undergone multiple clinical trials, and currently being evaluated for combination with Pembrolizumab for head and neck cancer patients who have failed platinum regimen (ClinicalTrials.gov Identifier: NCT03771820).
Polymer drug conjugates have been utilized in the pharmaceutical industry for decades, most notably, polyethylene glycol (PEG), for improving PK profiles by reducing immunogenicity, preventing degradation, and reducing plasma clearance [ 140 ]. There are a multitude of polymer-drug formulations, particularly as technological advances are made regarding design and synthetic procedures. Natural polymers such as chitosan, polysaccharides, polysialic acid, hyaluronic acid, and polypeptides have the advantage of greater biodegradability and biocompatibility over PEG [ 141 ]. Opaxio®, (formerly Xyotax®) utilizing a polyglutamate-PTX conjugate, was granted orphan drug designation by the FDA, and is currently in a Phase 3 clinical trial for treatment of patients with stage III/IV ovarian epithelial, peritoneal, or fallopian tube cancers (ClinicalTrials.gov Identifier: NCT00108745). A Phase 1 trial is underway to evaluate PEGylated Irinotecan (JK-1201I) in patients with malignant solid tumors (ClinicalTrials.gov Identifier: NCT04366648). PEG-BCT-100 is a novel PEGylated formulation of recombinant human arginase, which can deplete arginine levels and starve cancer cells. It has thus far shown to be safe to use and is entering Phase 2 trials (ClinicalTrials.gov Identifier: NCT03455140).
Polymeric nanoparticles (NPs) are unmatched in versatility, having a plethora of design elements with endless possibilities. Base materials can be synthesized from monomers or biomacromolecules, or a combination of both, with drugs directly conjugated or loaded. Surface charge, size, and density can be modulated to suit applications ranging from drug-loaded hydrogels to core–shell NPs for gene therapy, and fabrication technique can be adjusted according to desired material [ 26 , 43 ]. Nanoparticle composition can be controlled to best complement the cargo properties and target, incorporating elements to increase biocompatibility, biodistribution, stability, and efficacy [ 142 ]. Most importantly, synthetic flexibility of polymer-based NPs allows for built-in functionalities that can enable specific targeting and release [ 143 ]. However, with greater intricacy comes greater challenges for manufacturing and uniformity, which is a significant consideration for translation to clinical use [ 144 ]. A novel nanoparticle-drug conjugate (EP0057, formerly CLX101/IT-101) composed of a cyclodextrin-based polymer backbone linked to camptothecin (CPT), a topoisomerase 1 (Topo 1) inhibitor, was investigated in a Phase 1b/2 trial in patients with epithelial ovarian cancer (ClinicalTrials.gov Identifier: NCT02389985) and currently a Phase 1/2 trial for lung cancer treatment combined with olaparib (ClinicalTrials.gov Identifier: NCT02769962). CPT stabilizes the Topo 1-DNA cleavage complex during DNA replication and prevents Topo 1 mediated DNA re-ligation, ultimately leading to apoptosis [ 145 ]. In preclinical studies, EP0057 induced down-regulation of HIF-1α, a transcription factor associated with angiogenesis, metastasis, and vascular endothelial growth factor (VEGF) inhibitor resistance, and was also shown to accumulate preferentially in human tumor tissue and not in adjacent tissue [ 145 , 146 ]. Upon evaluation of PK properties, the nanoparticle formulation exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with PTX [ 147 ]. Somatostatin receptors (SSRs) are overexpressed in colorectal cancer cells, and currently a Phase 1 clinical trial is underway to investigate ethylcellulose polymeric NPs loaded with Cetuximab and decorated with octreotide, a SSR agonist, to induce specific targeting to colorectal cancer cells [ 148 ]. The novel formulation will release Cetuximab at pH 6.8 but is stable at pH 1.5, protecting the stomach and decreasing overall toxicity (ClinicalTrials.gov Identifier: NCT03774680).
Proteins have been widely used for drug delivery systems and diagnostic purposes. Intrinsic properties of proteins such as biocompatibility and biodegradability are highly desirable for nanoformulation, and specific protein interactions can be utilized for selective targeting or uptake. For example, the selective binding of albumin to membrane-associated gp60 (albondin) on the surface of endothelial cells, initiates internalization and active transportation [ 149 ]. Caveolae carry albumin and other plasma constituents to the extravascular space of tumors, where further interaction with osteonectin results in accumulation of albumin-bound drugs in the tumor interstitial space, therefore making albumin an excellent vehicle for targeted delivery of anticancer drugs [ 150 ]. Abraxane® is an FDA-approved albumin-nanoparticle formulation of PTX which utilizes this mechanism as first line treatment for metastatic breast cancer, advanced non-small cell lung cancer (NSCLC) and late-stage (metastatic) pancreatic cancer [ 151 ]. Celgene corporation, the manufacturer of Abraxane®, has developed several albumin-bound therapeutics, with albumin-bound rapamycin (ABI-009) under current investigation in combination with Bevacizumab and mFOLFOX6 in patients with advanced or metastatic colorectal cancer (ClinicalTrials.gov Identifier: NCT03439462). INNO-206, an albumin-DOX conjugate has completed multiple clinical trials, and is now being evaluated as part of combination therapy against locally advanced or metastatic pancreatic cancer (ClinicalTrials.gov Identifier: NCT04390399).
Antibody–drug conjugates (ADCs) have been gaining momentum for cancer therapies, with several FDA approved within the last few years [ 152 ]. They target specific antigens that are overexpressed on tumor cells but minimally expressed in healthy cells and deliver a cytotoxic drug upon cellular uptake and subsequent cleavage of a linker molecule [ 153 ]. ADCs have several advantages including minimal immunogenicity, prolonged half-life of cytotoxic drugs, and efficient receptor-mediated endocytosis. The linker is a critical point of design for ADCs since it must be stable enough to keep the ADC intact while in circulation and labile enough to release the payload at the target site [ 66 , 154 ]. Cleavable linkers can be beneficial as they can be tuned to specific environmental stimuli to release the drug from antibody, while non-cleavable linkers are more stable while circulating and depend on antibody degradation. Site-specific conjugation further contributes to PK/PD parameters and stability [ 155 ]. There are over 100 ADCs undergoing active clinical trials, and several that were FDA approved within the last two years, revealing next-generation ADCs with optimized linkers.
Diffuse large B-cell lymphoma (DLBCL) is the most frequent form of the aggressive non-Hodgkin lymphoma, accounting for approximately 30–58% of cases, and long-term survival is rare, thus new therapies are in high demand [ 156 ]. Earlier this year, Zynlonta (loncastuximab tesirine) was approved for relapsed or refractory DLBCL, including patients who failed to respond to CAR-T therapy, which accounts for approximately 40–50% of patients [ 157 ]. In 2020, Trodelvy (sacituzumab govitecan) was approved by the FDA for triple negative breast cancer (TNBC) [ 158 ]. Trodelvy targets Trop-2, which is over-expressed on TNBC, using a mAb and a proprietary hydrolysable linker to deliver the cytotoxic payload SN-38 to tumors. This linker, importantly, also creates an effective bystander effect in the tumor micro-environment and can deliver large quantities of SN-38 directly to tumors [ 159 ]. CAFs exist in the TME and are known to promote angiogenesis, tumorigenicity, and metastatic dissemination of cancer cells [ 99 ]. CAFs express fibroblast activation protein (FAP), a type II transmembrane protein overexpressed in over 90% of colon, breast, and lung cancer CAFs [ 160 ]. Antibody-conjugated drug Enfortumab Vedotin targeting FAP-positive CAFs was highly effective in clinical trials for advanced bladder cancers and was awarded FDA approval in 2019. Three other ADCs were approved in 2019, Polivy(polatuzumab vedotin-piiq) for DLBCL, Padcev (enfortumab vedotin) to treat locally advanced or metastatic urothelial cancer, and Enhertu (trastuzumab deruxtecan) to treat HER-2 + breast cancer and gastric or gastroesophageal junction (GEJ) adenocarcinoma [ 161 ].
The oncofetal tumor-associated antigen 5T4 has been linked with cancer stem cell properties in multiple cancer types and is associated with the spread of tumors [ 162 ]. Furthermore, the 5T4 protein is expressed by many different cancers but rarely in normal adult tissues, making it an attractive candidate to improve specificity for cancer therapeutics [ 163 ]. There are currently clinical trials underway with therapeutics targeting the 5T4 antigen (ClinicalTrials.gov Identifier: NCT04202705). SYD1875 is a next generation ADC, comprised of a humanized IgG1 monoclonal antibody targeting the 5T4 oncofetal antigen, and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA), employing site specific conjugation that improves efficacy, exposure, and manufacturing process [ 164 ]. This proprietary ADC utilizes an inactivated synthetic duocarmycin-based cytotoxin that rapidly decomposes if released prematurely, further demonstrating its specificity and stability [ 155 ]. A similar next-generation ADC (SYD985) targeting HER2 received fast track designation from the FDA and is currently in a pivotal Phase 3 clinical trial for locally advanced or metastatic breast cancer (ClinicalTrials.gov Identifier: NCT03262935). It is also in two Phase 2 clinical trials for early-stage breast cancer (NCT01042379), advanced or metastatic endometrial cancer (NCT04205630), and Phase 1 trial in combination with the PARP inhibitor niraparib in patients with solid tumors (NCT04235101).
3.2.2 Nanocarriers for gene therapy
Gene therapy is a major player in the fight against cancer, delivering nucleic acids to express pro-apoptotic proteins, substitute mutated genes, down-regulate or silence oncogenic pathways, produce anti-cancer cytokines, and/or activate the immune system against cancer [ 165 ]. One of the major challenges of gene delivery is successful delivery of nucleic acids to the target site while avoiding degradation. In 2019, Patisiran (ONPATTRO®) was the first siRNA-delivering liposome to be FDA approved, delivering siRNA against the gene responsible for transthyretin protein expression, which can cause hereditary transthyretin amyloidosis. Efficient and safe delivery methods for gene therapy continue to present challenges for clinical translation. Recombinant viral vectors are superior to nonviral vectors with regards to gene delivery, but also come with limitations such as immune response, large-scale manufacturing, gene size limitation, narrow cell tropisms, and lack of surface modifiability without compromising vector integrity [ 166 ]. Non-viral vectors are synthetically dynamic, exhibit low immunogenicity, and have simpler large-scale production, but can have reduced transfection capability compared to viral vectors. Recently, two vaccines against the SARS-CoV-2 virus utilizing adenovirus vectors have been linked to several cases of thrombotic thrombocytopenia but are still under scientific investigation, while interestingly, the Moderna and Pfizer/BioNTech vaccines employing lipid-based carriers demonstrate higher efficacy and no link to thrombotic complications [ 167 , 168 ]. Continued development of inert and efficient nanocarriers for nucleic acid-based cancer therapies remains a priority, and there are several currently being tested in clinical trials.
Polo-like kinase 1 (PLK1) is overexpressed in a multitude of human cancers, and inhibition of PLK1 can induce mitotic arrest and apoptosis, indicating utility for siRNA to silence PLK1. Stable nucleic acid lipid particles (SNALPs) are composed of a high transition temperature phospholipid, a PEGylated lipid, and an ionizable cationic phospholipid [ 169 ]. The result is high encapsulation efficiency, with neutralization of the net surface charge upon nucleic acid encapsulation, creating more stable vesicles than conventional cationic liposomes. TKM-080301 is a SNALP formulation containing siRNA against the PLK1 gene currently being studied for use in patients with primary or secondary liver cancer (ClinicalTrials.gov Identifier: NCT01437007). In previous clinical studies, TKM-080301 was generally well-tolerated by solid tumor patients and demonstrated a preliminary antitumor efficacy (ClinicalTrials.gov Identifier: NCT02191878).
Eph receptor A2 (EphA2) is part of the receptor tyrosine kinase family that modulates cell differentiation, survival, and proliferation, and it is overexpressed in multiple cancer types [ 170 ]. A Phase 1 trial is currently evaluating 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC)-liposomes delivering EphA2 siRNA in treating patients with advanced and/or recurrent solid tumors (ClinicalTrials.gov Identifier: NCT01591356). The transforming growth factor-β (TGF-β) is a family of structurally related proteins that control numerous cellular functions including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and migration [ 171 ]. It has been implicated in tumor promoting effects, particularly in late stages of several cancer types. STP705 is a proprietary polypeptide nanoparticle delivering siRNA against both TGF-β1 and cyclooxygenase-2 (COX-2) [ 172 ]. COX-2 is also overexpressed in many types of cancers, promoting carcinogenesis, and inducing resistance to both chemo- and radiotherapies. STP705 is currently being investigated as gene therapy for cutaneous squamous cell carcinoma, hepatocellular carcinoma, and basal cell carcinoma (ClinicalTrials.gov Identifier: NCT04844983, NCT04676633, NCT04669808).
For treatment of NSCLC, GPX-001 (quaratusugene ozeplasmid) is a lipid nanoparticle delivering the gene for TUSC2, a protein which elicits anti-tumor effects through regulating G1 cell cycle progression, apoptosis, calcium homeostasis, gene expression, and tyrosine and Ser/Thy kinase activity [ 173 ]. Gene carriers delivering TUSC2 have been shown to interrupt cell signaling pathways that cause replication and proliferation of cancer cells, re-establish pathways for apoptosis, block drug resistance mechanisms, and modulate the immune response against cancer cells [ 174 , 175 ]. In January 2020, the FDA granted Fast Track Designation for GPX-001 for NSCLC in combination therapy with osimertinib for patients with EFGR mutations whose tumors progressed after treatment with osimertinib alone (ClinicalTrials.gov Identifier: NCT04486833).
Rexin-G was the first targeted gene therapy vector to gain fast track designation and orphan drug priorities for multiple cancer indications in the US. Rexin-G is a replication-incompetent retroviral vector utilizing a cryptic collagen-binding motif on its envelope for targeting abnormal Signature (SIG) proteins in tumors (ClinicalTrials.gov Identifier: NCT00504998) [ 176 ]. Abnormal collagenous SIG proteins are a consequence of tumor invasion, angiogenesis, and stroma formation, thus targeting will induce vector accumulation within the TME [ 177 ]. CCNG1 gene expression is highly involved in cell cycle regulation, and is tightly associated with oncoproteins such as Mdm2 and cMyc, and the p53 tumor suppressor protein [ 178 ]. CCNG1 is overexpressed in over 50% of various malignancies, including pancreas, breast, prostate, ovarian, and colon cancer [ 179 ]. Rexin-G encodes a dominant-negative mutant construct (dnG1) of human cyclin G1 (CCNG1) to produce a cytocidal dnG1 protein that effectively blocks a pivotal checkpoint of the cell division cycle, resulting in apoptosis. Rexin-G was shown be exceptionally safe and exhibit dose-dependent antitumor activity in patients with gemcitabine-refractory metastatic pancreatic adenocarcinoma [ 176 ]. NG-641 is an oncolytic adenoviral vector encoding four genes: a bi-specific FAP-targeted T-cell activator to activate T-cells to kill fibroblasts, plus three additional genes to further recruit and activate those T-cells (CXCL9, CXCL10, and interferon alpha) [ 180 ]. A phase 1, first in-human study is underway to evaluate safety and tolerability combination with nivolumab in patients with metastatic or advanced epithelial tumors and to determine the recommended dose (ClinicalTrials.gov Identifier: NCT05043714). Another first in-human study is beginning for rQNestin34.5v.2, an oncolytic viral vector made from the herpes simplex virus type 1 (HSV1). In some cases, HSV1 can cause severe infection of the brain and liver and/or death, however the rQNestin virus has been modified to replicate only in glioma cells but not in normal, healthy cells [ 181 ]. The UL39 gene encoding the viral ribonucleotide reductase large subunit infected cell protein 6 (ICP6) and both endogenous copies of the gamma34.5 gene that encodes for the RL1 neurovirulence protein infected cell protein 34.5 (ICP34.5) (needed for robust viral growth in an infected cell) are deleted, and one copy of the gamma34.5 gene is reinserted under control of a nestin promoter, which is selectively activated in gliomas [ 182 ]. By inactivating UL39, viral ribonucleotide reductase activity is disrupted, resulting in the inhibition of nucleotide metabolism and viral DNA synthesis in non-dividing, healthy cells but not in dividing cells [ 183 ]. This clinical study will determine the safety and dosing of rQNestin (ClinicalTrials.gov Identifier: NCT03152318). AAV2hAQP1, utilizes an adeno-associated viral (AAV) vector to encode human aquaporin-1 to one parotid salivary gland. Though not directly used to treat cancer, it is currently being tested to alleviate severe dry-mouth associated with radiation therapy [ 184 ]. After testing with an adenovirus vector, which demonstrated efficacy but some immunogenicity, it is expected that the AAV vector can safely transfer the human aquaporin-1 (hAQP1) cDNA gene to parotid glands of adult patients with IR-induced salivary hypofunction to elevate salivary output (ClinicalTrials.gov Identifier: NCT02446249).
Exosomes are 30–100 nm in diameter and contain DNA, miRNA, mRNA, lncRNA, proteins, and other cellular components within their lipid bilayer membrane [ 185 ]. Exosomes can enter recipient cells via membrane fusion, and induce transcriptional and translational changes [ 186 , 187 ]. They are highly biocompatible and stable, exhibit tumor homing, and can be modified, thus hold great potential for cancer therapy [ 188 ]. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D (iExosomes), a common mutation in pancreatic cancer (ClinicalTrials.gov Identifier: NCT03608631). Compared to liposomes, iExosomes target oncogenic Kras with an enhanced efficacy that is dependent on CD47, and is facilitated by micropinocytosis [ 189 ]. iExosomes treatment suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased their overall survival. This phase I trial studies the best dose and side effects of mesenchymal stromal cells-derived exosomes with KrasG12D siRNA (iExosomes) in treating participants with pancreatic cancer with KrasG12D mutation that has spread to other places in the body.
3.2.3 Immunotherapeutic applications of nanotechnology
Breakthrough achievements have been made in the realm of immunotherapies for cancer including CAR-T cell therapy, immune checkpoint inhibitors, and cancer vaccines. The guiding principle behind immunotherapy is recognition of tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) by the adaptive immune system [ 190 ]. TAAs can be found across all cell types, but are typically overexpressed in tumor cells while TSAs are present only in tumor cells [ 191 ]. In order to generate tumor-directed immune responses, the tumor-associated protein is taken up by antigen-presenting cells (APCs) and processed in small protein fragments [ 192 ]. After binding to patient-specific human leukocyte antigen (HLA) molecules, the HLA-peptide complex is recognized by the T cell receptors (TCR) and upon binding, the T cell induces tumor cell death [ 193 ].
Some TAAs can come from reactivation of embryonic genes which are normally found in differentiated cells, and New York esophageal squamous cell carcinoma 1 ( NY-ESO-1) is a cancer-testis antigen normally expressed in testicular germ cells and trophoblasts of the placenta [ 194 ]. NY-ESO-1 is also expressed in a wide range of cancers with a high incidence (around 20–40% of several advanced cancers, such as melanoma [46%], round cell liposarcoma [89–100%], neuroblastoma [82%], and ovarian [43%] cancer). The NY-ESO-1 antigen has been used in dozens of clinical studies, inducing an improved immune response and positive outcomes in certain trials thereby confirming its utility for cancer therapy. Invariant natural killer T (iNKT) cells are a subset of immune cells that recognize glycolipid antigens presented by the non-polymorphic MHC class I-like molecule, CD1d. [ 195 , 196 ]. Upon activation they efficiently produce cytokines that stimulate other immune cells and boost cytotoxic T cell responses, and iNKT agonists have high adjuvant effects when administered simultaneously, even at low doses [ 197 , 198 ]. Poly(lacto-co-glycolic acid) (PLGA) is a biodegradable polymer with minimal (systemic) toxicity, approved by the FDA and the European Medicines Agency (EMA) for use in various drug-carrying platforms. PLGA-based NPs containing the tumor antigen NY-ESO-1 and the iNKT cell activator IMM60 are currently in a Phase 1 clinical trial to test anti-tumor responses in cancer patients (ClinicalTrials.gov Identifier: NCT04751786). Encapsulating antigens and adjuvants within the same polymeric nanoparticle can enhance T cell responses [ 199 ]. In earlier studies, the NY-ESO-1 whole protein was encapsulated in adjuvant ISCOMATRIX and shown to induce specific T cell responses in a majority of patients [ 200 ]. Previous clinical trials have already shown the safety and tolerability of the NY-ESO-1 protein and peptides in patients with advanced cancer.
To facilitate NY-ESO-1 antigen encapsulation, long (85–111(peptide #2) and 117–143(peptide #3)) and short (157–165(peptide #4)) peptides are incorporated into NPs. Similar peptides (79–116 and 118–143) were previously loaded onto DCs together with α-GalCer and delivered to cancer patients in a recent clinical trial. The results of that trial demonstrated iNKT cell expansion, CD4 + T cell responses against the 118–143 peptide in 7/8 patients, and CD8 + T cell responses against the 79–116 peptide in 3/8 patients [ 201 ]. Here, an additional short peptide (157–165) is included, which is presented by the highly prevalent HLA-A2.1 molecule. Hence, higher CD8 + T cell responses against this epitope and superior activation of human iNKT cells by IMM60 are expected due to co-encapsulation [ 199 , 202 ].
mRNA cancer vaccines are an emerging asset in the fight against cancer, designed to work against TSAs [ 203 ]. These antigens can be identified quickly through next-generation sequencing and bioinformatics tools, and engineered into mRNA vaccines, which have recently taken limelight with the success of mRNA SARS-CoV-2 vaccines. mRNA vaccines have considerable advantages over DNA vaccines including higher levels of protein expression, fast and temporary protein expression, simpler manufacturing process, and no genomic integration [ 203 , 204 ]. However, nucleic-acid based therapies are subject to swift degradation and insufficient cellular uptake, therefore nanoformulation is essential for proper delivery [ 165 ]. Both Moderna and BioNTech have developed promising nanoformulated, mRNA-based cancer vaccines, and are currently being tested in clinical trials [ 203 ]. Moderna’s personalized cancer vaccines are derived from individual tumor sequencing to elicit a more effective anti-tumor response against TSAs [ 205 , 206 ]. A single vaccine may deliver mRNA encoding up to 34 unique TSAs, pushing therapeutics into the next era of personalized medicine [ 207 ]. In the current trial, mRNA-4157 coated with lipid NPs is given alone to participants with resected solid tumors and in combination with Pembrolizumab in participants with unresectable solid tumors (ClinicalTrials.gov Identifier: NCT03313778). Interim data showed that mRNA-4157 given in combination with Pembrolizumab is well tolerated at all dose levels and produced responses as measured by tumor shrinkage by in human papillomavirus (HPV)(-) head and neck squamous cell carcinoma (HNSCC) patients [ 208 ].
The Lipo-MERIT trial is the first in-human testing an mRNA vaccine (BNT111/Melanoma FixVac), a liposomal formulation of mRNA encoded against four distinct malignant melanoma-associated antigens: NY-ESO-1, melanoma-associated antigen A3, tyrosinase, and transmembrane phosphatase with tensin homology (ClinicalTrials.gov Identifier: NCT02410733). In preclinical murine studies, the RNA-lipoplexes were engineered to target dendritic cells (DCs) by altering the lipid:RNA ratio, and they effectively transfected splenic antigen-presenting cells, activated NK, B, CD4 + , CD8 + T cells, and produced interferon alpha (IFN-α).) [ 209 ]. An exploratory interim analysis showed that vaccine, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. [ 210 ]. Clinical responses were accompanied by the induction of strong CD4 + and CD8 + T cell immunity against the vaccine antigens. Further FixVac cancer vaccine candidates are currently investigated in Phase 1 clinical trials for prostate cancer (BNT112) (Clinicaltrials.gov Identifier NCT04382898), HPV16-positive cancers (BNT113) (Clinicaltrials.gov Identifier NCT03418480), triple negative breast cancer (BNT114) (Clinicaltrials.gov Identifier NCT02316457) and ovarian cancer (BNT115) (Clinicaltrials.gov Identifier NCT04163094). The first-in-human, open label Phase 1 study is underway to investigate a liposomal mRNA vaccine (W_ova1 vaccine) delivering three ovarian cancer TSA RNAs in ovarian cancer patients, where patients will be vaccinated intravenously prior, and during (neo)-adjuvant chemotherapy (ClinicalTrials.gov Identifier: NCT04163094). Overall, mRNA vaccines formulated in nanocarriers have shown initial clinical promise by targeted delivery to APCs. These nanovaccines are standalone immunotherapeutics that activate the immune system against specific antigens and have also been combined with checkpoint antibodies in several recent trials, which are expected to achieve better therapeutic outcomes [ 211 ].
3.3 Prospective nanotechnologies to advance cancer therapy
As emerging nanotechnologies seek to improve PK/PD, efficacy, and specificity, many preclinical studies are underway to achieve triggered drug release and multi-modal therapies that will be highly selective toward cancerous cells. Targeted drug release can further decrease minimum required dose and ultimately decrease overall toxicity, improving efficacy and patient quality of life (Fig. 6 ) [ 30 ]. As technology advances to utilize specific delivery, therapeutics can be formulated to achieve optimal efficacy and minimal toxicity.
Tumor heterogeneity and drug resistance are two major obstacles that conventional chemotherapy face. Nanotechnology can overcome these obstacles through multi-modal treatments and increase therapeutic efficacy while decreasing dosage by utilizing targeted delivery, stimuli-triggered release, and formulations to improve PK/PD profiles. Adapted with permission, [ 30 ] https://doi.org/10.1016/j.addr.2015.10.019
Certain targeted therapies can exhibit tumor specificity but have clinical limitations due to PK/PD properties or biodistribution. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal anti-cancer agent because of its potency and specificity toward cancerous cells while leaving healthy cells unaffected. [ 212 ]. However, it struggles to move past preclinical because of a short half-life and rapid renal clearance of the off-targeted TRAIL [ 213 ]. A new development of a TRAIL-active trimer ferritin nanocage (TRAIL-ATNC) has 16 times longer serum half-life while maintaining anti-tumor efficacy in vivo in xenograft breast cancer and orthotopic pancreatic models [ 64 ]. Nanoformulation has the potential to improve PK/PD parameters for any therapeutic, opening the door to drug repurposing [ 214 ]. Recently, lipid tail modifications of cationic liposomes were shown to increase the loading capacity of highly hydrophobic PTX helpful for the development of liposomal delivery of PTX to reduce the side effects and cost. It was found that lipid tails containing one oleoyl (DOPC/DOTAP) had lower loading capacity compared to the newly synthesized DLinTAP containing two linoleoyl tails, demonstrating that even minor modifications to nanoformulation can significantly improve drug delivery systems. [ 122 ].
Stimuli-responsive carriers are designed to release payload under specific conditions such as changes in pH, changes in temperature, overexpression of specific enzymes found within TME, increased levels of intracellular components such as glutathione, and external stimuli such as radiation, ultrasound, magnetic field, etc. [ 56 ]. In this respect, specific delivery can be achieved with drug release within the TME or other desired targeted areas. TP53 is the one of the most frequently mutated or deleted genes in breast cancer, with the mutation observed in up to 44% of TNBC compared with 15% in ER-positive breast cancers [ 215 ]. Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies [ 216 ]. pH-activated NPs were used to enhance the bioavailability and improve endo/lysomal escape of POLR2A siRNA for treatment of TNBC, where POLR2A in the TP53-neighbouring region was identified as a collateral vulnerability target in TNBC tumors. [ 217 ].
Cancer immunotherapy currently relies on two major strategies: modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies. Integrating the two strategies into one system may be the future of cancer immunotherapy, and it was recently demonstrated in a versatile antibody immobilization nanoplatform constructed by attaching anti-IgG (Fc specific) antibody (αFc) on the surface of a nanoparticle (αFc-NP), allowing two types of monoclonal antibodies to be immobilized (Fig. 7 ) [ 218 ]. Immunomodulating nano-adaptors (imNAs) outperformed a combination of mABs in T cell and natural killer cell, and macrophage driven immune response in multiple murine tumor models.
A Conjugation of an anti-IgG (Fc specific) antibody (αFc) to nanoparticle (αFc-NP). B Two types of immunomodulating monoclonal antibodies (mAbs) targeting effector cells and tumor cells immobilized onto αFc-NP to create immunomodulating nanoadaptors (imNA). C imNAs were validated in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models. Reprinted with permission, [ 218 ] https://doi.org/10.1038/s41467-021-21497-6
Novel nanomaterials can further enhance cancer immune therapies, for example outer membrane vesicles (OMVs) are secreted by Gram-negative bacteria, sized 30–250 nm, which serve as a mediator of bacteria communication and homeostasis [ 219 ]. They possess intrinsic immunostimulatory properties and have desirable properties for vaccine delivery such as small size and ease of scale-up production [ 220 ]. It was recently shown that tumor antigens can be displayed on OMV surfaces as ClyA fusion proteins that can induce T-cell mediated, specific anti-tumor immunity. [ 221 ]. Furthermore, using protein “Plug-and Display” technology, a protein tag can spontaneously bind to the protein catcher through isopeptide bond formation. Various tumor antigens linked to protein tags can be rapidly and simultaneously displayed on the OMV surface, and after accumulation in draining lymph nodes, can be processed and presented by DCs [ 220 ].
Nanomaterials have shown to be extremely useful for co-delivery of multiple chemotherapeutic agents. Drugs have various biochemical properties that can be drastically different from its synergistic complement, therefore co-delivery within a single carrier can normalize distribution and delivery [ 222 ]. Anti-PD-1/PD-L1 antibodies are currently used in the clinic to interrupt the immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer [ 223 ]. A liposomal formulation of histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1) and DOX was recently reported to promotes T cell infiltration/activity and significantly reduce tumor immunosuppressive factors. [ 224 ]. In vivo studies showed reduced growth of various murine tumors (subcutaneous, orthotopic, and lung metastasis), and offers a long-term immunological memory function against tumor rechallenging. The study showed that IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and synergistically enhances DOX-induced immune-stimulatory immunogenic cell death. Nanoformulation can tune release kinetics for dual-drug loading, optimizing drug release depending upon desired outcome [ 57 ]. Drug release can occur through various modes of activation; therefore, the release rate can be highly specific to the stimuli-responsive enhancements [ 71 ]. Mesoporous silica NPs (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) were recently engineered for co-delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and PTX (PL-PMSN-PTX/ATO).) [ 225 ]. Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. The drug-loaded NPs displayed a dual-pH-responsive (pHe 6.5, pHendo 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH 6.5, whereas ATO was mainly released at pH 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered NPs displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the NPs into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.
CRISPR-Cas9 gene editing has the potential to permanently disrupt tumor survival genes, which could supersede current limitations and pitfalls of traditional therapies [ 226 ]. Several companies are currently developing CRISPR–Cas9 therapeutics, but development of safe and efficient delivery modes remains a need for CRISPR-based therapies to be utilized in clinical applications. A novel amino-ionizable lipid nanoparticle (LNP) was recently formulated for the delivery of Cas9 mRNA and sgRNAs [ 227 ]. A single intracerebral injection of CRISPR-LNPs against PLK1 (sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~ 70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for EGFR-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~ 80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%. In another recent study, controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and codelivery with antitumor photosensitizer chlorin e6 (Ce6) was achieved using near-infrared (NIR)– and reducing agent–responsive NPs in a mouse tumor model [ 228 ]. Nitrilotriacetic acid–decorated micelles bound His-tagged Cas9 RNP, and lysosomal escape of NPs was triggered by NIR-induced reactive oxygen species (ROS) generation by Ce6 in tumor cells. Reduction of disulfide bond allowed cytoplasmic release of Cas9/single-guide RNA (sgRNA) targeting the antioxidant regulator Nrf2 , enhancing tumor cell sensitivity to ROS, and demonstrating synergistic therapy in vivo. A plethora of exciting nanotechnologies exist that substantially improve cancer therapies, but there remain some obstacles for clinical translation such as scalability, homogeneity, and regulatory guidelines.
4 Cancer diagnostics on the nanoscale
As the saying goes, “an ounce of prevention is worth a pound of cure”; with regards to cancer treatments, it may be worth one metric ton of cure. Development of cancer pharmaceuticals is a costly endeavor, to say the least. The cost for developing a successful drug can enter the billion-dollar realm, and the majority of drug candidates do not pass clinical trials [ 229 ]. Each year, the total oncology pipeline consists of hundreds of molecules in late-stage development, but only 50 new small molecule anti-cancer drugs were approved by the FDA from 2015–2020 [ 230 ]. As aforementioned, the prevalence of drug resistance necessitates development of new therapeutics, driving up costs. Conversely, an highly accurate diagnostic test can be indefinitely rewarding and impactful by effectively detecting cancer at early stages, lowering patient costs, and extending survival [ 231 ]. Early detection of cancer has major implications for likelihood of treatment success and overall survival statistics since 90% of cancer-related deaths are caused by metastasis. [ 232 ]. Even average patient cost is significantly increased for treatment of late-stage cancer diagnosis vs. early stage. [ 233 ]. The benefits of early detection and routine screening are innumerable, particularly since certain cancers exhibit symptoms only in late stages, and screening methods can be further utilized to evaluate and optimize treatment specifically to each patient [ 234 , 235 ]. Although technology has advanced in several areas, the need remains for efficient routine screening methods that can accurately detect any type of cancer at early stages without overdiagnosis [ 236 ]. Nanomaterials may meet this need as their unique optical, magnetic, mechanical, chemical, and physical properties can enhance sensitivity and precision for cancer biomarker detection.
4.1 Classic diagnostic techniques
Aside from a few selected cancers which are routinely screened, certain cancer diagnoses occur only after the onset of symptoms, when cancer is typically in later stages [ 237 , 238 ]. Traditional diagnostic methods rely mostly on classic imaging methods with ultrasound, MRI, CT scans, and X-ray, the Papanicolau test to detect cervical cancer, prostate-specific antigen level detection in blood samples, and occult blood detection for colon cancer [ 239 , 240 , 241 , 242 ]. However, currently available cancer screenings are typically only available to a subset of patients depending on risk level and/or age, specific for the aforementioned cancers as opposed to comprehensive screening of multiple cancer types [ 243 , 244 , 245 ]. A solid-tumor cancer will be detected after there has been a significant physical change to the tissue, leaving a large window of time for the undiagnosed cancer to spread and for survival odds to decrease. A tissue biopsy, which is painful and invasive, is needed to confirm and assess for proper treatment selection. Although some metastatic cancers can be obvious to detect, it is nearly impossible to determine via conventional imaging depending on where metastasis is beginning to occur [ 246 ]. Surgical resection is typically the next step, but cannot guarantee complete removal of all cancerous cells, especially when attempting to spare as much healthy tissue as possible, and success is highly dependent on tumor margin [ 247 ].
4.2 Nanotechnology-improved diagnostics, imaging, and treatment monitoring
With classic imaging techniques incapable of early diagnosis, nanomaterials can considerably improve tumor detection through tumor targeting and specific intrinsic physico-chemical properties that can enhance signal [ 81 ]. Certain nanomaterials can further enable new imaging platforms and techniques that have higher sensitivity and without possible harmful effects [ 85 , 248 ]. NPs are currently utilized in multiple medical tests and screenings, but with very few clinical applications specific for cancer screening [ 249 ]. Nano-sensors are extremely sensitive, specific, and capable of multiple target capture, thus are ideal for blood biomarker screening [ 250 , 251 ]. Furthermore, the accessibility of genetic sequencing enables efficient, detailed diagnosis/prognosis to optimize the treatment course, and several nanoformulations are currently being studied for clinical use (Table 3 ).
During cancer dissemination, tumor cell motility and invasiveness increase, enabling tumor cells to enter the bloodstream as CTCs [ 252 ]. Eventually, the most aggressive CTCs invade other tissues and form metastatic tumors, resulting in worsened prognosis. Early detection of CTCs can have a tremendous impact on early and accurate diagnosis of cancer, and detailed analyses can identify specific biomarkers to deduce patient prognosis and response to treatment [ 253 , 254 ]. However, several challenges need addressing for CTC detection to be a reliable clinical diagnostic/prognostic tool for cancer. During early stages of cancer, proportion of CTCs found in circulation is miniscule, and heterogeneity makes them difficult to isolate and analyze [ 255 , 256 ]. Nanotechnology has several advantages for CTC detection in an accurate, consistent, and robust manner. Various nanostructures have been used for CTC detection including polymeric, magnetic, carbon-based, metal NPs, and quantum dots [ 87 , 257 , 258 , 259 , 260 , 261 ].
The epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that is overexpressed on the majority of primary and metastatic tumors, and is involved in gene regulation, cell proliferation, and cancer cell differentiation and renewal [ 262 ]. As aforementioned, CellSearch® system uses EpCAM- targeting magnetic NPs and cell staining to identify CTCs, and there are several currently being tested in clinical trials (ClinicalTrials.gov Identifier: NCT04290923). There are currently two FDA-approved companion diagnostics (Guardant360 CDx and FoundationOne Liquid CDx) that utilize cell-free DNA screening for multiple cancers without nanotechnology enhancement, but there remains a need for accurate early-stage cancer screening. Despite being considered the “gold standard” clinical CTC platform, previous studies have shown that in some diseases such as prostate cancer, CTCs are undetectable in ~ 30% of patients despite the presence of widespread metastatic disease, and particularly CTCs with a purely mesenchymal phenotype [ 263 , 264 ]. Metastasis has been linked to epithelial to mesenchymal transition (EMT), during which cells undergo morphological changes that induce greater migratory and invasive capabilities and resistance to apoptosis [ 265 , 266 ]. Microfluidics is another area of technology applicable to CTC detection due to portability, high-throughput capability, and precise control within the microchannel. Certain microfluidics platforms (Parsortix® and Vycap systems) can recover CTCs based upon size and deformability instead of EMT status, and transcriptomic analysis of CTCs can be performed at the scale of a cell after isolation [ 267 , 268 ]. Transcriptome analysis then provides information on the state of the cell as to its position in the EMT thanks to a molecular signature by phenotype [ 269 ]. This highly sensitive and innovative technique will allow the study of the gene expression profile of CTCs, and several devices are currently being tested in clinical trials (ClinicalTrials.gov Identifier: NCT04696744, NCT04239105, NCT03427450).
Screening for prostate cancer relies on the serum prostate-specific antigen test, leading to a high rate of false positives (80%), subsequently unnecessary biopsies and overtreatment [ 270 ]. Considering the frequency of the test, there is a critical unmet need of precision screening for prostate cancer. A urinary multi-marker microfluidic biosensor utilizing machine learning is currently under investigation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT04825002). In preclinical studies, the correlation of clinical state with the signals from urinary multi-markers was analyzed by two common machine learning algorithms [ 271 ]. As the number of biomarkers was increased, both algorithms provided a monotonic increase in screening performance. Under the best combination of biomarkers, the machine learning algorithms screened prostate cancer patients with more than 99% accuracy using 76 urine specimens. A novel and emerging approach to diagnostics involves investigating exosomes secreted by various cell types and their association with cancer progression [ 272 , 273 ]. Since tumor cells secrete exosomes more abundantly and have been implicated in tumorigenesis, metastasis, and TME formation, they are a target for liquid biopsy development [ 274 ]. Obesity is prevalent among many populations, and has strong correlation with aggressive prostate cancer and metastasis, though the exact mechanism is still being explored [ 275 ]. A current clinical study is underway to analyze exosomes excreted from fat tissue in lean and obese patients who are currently undergoing radical prostatectomy (ClinicalTrials.gov Identifier: NCT04167722, NCT03694483).
The success of diagnostic screening devices relies heavily on non-invasiveness and patient compliance. Testing urine, saliva, or breath are non-invasive, particularly when compared to biopsies or blood draws [ 276 ]. Exhaled breath contains minute concentrations of volatile organic compounds (VOCs), even in the healthy state, but in a diseased state the concentrations and composition can distinguish the type and phase of cancer [ 277 , 278 ]. Na-nose is a nanosenor array utilizing gold nanomaterials to capture and detect VOCs [ 279 ]. Chemical interactions between VOCs and gold particles occur at the nanosensor surface, and electron density change causes a maximum shift in the surface plasmon absorption [ 280 ]. The gold NPs can also be conjugated with organic molecules for the capture of VOCs, then analyzed using gas chromatography and mass spectrometry. The Na-nose has the advantages of low cost, easy to use, good reproducibility, and real-time detection for large scale clinical application (ClinicalTrials.gov Identifier: NCT03967652).
Chronic infection with oncogenic HPV is the prominent cause of cervical cancer, followed by clonal progression of infected epithelium to cervical precancer, then further invasion [ 281 ]. Over 200 different HPV subtypes have been identified, with a subset of these being classified as high risk for oncogenesis [ 282 , 283 ]. An electrosensing antibody probing system (e- Ab sensor), is currently testing in clinical trials the interaction kinetics between anti-high-risk HPV and its antigen (high-risk HPV) present in patients (ClinicalTrials.gov Identifier: NCT01359436). It uses engineered semiconductive antibodies or virus in vertical and lateral chip (eAbchip) or lateral flow through (eAbsignal) formats. Semiconductive antibodies are bound as a suitable electrosensing probe, which specifically and selectively binds targeted molecules (high-risk HPV) in the test specimens [ 284 ]. From assessment of the electric signature of semiconductive anti- high-risk HPV antibodies, the eABprobe could offer sensitive detection and precise quantification of high-risk HPV, thus providing an efficient and accurate screening for cervical cancer.
In addition to early detection of cancers, it is equally important to detect minimal residual disease (MRD) to help predict outcome, identify high risk patients, and monitor treatment efficacy. A concerted effort to increase test sensitivity and accuracy for both early detection and MRD can make a significant impact on treatment course and overall patient survival [ 285 ]. Traditionally, leukemia and lymphoma cells are detected through morphological analysis, immunohistochemistry, antibody microarrays, flow cytometry using fluorescent markers, fluorescence in situ hybridization, PCR, and DNA sequencing [ 286 ]. Because these cancer types are extremely common and aggressive, effective treatment depends greatly on the accuracy and sensitivity of diagnosis. Signal amplification coupled with NPs may be a viable approach for earlier detection. To improve the detection of leukemia cells in the marrow, antibodies against the acute leukemia antigen CD34 were conjugated to SPIONs and coupled with a “magnetic needle” biopsy (ClinicalTrials.gov Identifier: NCT01411904). In preclinical studies, leukemia cell lines expressing high or minimal CD34 were incubated with anti-CD34-conjugated SPIONs [ 287 ]. Microscopy, Superconducting Quantum Interference Device (SQUID) magnetometry, and in vitro magnetic needle extraction were used to assess cell sampling, finding anti-CD34-conjugated NPs preferentially bind high CD34-expressing cell lines. Furthermore, the magnetic needle enabled identification of both cell line and patient leukemia cells diluted into normal blood at concentrations below those normally found in remission marrow samples. Finally, the magnetic needle enhanced the percentage of lymphoblasts detectable by light microscopy by ten-fold in samples of fresh bone marrow aspirate. This signal amplification can have positive impact on MRD detection, thus allowing oncologists to optimize treatment course.
Following initial treatment regimens, cancer patients can relapse with local and/or distant recurrence, with certain cancers at higher risk than others. The metastasis of a lymph node (LN) indicates systemic disease with increased risk of progression, thus detection of LN metastasis can have tremendous impact on prognosis and treatment course [ 288 , 289 ]. In the past, prostate cancer patients with LN metastasis have had poor prognoses due to inaccurate staging techniques and toxic treatment regimens such as radiotherapy [ 290 , 291 ]. Radiotherapy of LN metastases also has limitations with a high percentage of patients having metastatic LN outside the routine radiation field [ 292 , 293 ]. Conventional imaging techniques using CT and MRI are also not sensitive enough to detect a comprehensive total of LN metastases for certain cancers such as prostate cancer [ 294 ]. As a result, there is a need to improve lymph node tracers to help improve the amount of lymph node harvest as well as determine the extent of micro-metastases [ 295 ]. Sentinel lymph node (SLN) mapping is used in various cancer types, which relies on specific pattern of lymph drainage away from the tumor, therefore if the SLN, or first node, is negative for metastasis, then the nodes after the SLN should also be negative [ 296 ]. Indocyanine green (ICG) is fluorescent dye used to identify the lymphatic channels and decipher which nodes to remove [ 297 ]. By doing so, patients avoid a complete lymphadenectomy, however disease must be thoroughly staged for accurate prognosis and determination of appropriate treatment approach. Several clinical studies are currently underway to investigate different nanomaterials as lymph node tracers such as fluorescent cRGDY-PEG-Cy5.5-C quantum dots (ClinicalTrials.gov Identifier: NCT02106598), carbon NPs (NCT03550001, NCT04482803), and silica NPs (NCT04167969).
Despite advancements in traditional imaging devices regarding both preoperative diagnostics and staging, there remains room for improvement regarding sensitivity, resolution, and intraoperative procedures. Progress continues for enhancing image-guided surgeries by incorporating specific targeting, optically-active materials, and nano-sized probes for alternative modes of imaging [ 298 , 299 ]. Nano-enhanced imaging has potential to drastically improve early-stage detection of metastases and residual tumor cells to improve patient prognoses. Ferumoxtran-10, an ultrasmall superparamagnetic iron oxide (USPIO) particle has proven to be a valuable contrast agent for detecting lymph node metastases using a 1.5 Tesla or 3 Tesla MRI scanner in various types of cancer [ 300 ]. It is currently being studied in several clinical trials for SLN mapping, including to improve the resolution and sensitivity of nano-MRI by using a 7 Tesla scanner, particularly for small lymph nodes (ClinicalTrials.gov Identifier: NCT03280277, NCT04300673, NCT03817307, NCT02857218, NCT04261777). A precision nano-enhanced approach for monitoring disease progression utilizes triggered aggregation in the TME (Target-Enabled in situ Ligand Assembly [TESLA]) [ 301 ]. The particles are built in situ at tumor sites from precursors containing specific moieties which can form larger NPs only after being cleaved by enzymes specific to cancer cell apoptosis. The NPs carry various image contrast agents for monitoring tumor therapy response to optimize effective dosing regimens, and TESLA is currently being investigated for rectal and breast cancer (ClinicalTrials.gov Identifier: NCT02751606).
The margin status of a tumor remains the main prognostic factor after surgical resection in HNSCC [ 302 ]. Margin sizes are used to determine adjuvant therapy or need for re-operation, and currently no technology is available in the operating room which reliably supports tumor excision in terms of margin status [ 303 ]. In fact, surgeons can only combine pre- operative imaging data with tactile and visual information during surgery for assessing tumor margins with limited accuracy. Near infrared (NIR) fluorescent optical contrast agents can be coupled to targeted compounds to create highly specific and well-resolved image-guided assessment of tumor margins [ 304 ]. Tracers utilize antibodies directed against VEGF-A (bevacizumab-IRDye800CW) for breast cancer or against EGFR, (cetuximab-IRDye800CW) for malignant glioma and pancreatic cancer (ClinicalTrials.gov Identifier: NCT01508572, NCT02855086, NCT02736578). First trials have shown that systemic administration of these compounds is safe and tumor specific. Clinical trials for the intraoperative assessment of tumor margins during surgical treatment of HNSCC and esophageal squamous cell carcinoma are currently underway using cetuximab-IRDye800CW (ClinicalTrials.gov Identifier: NCT03134846, NCT04161560).
4.3 The future of cancer diagnostics and imaging
As previously discussed, non-invasive, sensitive methods for cancer screening will be the key to clinically relevant diagnostics. Ultrasmall gold nanoclusters (AuNCs) have been found to make excellent probes for in vivo imaging because of their accumulation at tumor sites and efficient clearance via urine [ 305 ]. Multifunction protease nanosensors that react in the cancer cell microenvironment produce a colorimetric signal that could be monitored via urine. It was found in collected urine samples from colorectal cancer mouse models that tumor affected mice had a 13-fold increase in signal compared to healthy mice. Furthermore, novel imaging agents with better sensitivity and specificity can improve early detection during routine screening and help with tumor margin visualization during surgical resection. Recently, optical properties were investigated for multiple dyes and pigments used in tattoo inks, foods, drugs, and cosmetics already FDA approved [ 306 ]. Absorption, fluorescence, and Raman scattering properties were evaluated, and several exhibit a multitude of useful optical properties, outperforming some of the clinically approved imaging dyes on the market. The best performing optical inks (Green 8 and Orange 16) were formulated into liposomal NPs to assess their tumor targeting and optical imaging potential in mouse xenograft models of colorectal, cervical and lymphoma tumors. After intravenous injection, fluorescence imaging revealed significant localization of the new “optical ink” liposomal NPs in all three tumor models as opposed to their neighboring healthy tissues (p < 0.05). Nanoformulations of highly sensitive imaging contrast agents have potential to greatly improve cancer imaging, diagnosis, and surgical removal of tumor tissue.
Nanotechnology has greatly impacted the realm of genetic sequencing through various nanopore-based systems, and subsequently, the realm of disease screening. The single molecule real time sequencing (SMRT) system is based on a single DNA polymerase within 60–100 nm cavities prepared by electron beam lithography on a thin aluminum 100 nm sheet deposited on a silica substrate [ 307 ]. This technique allows for optical monitoring of DNA sequence with use of fluorescent nucleotides added to the complement strand. Oxford Nanopore relies on passing a single DNA molecule through a nano-sized protein pore set within an electrically-resistant polymer membrane, where each DNA nucleotide base causes specific disruption in the current passing across the membrane [ 308 ]. Although both techniques present immense utility for omics data collection, circulating tumor DNA (ctDNA) analysis remains a challenge [ 309 ]. Recently, a new method using statistical analysis of the length of time for genetic code to unzip and blocking of the current has shown promise in identifying the precise position of genetic mutations [ 310 ]. This proof-of-concept study was demonstrated on oligonucleotides and is being further developed for liquid biopsies. Alternatively, targeted extracellular vesicle (EV) capture holds promise for liquid biopsy development since miRNA, mRNA, and proteins in/on EVs represent potential cancer biomarkers [ 311 ]. A high-throughput nano-biochip (HNCIB) for high-efficiency, targeted EV capture was recently developed using total internal reflective fluorescence microscopy for detection. HNCIB detected an up-regulated expression of programmed death-ligand 1 mRNA and protein and miR-21 in EVs derived from patients with lung adenocarcinoma compared to those from healthy donors. In addition to its high-throughput capabilities, it has low sample requirement and fast assay time. EV monitoring has further been useful for drug treatment monitoring effects, which was previously limited to invasive tissue biopsies and complex processes to analyze drug-target interactions. EV monitoring of small-molecular chemical occupancy and protein expression (ExoSCOPE) measures changes in drug occupancy and the composition of proteins present of in small volumes of blood to assess diseases status and success of targeted treatments [ 312 ]. It measures changes in drug occupancy and protein composition in molecular subpopulations of extracellular vesicles, and when used to monitor various targeted therapies, the ExoSCOPE revealed EV signatures that closely reflected cellular treatment efficacy. Using a small volume of blood, the ExoSCOPE accurately classified disease status and rapidly distinguished between targeted treatment outcomes, within 24 h after treatment initiation.
Theranostics aim to deliver point-of-care diagnosis and treatment with the same nanoformulation [ 313 ]. Theranostic agents can monitor the accumulation of nanomedicine compounds at the target site, visualize biodistribution, quantify triggered drug release, and assess therapeutic efficacy [ 314 , 315 , 316 ]. One of the most important aspects of theranostics is the capability to predict response in individual patients, thus paving the way for personalized medicine [ 317 ]. They may also offer a means of dealing with tumor heterogeneity since they can indicate the presence of a target and its exact location in the body [ 318 ]. The innovative concepts and strategies of theranostics have not yet been fully evaluated in clinical trials but there is a plethora of preclinical studies on the verge of clinical translation. Theranostic NPs were engineered by encapsulating the NIR-II nanofluorophore boron-dipyrromethene within amphipathic poly(styrene-co-chloromethylstyrene)-graft-poly-(ethylene glycol) nanocarriers functionalized with cell death-ligand 1 (PD-L1) monoclonal antibody (Fig. 8 ) [ 319 ]. Upon an 808 nm laser excitation, the targeted NPs produce an emission wavelength above 1200 nm to image a tumor to a normal tissue signal ratio (T/NT) at an approximate value of 14.1. These NPs exhibit high singlet oxygen quantum yield (ΦΔ = 73%), and an eliminating effect of primary cancers. The NPs also allow for profiling PD-L1 expression as well as accumulating in MC38 tumor and enabling molecular imaging in vivo. MC38 tumors in mice were eliminated by combining photodynamic therapy and immunotherapy within 30 days, with no tumor recurrence within a period of 40 days. In addition, the tumors do not grow in the rechallenged mice within 7 days of inoculation. These NPs showed durable immune memory effect against tumor rechallenging without toxic side effects to major organs. A proof-of-principle report showed agglomerated single-walled carbon nanotubes (SWCNTs) to be a potentially promising theranostic tool that allows for photoactivated destruction of cancer cells while keeping the local environment alive [ 320 ]. Absorptions of picosecond pulses of light by the SWCNTs creates photoacoustic induced cellular destruction without destroying the nearby environment allowing for continuous monitoring.
A and B Synthesis of boron-dipyrromethene compounds and subsequent assembly of nanocarriers functionalized with cell death-ligand 1 (PD-L1) monoclonal antibody. C and D Schematic of the BDP-I-N-anti-PD-L1-mediated phototoxicity and immune efficacy for tumor cells. Reprinted with permission, [ 319 ] https://doi.org/10.1021/acsnano.0c05317
5 Cancer radiation therapy
5.1 current approaches to radiotherapy.
Approximately 60% of cancer patients receive radiation treatment during the course of disease, depending on cancer type, stage, and time of diagnosis [ 321 ]. Radiation therapy (RT) is highly utilized to combat cancer because of its effectiveness in inducing DNA damage and subsequent cellular death, particularly in rapidly dividing cancer cells [ 322 ]. Although highly effective, radiotherapy is still not localized enough to avoid harmful effects on other parts of the body. Combination chemoradiotherapy is standard of care for many types of cancer, but further increases likelihood of systemic toxicity, however certain technological advancements in the past few decades have led to significant improvements [ 323 ]. 3D conformal radiation treatments, such as stereotactic (body) radiotherapy, intensity-modulated RT and improved imaging systems (i.e., image-guided RT), coupled with superior understanding of tumor biology have increased cancer RT survival rates from 30 to 80% [ 3 ]. Lastly, some cancers are known to be resistant to radiotherapy thus utilizing nanomaterials to enhance and hone specificity can greatly reduce toxicity of treatment [ 324 ].
5.2 Emerging nanotechnologies for RT in clinical applications
RT can benefit from nanotechnology enhancements since nanomaterials have specific properties conducive to atomic-level interactions with radiation and tumoral accumulation. High atomic number NPs have been shown to enhance Compton and photoelectric effects of conventional RT, and certain nanomaterials can utilize radiation-triggered drug release while others can serve as radiosensitizers [ 325 , 326 ]. There are several clinical studies underway that utilize nanomaterials for enhancing RT further elucidated in this section (Table 4 ).
AGuIX is a nanoparticle composed of polysiloxane-based inorganic matrix bound to chelating agent DOTA (1,4,7,10-tetra-azacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid) covalently bound to the paramagnetic contrast enhancer Gd [ 327 , 328 ]. Upon placement in a magnetic field, AGuIX produces a large magnetic moment and subsequently a large local magnetic field, which can enhance the relaxation rate of nearby protons, increasing MRI signal in tumor tissues where they have accumulated. The ultra-small NPs, less than 5 nm in diameter, allow for rapid renal clearance and reduced toxicity, and amplified radiation effects of AGuIX NPs were recently elucidated, attributed to the emission of low-energy photoelectrons and Auger electron interactions [ 329 ]. The preclinical study showed AGuIX NPs exacerbated radiation-induced DNA double-strand break damage and reduced DNA repair in the H1299 NSCLC cell line and is currently being tested in clinical trials (ClinicalTrials.gov Identifier: NCT04789486).
Certain NPs can combine radiation with localized PDT to induce tumor tissue destruction via ROS generation and radiosensitization, providing the benefit of physical ablation to deep tissue targets [ 330 ]. AuroLase therapy is a particle-directed photothermal therapy used with infrared-absorbing Auroshell NPs within tumor tissue to generate lethal doses of heat [ 331 ]. Auroshell particles consist of a gold metal shell surrounding a silica core, and a near-infrared (NIR)-tuned optical fiber can specifically deliver photonic laser energy which the NPs can absorb and create lethal photothermal lesions that are confined to the tumor tissue where Auroshells have accumulated [ 332 ]. In initial clinical studies, NP-mediated focal laser ablation was successful in 15/16 prostate cancer patients, and they are currently being investigated in an expanded clinical study (ClinicalTrials.gov Identifier: NCT04240639).
Normal X-ray radiation induces DNA damage through ROS generation after interaction with water molecules. NBTXR3 are hafnium oxide NPs engineered to increase energy deposit due to high electron density, thereby inducing greater oxidative stress within tumor cells and subsequent physical ablation [ 333 ]. Soft tissue sarcomas of limbs or trunk enable direct injection of NPs into the tumor, where the radiotherapy enhancement can be localized to cancerous tissue, but locally advanced soft tissue sarcomas (high risk that are typically unresectable) often requires pre-operative radiotherapy, making ideal cancer types for testing NBTXR3 [ 334 ]. In a recent phase 2/3 trial (ClinicalTrials.gov Identifier: NCT02379845), the rate of pathologic complete response (< 5% remaining viable tumor cells) was achieved in twice as many patients in test arm as in the control arm (16 vs 8%; P = 0.044), and the NPs were well tolerated. NBTXR3 is currently being evaluated in 8 clinical studies on various cancers ( ClinicalTrials.gov Identifiers: NCT01946867, NCT04505267, NCT03589339, NCT04484909, NCT04615013, NCT04862455, NCT04834349, NCT04892173). Radiation-induced liver disease (RILD) or radiation hepatitis is a sub-acute form of liver injury due to radiation [ 335 ]. It is one of the most severe side effects of radiation which prevents radiation dose escalation and re-irradiation for hepatobiliary or upper gastrointestinal malignancies. Hepatic cirrhosis in patients with hepatocellular carcinomas (HCC), or chemotherapy-induced hepatic atrophy or hepatosteatosis in patients with liver metastases can be associated with high risk of RILD after stereotactic body radiotherapy (SBRT) [ 336 , 337 ]. However, hepatotoxicity can be greatly reduced by switching to MRI-guided radiotherapy with SPION on 1.5 Tesla MR-Linac as opposed to nuclear medicine [ 338 ]. MRI-SPION radiotherapy is expected to facilitate detection and maximize avoidance of residual, functionally-active hepatic parenchyma from over-the-threshold irradiation, thus increasing safety of liver stereotactic body radiotherapy in patients with pre-existing liver conditions ( ClinicalTrials.gov Identifier: NCT04682847).
5.3 Nanomaterials to improve and augment RT
Drug resistance and cancer heterogeneity can be addressed by physical destruction of tumor cells through RT, but there is room for improvement with respect to specificity and enhanced efficacy. Previous research has shown that radiotherapy can be utilized to activate the immune system by inducing immunogenic cell death (ICD), an immune response against the antigens of dead or dying tumor cells [ 339 ]. ICD-associated damage via ROS production could possibly promote the activation and migration of dendritic cells to prime T cells for systemic anti-tumor immune responses [ 340 , 341 ]. However, radiation-stimulated immune responses have shown limited efficacy, particularly when tumors exhibit low X-ray absorption and energy deposition capacities [ 342 , 343 ]. Disjoint oxygen supply and demand within tumors result in hypoxic areas with high levels of hydrogen peroxide, which induce adaptive antioxidant mechanisms [ 344 , 345 ]. Subsequently, high concentrations of reducing substances, such as glutathione, quench •OH generated by RT, ultimately reducing its efficacy [ 346 ]. One solution to amplify RT mediated oxidative stress to induce ICD for antitumor immunity activation was developed via a novel radiosensitizer that incorporates nanoscale coordination polymers (NCPs) based on Gd 3+ and 5′-Guanosine monophosphate (5′-GMP) via supramolecular self-assembly (Fig. 9 ) [ 347 ]. Hemin (PANHEMATIN®) with peroxidase-mimic catalytic activity was incorporated into the Gd 3+ /5′-GMP NCPs (Gd-NCPs) to form Hemin@ Gd 3+ /5′-GMP NCPs (H@Gd-NCPs). Furthermore, presence of metal element Gd, H@Gd-NCPs can act as an MRI contrast agent, adding to its utility for clinical use. The H@Gd-NCPs effectively enhance X-ray absorption and produce more ROS, especially hydroxyl radicals within tumor tissues. The encapsulated hemin can enhance peroxidase-like properties to utilize overexpressed hydrogen peroxide in TME to deplete GSH. Combination of ROS enhancement and GSH depletion amplifies irradiation-mediated oxidative stress and induce ICD. The antitumor immunity activated by H@Gd-NCPs can further be strengthened by immune checkpoint blockade therapy against primary, distant, and metastatic tumors. Another approach to address hypoxic environmental impact on RT is to utilize nitric oxide (NO) prodrugs, shown to be efficient radiosensitizers as cell respiration inhibitors, and co-delivery with exogenous oxygen resources [ 348 , 349 ]. Recent work has shown potential solution to this obstacle through a hybrid semiconducting organosilica-based O 2 nanoeconomizer which in an acidic tumor environment releases NO and, via mild photothermal treatment, releases O 2 resulting in enhanced efficacy of radiotherapy in vitro and in vivo [ 350 ]. A semiconducting polymer brush (SPB) framework has an electron donor and acceptor backbone, providing NIR II fluorescence, photoacoustic contrast, and photothermal conversion for theranostic application. It can be tuned for mild hyperthermia with tumor oxygenation improvement to boost RT, or higher temperature physical ablation. A hybridized fluorocarbon (FC) chain provides ease for oxygen loading and photothermally-controlled release, and in situ polymerization of PEG and alkyl chains improves biocompatibility and loading/retention of NO prodrugs. This novel nanoplatform (pHPFON-NO/O 2 ) demonstrates tunable, pH-activated NO release and radiation-activated O 2 delivery for enhanced radiosenstivity. An alternative to photon irradiation is the use of fast ion beams (proton therapy and hadron therapy [70–400 MeV amu −1 ]) to treat solid tumors [ 351 ]. Since ion irradiation has more specific tumor targeting, they are generally used for tumors in highly sensitive tissues such as eyes and brain, pediatric cancers, and/or radioresistant tumors [ 352 ]. However, one significant drawback remains as the damage sustained to healthy tissue in front of the tumor, so radiosensitizers can amplify the radiation effects within the tumor area while lowering dosage to the healthy tissue. [ 353 ] A Gd-chelated polysiloxane matrix based-nanoparticle was recently engineered to increase dose effect through generation of a high number of radicals via direct or indirect interaction of high-energy particles with Gd [ 354 ].The efficiency of AGuIX NPs to amplify the effects of medical protons was demonstrated using a 150 MeV proton beam under two irradiation conditions mimicking the entrance (0.44 keV µm −1 ) and the end (3.6 keV µm −1 ) of the proton track on plasmid pBR322, and is currently under clinical investigation in France [ 327 ].
A Preparation of a novel radiosensitizer that incorporates nanoscale coordination polymers (NCPs) based on gadolinium (Gd 3+ ) and 5′-Guanosine monophosphate (5′-GMP) via supramolecular self-assembly. B Mechanism of radiosensitization via amplification of radiotherapy-mediated oxidative stress. Dendritic cells (DCs), glutathione (GSH), oxidized glutathione (GSSG), hydroxyl radicals (•OH), calreticulin (CRT), high mobility group protein B1 (HMGB1), adenosine triphosphate (ATP). Reprinted with permission, [ 347 ] https://doi.org/10.1038/s41467-020-20243-8
Hyperthermia (localized heat to kill cells) is a promising method for elimination of cancerous tissue, and certain nanomaterials have been shown to enhance hyperthermal effects [ 355 , 356 ]. Uniform and selective hyperthermia can be achieved using nanomaterials with a high-absorption cross-section, which can convert an external energy source into heat [ 357 , 358 ]. Dynamic nanomaterials can achieve maximum therapeutic effects through multi-modal cancer treatments. Multi-modal treatments pose the possibility of eliminating cancer via physical activation such as photothermal, photodynamic, radiation, and magnetic. Specifically, gold and carbon nanomaterials have been extensively used to induce hyperthermal effects upon near-infrared light (NIR) irradiation [ 248 , 359 ]. They can further be utilized for triggered drug release with therapeutics tethered to the surface or encapsulated within, and payload can release upon change in temperature or irradiation [ 360 , 361 ]. This approach can incorporate a combinatorial approach by using therapeutic agents in conjunction with an external trigger to localize treatment and/or destroy cancerous cells with physical ablation [ 362 ]. Recently, activatable polymeric pro-nanoagonist (APNA) triggers tumor ablation by the photothermal effect and induces immunogenic cell death and is activated by second near-infrared (NIR-II) light which enables deep-tissue penetration and represents a strategy for future RT [ 363 ]. APNA is constructed from covalent conjugation of toll-like receptor type 7 and 8 agonist (Resiquimod: R848) onto a NIR-II semiconducting transducer through a labile thermo-responsive linker. Upon NIR-II photoirradiation, APNA mediates photothermal effect, triggers tumor ablation, immunogenic cell death, and initiates the cleavage of thermolabile linker to liberate caged agonist for in-situ immune activation in deep solid tumor (8 mm). Cancer stem cells are particularly concerning due to their resistance for anticancer drugs, thus alternative methods are necessary [ 364 ]. A novel approach to utilizing nanomaterials with radiation is photothermal control of heat-sensitive TRPV1 or TRPV2 ion channels to regulate cell stemness [ 365 ]. This recent study demonstrates NIR-photoactive nanocarbon complexes can stimulate TRPV2 overexpression in cancer cells, disrupting intracellular Ca 2+ regulation, suppressing Wnt/β-catenin signaling, which resulted in the destruction of cancer cells and inhibition of stemness in both in vitro and in vivo models.
Although photothermal agents (PTAs) have shown promising results in clinical studies, rapid degradation of PTA limits the photothermal stability required for efficacious treatment yet those with high photothermal stability degrade slowly thus have greater safety concerns [ 366 , 367 ]. Currently, there are few PTAs with high photothermal stability and rapid degradation. Recently, it was shown that the inherent Cu 2+ -capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability [ 368 ]. The incorporation of Cu 2+ into BP@Cu nanostructures further enables chemodynamic therapy-enhanced PTT. Moreover, by employing 64 Cu 2+ , PET imaging can be achieved for in vivo real-time and quantitative tracking.
6 Perspectives and conclusion
Nanomaterials are highly versatile, adaptable, and have many advantages that can improve cancer treatments and diagnostics (Fig. 10 ). However, factors such as production cost, scalability, safety, and complexity of nanoformulations must be considered and weighed against the potential benefits. As complexity of design and materials increases, so do costs, manufacturing criteria, and testing parameters [ 144 ]. Some nanomedicines may present a clear clinical benefit over conventional formulation, but if cost and production requirements are unattainable, clinical translation may never be realized. An increasingly important factor for commercial production is the environmental impact, not only of the nanomaterials themselves, but manufacturing by-products and energy costs [ 369 ]. In addition, there is a shadow of uncharted territory for FDA approval that many nanomedicines may face. The FDA has 3 product areas based on whether the product has a chemical mode of action (drug), a mechanical mode of action (device), or a biological source (biologic), and certain nanoformulations can span all 3 areas, categorizing them as a combination product. With rapidly advancing technologies for nanomedicine, there seems to be a need for more consistent and robust guidelines to evaluate clinical trials for nanomaterials. In 2006, the FDA Nanotechnology Task Force was created to address the regulatory deficiencies regarding nanoformulated medicines and devices, but determined that no new regulations were warranted [ 370 ]. The FDA published two documents regarding nanotechnology application and status, risk-based framework, specific requirements for conduct of nonclinical and clinical trials, manufacturing quality and controls, and environmental considerations [ 371 , 372 ]. However, considering the pace and magnitude of nanotechnology research, a 15-year-old guidance is now exceedingly outdated. Although breakthrough status and subsequent accelerated approval can be achieved for certain drugs/devices/biologics, the gap in cohesive regulation for nanotechnology remains unclosed. Without comprehensive, updated evaluation and policy regarding nanotechnology in medicine and devices, the cost vs. benefit analysis will be unclear, and possibly a roadblock for critical research.
Conventional cancer therapies, diagnostics, radiation treatments, and imaging can be significantly improved through nanotechnological applications. Nanotechnologies are emerging in all fields at an increasing rate, and future applications hold great promise to significantly improve patient prognoses and quality of life
Cost vs. benefit analysis of nanomedicine poses many questions even without the issue of unclear regulatory guidelines. Nanomedicine can have much higher manufacturing costs than conventional drugs, depending upon formulation and complexity, however it is not as simple as comparing apples to apples [ 144 ]. Quality of life is typically only addressed for the duration of clinical trials; a recent study found that in only 5 of 149 studies (3.4%), quality of life was assessed until death, with only 1 out of 74 studies on metastatic or incurable cancers, and it is often not a co-primary endpoint [ 373 ]. Of course, quality of life may not be assigned a price, but certain quantifiable metrics may be applicable to evaluating the worth of nano-focused research and development. A 2011 survey found that one third of cancer survivors experienced limitations in their ability to perform usual daily activities outside of work, 25.1% felt cancer interfered with physical work tasks, and 24.7% overall felt less productive at work [ 374 ]. As previously noted, nanoformulations are often engineered to increase specificity, efficacy, and guard against drug resistance, thus patient quality of life is an important metric to evaluate for a prolonged period. There are many intricacies and considerations in determining the viability of drug products that go beyond merely cost of development vs. clinical outcome, and nanomedicine certainly adds to the equation.
Accessibility of information is at an apex, available at the touch of a button, which has greatly accelerated the advancement of scientific research. While extremely beneficial, it has also created a need for hierarchal and centralized organization as the scientific “toolbox” is flooded with data and new techniques. A search for the words “nano cancer” within only Nature publications for the year 2019 yielded 932 research articles, with Nature publications known to critically evaluate and publish highly impactful research. A recent study from MIT has constructed a machine learning framework to indicate “impactful” research that is overlooked by current metrics, opening the door to a possibility of machine-assisted direction of research [ 375 ]. While many in the scientific community were critical of the study and its implications, the idea of utilizing artificial intelligence to guide basic research has great potential. A multitude of parameters can be used to determine likelihood of clinical translation for nanotechnologies, as well as cross-reference with existing and emerging research to optimize formulation and strategy. Nanomedicine can greatly benefit from machine learning applications from analysis of patient tumor profiles and drug response to nanoparticle design, determining optimum material according to drug target, mechanistic attributes, and individualized prognoses [ 376 , 377 ]. Machine learning was recently shown to estimate the cellular internalization of NPs based on their surface design, along with a machine learning-based model to sense breast cancer cells via internalization of eight differently functionalized carbon NPs (CNPs) [ 378 ]. The model accurately predicted the internalization of CNPs based on their structural features. NP cellular internalization were evaluated using different endocytic pathways, and artificial intelligence was then utilized to rank specific NP properties for optimum design. Furthermore, patient-specific cancer profiles were determined with machine learning techniques and cellular internalization profiles, demonstrating an efficient platform to render distinct fingerprints for individual cancer cell types. Neural networks are also demonstrating their use for diagnostics as well, from evaluating omics data to tumor imaging, and even optimizing radiotherapy [ 379 , 380 , 381 , 382 ].
The future of nanomedicine is certainly auspicious, with highly developed technologies improving treatments and diagnostics, and machine learning applications augmenting to save significant time and resources. There are multitudes of clinical and preclinical studies demonstrating the benefits of nanotechnology in cancer treatment, imaging, and diagnostics, but it is critical that these advances are clinically translatable. One key component in improving cancer patient outcome clearly lies in early detection methods. As previously discussed, early-stage cancers are generally much easier to treat, and early detection drastically improves 5-year survival rates and lowers patient cost. However, it is critical that diagnostic screenings are extremely accurate, otherwise misdiagnoses and overtreatments overshadow the benefits of early detection. Nanotechnology for cancer diagnostics, chemo- and radiotherapies stands to gain huge ground in the near future, creating a highly manageable cancer landscape for patients and oncologists. Although the dynamic nature of cancer refuses to yield, innovation continues to progress, and convergence of multiple technologies has promise to prevail.
Availability of data and materials
Antibody drug conjugate
Acute myeloid leukemia
Antigen presenting cells
Activatable polymeric pro-nanoagonist
Circulating tumor cell
Drug Response Prediction
Epidermal growth factor
Epidermal growth factor receptor
European Medicines Agency
Epithelial cell adhesion molecule
Enhanced permeation and retention
Fibroblast activation protein
U.S. Food and Drug Administration
Human leukocyte antigen
Head and neck squamous cell carcinoma
Immunogenic cell death
Invariant natural killer T
Minimal residual disease
Magnetic resonance imaging
Mesoporous silica NPs
New York esophageal squamous cell carcinoma 1
Outer membrane vesicle
Polo-like kinase 1
Radiation-induced liver disease
Stereotactic body radiotherapy
Sentinel lymph node
Single molecule real time
Stable nucleic acid lipid particles
Superparamagnetic iron oxide nanoparticle
Single-walled carbon nanotube
Tumor associated antigen
T cell receptors
Target-Enabled in situ Ligand Assembly
Tyrosine kinase inhibitor
Triple negative breast cancer
Tumor necrosis factor-related apoptosis-inducing ligand
Tumor specific antigen
Ultrasmall superparamagnetic iron oxide
Vascular endothelial growth factor
Volatile organic compounds
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This work was financially supported by an NIH R21 grant (1R21CA228099-01A1).
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Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA
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Young Jik Kwon
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Kemp, J.A., Kwon, Y.J. Cancer nanotechnology: current status and perspectives. Nano Convergence 8 , 34 (2021). https://doi.org/10.1186/s40580-021-00282-7
Received : 30 June 2021
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DOI : https://doi.org/10.1186/s40580-021-00282-7
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The History of Nanoscience and Nanotechnology: From Chemical–Physical Applications to Nanomedicine
1 Department of Chemistry, Faculty of Sciences, Jinan University, Tripoli 818, Lebanon
2 Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; [email protected]
3 PhD School in Science and Technology of Bio and Nanomaterials, University Ca’ Foscari of Venice, 30170 Venice, Italy
4 Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; [email protected]
5 Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), 28049 Madrid, Spain; [email protected]
6 Department of Molecular science and Nanosystems, University Ca’ Foscari of Venice, 30170 Venice, Italy
Nanoscience breakthroughs in almost every field of science and nanotechnologies make life easier in this era. Nanoscience and nanotechnology represent an expanding research area, which involves structures, devices, and systems with novel properties and functions due to the arrangement of their atoms on the 1–100 nm scale. The field was subject to a growing public awareness and controversy in the early 2000s, and in turn, the beginnings of commercial applications of nanotechnology. Nanotechnologies contribute to almost every field of science, including physics, materials science, chemistry, biology, computer science, and engineering. Notably, in recent years nanotechnologies have been applied to human health with promising results, especially in the field of cancer treatment. To understand the nature of nanotechnology, it is helpful to review the timeline of discoveries that brought us to the current understanding of this science. This review illustrates the progress and main principles of nanoscience and nanotechnology and represents the pre-modern as well as modern timeline era of discoveries and milestones in these fields.
1. Definition of Nanoscience and Nanotechnology
The prefix ‘nano’ is referred to a Greek prefix meaning ‘dwarf’ or something very small and depicts one thousand millionth of a meter (10 −9 m). We should distinguish between nanoscience, and nanotechnology. Nanoscience is the study of structures and molecules on the scales of nanometers ranging between 1 and 100 nm, and the technology that utilizes it in practical applications such as devices etc. is called nanotechnology [ 1 ]. As a comparison, one must realize that a single human hair is 60,000 nm thickness and the DNA double helix has a radius of 1 nm ( Figure 1 ) [ 2 ]. The development of nanoscience can be traced to the time of the Greeks and Democritus in the 5th century B.C., when scientists considered the question of whether matter is continuous, and thus infinitely divisible into smaller pieces, or composed of small, indivisible and indestructible particles, which scientists now call atoms.
A comparison of sizes of nanomaterial. Reproduced with permission from reference [ 2 ].
Nanotechnology is one of the most promising technologies of the 21st century. It is the ability to convert the nanoscience theory to useful applications by observing, measuring, manipulating, assembling, controlling and manufacturing matter at the nanometer scale. The National Nanotechnology Initiative (NNI) in the United States define Nanotechnology as “a science, engineering, and technology conducted at the nanoscale (1 to 100 nm), where unique phenomena enable novel applications in a wide range of fields, from chemistry, physics and biology, to medicine, engineering and electronics” [ 3 ]. This definition suggests the presence of two conditions for nanotechnology. The first is an issue of scale: nanotechnology is concerned to use structures by controlling their shape and size at nanometer scale. The second issue has to do with novelty: nanotechnology must deal with small things in a way that takes advantage of some properties because of the nanoscale [ 4 ].
We should distinguish between nanoscience and nanotechnology. Nanoscience is a convergence of physics, materials science and biology, which deal with manipulation of materials at atomic and molecular scales; while nanotechnology is the ability to observe measure, manipulate, assemble, control, and manufacture matter at the nanometer scale. There are some reports available, which provided the history of nanoscience and technology, but no report is available which summarize the nanoscience and technology from the beginning to that era with progressive events. Therefore, it is of the utmost requirements to summarize main events in nanoscience and technology to completely understand their development in this field.
2. The Imaginative Pioneers of Nanotechnology
The American physicist and Nobel Prize laureate Richard Feynman introduce the concept of nanotechnology in 1959. During the annual meeting of the American Physical Society, Feynman presented a lecture entitled “There’s Plenty of Room at the Bottom” at the California Institute of Technology (Caltech). In this lecture, Feynman made the hypothesis “Why can’t we write the entire 24 volumes of the Encyclopedia Britannica on the head of a pin?”, and described a vision of using machines to construct smaller machines and down to the molecular level [ 5 ]. This new idea demonstrated that Feynman’s hypotheses have been proven correct, and for these reasons, he is considered the father of modern nanotechnology. After fifteen years, Norio Taniguchi, a Japanese scientist was the first to use and define the term “nanotechnology” in 1974 as: “nanotechnology mainly consists of the processing of separation, consolidation, and deformation of materials by one atom or one molecule” [ 6 ].
After Feynman had discovered this new field of research catching the interest of many scientists, two approaches have been developed describing the different possibilities for the synthesis of nanostructures. These manufacturing approaches fall under two categories: top-down and bottom-up, which differ in degrees of quality, speed and cost.
The top-down approach is essentially the breaking down of bulk material to get nano-sized particles. This can be achieved by using advanced techniques such as precision engineering and lithography which have been developed and optimized by industry during recent decades. Precision engineering supports the majority of the micro-electronics industry during the entire production process, and the high performance can be achieved through the use of a combination of improvements. These include the use of advanced nanostructure based on diamond or cubic boron nitride and sensors for size control, combined with numerical control and advanced servo-drive technologies. Lithography involves the patterning of a surface through exposure to light, ions or electrons, and the deposition of material on to that surface to produce the desired material [ 7 ].
The bottom-up approach refers to the build-up of nanostructures from the bottom: atom-by-atom or molecule-by-molecule by physical and chemical methods which are in a nanoscale range (1 nm to 100 nm) using controlled manipulation of self-assembly of atoms and molecules. Chemical synthesis is a method of producing rough materials which can be used either directly in product in their bulk disordered form, or as the building blocks of more advanced ordered materials. Self-assembly is a bottom-up approach in which atoms or molecules organize themselves into ordered nanostructures by chemical-physical interactions between them. Positional assembly is the only technique in which single atoms, molecules or cluster can be positioned freely one-by-one [ 7 ].
The general concept of top down and bottom up and different methods adopted to synthesized nanoparticles by using these techniques are summarized in Figure 2 . In 1986, K. Eric Drexler published the first book on nanotechnology “Engines of Creation: The Coming Era of Nanotechnology”, which led to the theory of “molecular engineering” becoming more popular [ 8 ]. Drexler described the build-up of complex machines from individual atoms, which can independently manipulate molecules and atoms and thereby produces self-assembly nanotructures. Later on, in 1991, Drexler, Peterson and Pergamit published another book entitled “Unbounding the Future: the Nanotechnology Revolution” in which they use the terms “nanobots” or “assemblers” for nano processes in medicine applications and then the famous term “nanomedicine” was used for the first time after that [ 9 ].
The concept of top down and bottom up technology: different methods for nanoparticle synthesis.
3. History of Nanotechnology
Nanoparticles and structures have been used by humans in fourth century AD, by the Roman, which demonstrated one of the most interesting examples of nanotechnology in the ancient world. The Lycurgus cup, from the British Museum collection, represents one of the most outstanding achievements in ancient glass industry. It is the oldest famous example of dichroic glass. Dichroic glass describes two different types of glass, which change color in certain lighting conditions. This means that the Cup have two different colors: the glass appears green in direct light, and red-purple when light shines through the glass ( Figure 3 ) [ 10 ].
The Lycurgus cup. The glass appears green in reflected light ( A ) and red-purple in transmitted light ( B ). Reproduced with permission from reference [ 10 ].
In 1990, the scientists analyzed the cup using a transmission electron microscopy (TEM) to explain the phenomenon of dichroism [ 11 ]. The observed dichroism (two colors) is due to the presence of nanoparticles with 50–100 nm in diameter. X-ray analysis showed that these nanoparticles are silver-gold (Ag-Au) alloy, with a ratio of Ag:Au of about 7:3, containing in addition about 10% copper (Cu) dispersed in a glass matrix [ 12 , 13 ]. The Au nanoparticles produce a red color as result of light absorption (~520 nm). The red-purple color is due to the absorption by the bigger particles while the green color is attributed to the light scattering by colloidal dispersions of Ag nanoparticles with a size > 40 nm. The Lycurgus cup is recognized as one of the oldest synthetic nanomaterials [ 1 ]. A similar effect is seen in late medieval church windows, shining a luminous red and yellow colors due to the fusion of Au and Ag nanoparticles into the glass. Figure 4 shows an example of the effect of these nanoparticles with different sizes to the stained glass windows [ 14 ].
Effect of nanoparticles on the colors of the stained glass windows. Reproduced with permission from reference [ 14 ].
During the 9th–17th centuries, glowing, glittering “luster” ceramic glazes used in the Islamic world, and later in Europe contained Ag or copper (Cu) or other nanoparticles [ 15 ]. The Italians also employed nanoparticles in creating Renaissance pottery during 16th century [ 16 ]. They were influenced by Ottoman techniques: during the 13th–18th centuries, to produce “Damascus” saber blades, cementite nanowires and carbon nanotubes were used to provide strength, resilience, and the ability to hold a keen edge [ 17 ]. These colors and material properties were produced intentionally for hundreds of years. Medieval artists and forgers, however, did not know the cause of these surprising effects.
In 1857, Michael Faraday studied the preparation and properties of colloidal suspensions of “Ruby” gold. Their unique optical and electronic properties make them some of the most interesting nanoparticles. Faraday demonstrated how gold nanoparticles produce different-colored solutions under certain lighting conditions [ 18 ]. The progression in nanotechnology due to the blessings of nanoscience are summarized in the Figure 5 .
Progresses in Nanotechnology.
4. Modern Era of Nanotechnology
There was a progress in nanotechnology since the early ideas of Feynman until 1981 when the physicists Gerd Binnig and Heinrich Rohrer invented a new type of microscope at IBM Zurich Research Laboratory, the Scanning Tunneling Microscope (STM) [ 19 , 20 ]. The STM uses a sharp tip that moves so close to a conductive surface that the electron wave functions of the atoms in the tip overlap with the surface atom wave functions. When a voltage is applied, electrons “tunnel” through the vacuum gap from the atom of the tip into the surface (or vice versa). In 1983, the group published the first STM image of the Si(111)-7 × 7 reconstructed surface, which nowadays can be routinely imaged as shown in Figure 6 [ 21 , 22 ].
STM image of the Si(111)-7 × 7 reconstructed surface showing atomic scale resolution of the top-most layer of silicon atoms. Reproduced with permission from reference [ 22 ].
A few years later, in 1990, Don Eigler of IBM in Almaden and his colleagues used a STM to manipulate 35 individual xenon atoms on a nickel surface and formed the letters of IBM logo ( Figure 7 ) [ 23 ]. The STM was invented to image surfaces at the atomic scale and has been used as a tool with which atoms and molecules can be manipulated to create structures. The tunneling current can be used to selectively break or induce chemical bonds.
35 Xenon atoms positioned on a nickel (110) substrate using a STM to form IBM logo. Reproduced with permission from reference [ 23 ].
In 1986, Binnig and Rohrer received the Nobel Prize in Physics “for their design of the STM”. This invention led to the development of the atomic force microscope (AFM) and scanning probe microscopes (SPM), which are the instruments of choice for nanotechnology researchers today [ 24 , 25 ]. At the same time, in 1985, Robert Curl, Harold Kroto, and Richard Smalley discovered that carbon can also exist in the form of very stable spheres, the fullerenes or buckyballs [ 26 ]. The carbon balls with chemical formula C60 or C70 are formed when graphite is evaporated in an inert atmosphere. A new carbon chemistry has been now developed, and it is possible to enclose metal atoms and create new organic compounds. A few years later, in 1991, Iijima et al. observed of hollow graphitic tubes or carbon nanotubes by Transmission Electron Microscopy (TEM) which form another member of the fullerene family ( Figure 8 ) [ 27 ]. The strength and flexibility of carbon nanotubes make them potentially useful in many nanotechnological applications. Currently, Carbon nanotubes are used as composite fibers in polymers and beton to improve the mechanical, thermal and electrical properties of the bulk product. They also have potential applications as field emitters, energy storage materials, catalysis, and molecular electronic components.
Schematic of a C60 buckyball (Fullerene) ( A ) and carbon nanotube ( B ).
In 2004, a new class of carbon nanomaterials called carbon dots (C-dots) with size below 10 nm was discovered accidentally by Xu et al. during the purification of single-walled carbon nanotubes [ 28 ]. C-dots with interesting properties have gradually become a rising star as a new nanocarbon member due to their benign, abundant and inexpensive nature [ 29 ]. Possessing such superior properties as low toxicity and good biocompatibility renders C-dots favorable materials for applications in bioimaging, biosensor and drug delivery [ 30 , 31 , 32 , 33 , 34 , 35 ]. Based on their excellent optical and electronic properties, C-dots can also offer exciting opportunities for catalysis, energy conversion, photovoltaic devices and nanoprobes for sensitive ion detection [ 36 , 37 , 38 , 39 ]. After the discovery of “graphene” in 2004, carbon-based materials became the backbone of almost every field of science and engineering.
In the meantime, nanoscience progressed in other fields of science like in computer science, bio and engineering. Nanoscience and technology progressed in computer science to decrease the size of a normal computer from a room size to highly efficient moveable laptops. Electrical engineers progressed to design the complex electrical circuits down to nanoscale level. Also, many advances are noticed in smart phone technology and other modern electronic devices for daily uses.
At the beginning of 21st century, there was an increased interest in the nanoscience and nanotechnology fields. In the United States, Feynman’s concept of manipulation of matter at the atomic level played an important role in shaping national science priorities. During a speech at Caltech on 21 January 2000, President Bill Clinton advocated for the funding of research in the field of nanotechnology. Three years later, President George W. Bush signed into law the 21st century Nanotechnology Research and Development Act. The legislation made nanotechnology research a national priority and created the National Technology Initiative (NNI).
Recently, a number of studies highlighted the huge potential that nanotechnologies play in biomedicine for the diagnosis and therapy of many human diseases [ 40 ]. In this regard, bio-nanotechnology is considered by many experts as one of the most intriguing field of application of nanoscience. During recent decades, the applications of nanotechnology in many biology related areas such as diagnosis, drug delivery, and molecular imaging are being intensively researched and offered excellent results. Remarkably, a plethora of medical-related products containing nanomaterials are currently on the market in the USA. Examples of “nanopharmaceuticals” include nanomaterials for drug delivery and regenerative medicine, as well as nanoparticles with antibacterial activities or functional nanostructures used for biomarker detection like nanobiochips, nanoelectrodes, or nanobiosensors [ 41 ].
One of the most important applications of nanotechnology to molecular biology has been related to nucleic acids. In 2006, Paul Rothemund developed the “scaffolded DNA origami”, by enhancing the complexity and size of self-assembled DNA nanostructures in a “one-pot” reaction [ 42 ]. The conceptual foundation for DNA nanotechnology was first laid out by Nadrian Seeman in 1982: “It is possible to generate sequences of oligomeric nucleic acids, which will preferentially associate to form migrationally immobile junctions, rather than linear duplexes, as they usually do” [ 43 ]. DNA nanotechnology has already become an interdisciplinary research area, with researchers from physics, chemistry, materials science, computer science, and medicine coming together to find solutions for future challenges in nanotechnology [ 44 , 45 , 46 , 47 ]. Notably, years of extensive studied made possible to use DNA and other biopolymers directly in array technologies for sensing and diagnostic applications.
Remarkable progresses have been made also in the field of nano-oncology by improving the efficacy of traditional chemotherapy drugs for a plethora of aggressive human cancers [ 48 , 49 ]. These advances have been achieved by targeting the tumour site with several functional molecules including nanoparticles, antibodies and cytotoxic agents. In this context, many studies showed that nanomaterials can be employed itself or to deliver therapeutic molecules to modulate essential biological processes, like autophagy, metabolism or oxidative stress, exerting anticancer activity [ 50 ].
Hence, nano-oncology is a very attractive application of nanoscience and allows for the improvement of tumour response rates in addition to a significant reduction of the systemic toxicity associated with current chemotherapy treatments.
Nanotechnology has been used to improve the environment and to produce more efficient and cost-effective energy, such as generating less pollution during the manufacture of materials, producing solar cells that generate electricity at a competitive cost, cleaning up organic chemicals polluting groundwater, and cleaning volatile organic compounds (VOCs) from air.
However, the application of computational approaches to nanomedicine is yet underdeveloped and is an exigent area of research. The need for computational applications at the nano scale has given rise to the field of nanoinformatics.
Powerful machine-learning algorithms and predictive analytics can considerably facilitate the design of more efficient nanocarriers. Such algorithms provide predictive knowledge on future data, have been mainly applied for predicting cellular uptake, activity, and cytotoxicity of nanoparticles.
Data mining, network analysis, quantitative structure-property relationship (QSPR), quantitative structure–activity relationship (QSAR), and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictors are some of the other prominent property evaluations being carried out in nanoinformatics.
Nanoinformatics has provided a major supplementary platform for nanoparticle design and analysis to overcome such in vitro barriers. Nanoinformatics exclusively deals with the assembling, sharing, envisaging, modeling, and evaluation of significant nanoscale level data and information. Nanoinformatics also facilitates chemotherapy by improving the nano-modeling of the tumor cells and aids detection of the drug-resistant tumors easily. Hyperthermia-based targeted drug delivery and gene therapy approaches are the latest nanoinformatics techniques proven to treat cancer with least side effects [ 51 ].
The progress of nanoscience and nanotechnology in different fields of science has expanded in different directions, to observe things from micro to nano, to even smaller scale sizes by different microscopes in physics, from micro size bulk matter to small size carbon dots in chemistry, from room size computers to mobile slim size laptops in computer science, and to observe deeply the behavior of the cell′s nucleus to study single complicated biomolecules at the nano level in biological science. All these progressions in different fields of science have been generally overviewed and summarized in Figure 9 .
Progress in nanoscience and nanotechnology in different fields of science.
In only a few decades, nanotechnology and nanoscience have become of fundamental importance to industrial applications and medical devices, such as diagnostic biosensors, drug delivery systems, and imaging probes. For example, in the food industry, nanomaterials have been exploited to increase drastically the production, packaging, shelf life, and bioavailability of nutrients. In contrast, zinc oxide nanostructures display antimicrobial activity against food-borne bacteria, and a plethora of different nanomaterials are nowadays used for diagnostic purposes as food sensors to detect food quality and safety [ 52 ].
Nanomaterials are being used to build a new generation of solar cells, hydrogen fuel cells, and novel hydrogen storage systems capable of delivering clean energy to countries still reliant on traditional, non-renewable contaminating fuels.
However, the most significant advances in nanotechnology fall in the broad field of biomedicine and especially in cancer therapeutics because of their great potential to offer innovative solutions to overcome the limitations deriving by traditional chemotherapy and radiotherapy approaches.
Recent advances made in the fields of physic, chemistry and material sciences have provided a number of nanomaterials with unique properties, which are expected to improve the treatment of many tumors otherwise resistant to current therapies. This will be possible by merit of their intrinsic cytotoxic activity and/or because of their capability to act as nanocarriers to deliver therapeutic molecules, such as drugs, proteins, nucleic acids or immune agents. These innovative biomedical applications are currently exploited in a variety of clinical trials and, in the near future, may support major development in the therapy of cancer.
In 2018, the budget for NNI was 1.2 billion dollars ($) to support nanoscience, engineering and technology. Still, scientists are working for new breakthroughs in nanoscience and nanotechnology in order to make human life easier and more comfortable.
In this context, Table 1 presents the historical development of nanoscience and nanotechnology.
Evolution Timeline of Nanoscience and Nanotechnology.
Authors are thankful to Fondazione AIRC per la Ricerca sul Cancro for funding.
Conceptualization, S.B. and F.R.; writing—Original draft preparation, S.B.; writing—Review and editing, S.B., M.A., T.T., and M.C.; supervision, F.R. All authors have read and agreed to the published version of the manuscript.
This research was funded by AIRC IG 2019 (No.23566).
Conflicts of Interest
The authors declare no conflict of interest.
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Editorial article, editorial: insights in nanobiotechnology 2022/2023: novel developments, current challenges, and future perspectives.
- 1 Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Pontedera, Italy
- 2 RCSI University of Medicine and Health Studies, Chemistry Department, Dublin, Ireland
Editorial on the Research Topic Insights in nanobiotechnology 2022/2023: novel developments, current challenges, and future perspectives
The Research Topic “ Insights in nanobiotechnology 2022/2023: novel developments, current challenges, and future perspectives ” is an annual Research Topic featuring peer reviewed reviews, opinion papers, and research articles that looks to explore new insights, novel developments, current challenges, latest discoveries, recent advances, and future perspectives in the field of Nanobiotechnology. Among the 10 peer reviewed manuscripts published in the framework of this Research Topic, we have four Original Researches, three Reviews, one Mini-Review, and two Opinions.
Testa et al. report on a whole transcriptomic analysis of stem cells cultured on microfabricated scaffolds, named “Nichoids”, showing as stemness is preserved with respect to traditional 2D cultures, highlighting the important implication this culture approach owns for different applications in biomedicine.
Moving to the fields of nanoparticles for theranostic applications, Ota el al. present an innovative strategy for liposome preparation, comparing its performance, in terms of encapsulation efficiency, drug loading, lamellarity, and user-friendliness with a commonly used microfluidic device.
Jakl et al. show a novel approach for large-scale manufacturing of small extracellular vesicles (EVs) from bone marrow-derived mesenchymal stromal cells. EVs are membrane-surrounded nanostructures secreted ubiquitously by cells, i.e. , “cellular nanoparticles” mediating communication among cells and containing hundreds of molecules, including miRNA, proteins, DNA, and lipids. These molecules work synergistically to activate multiple cells, and thus EV-based therapy is considered as the next-generation of stem cell therapy.
The last Original Research, from Rudi et al. is instead focused on the effects citrate-stabilized gold and silver nanoparticles on cultures of microalgae. These nanomaterials resulted to be a stress factor for red microalga Porphyridium cruentum, causing significant changes in both biotechnological and biomass safety parameters, and leading to an enhanced lipid accumulation and reduced malondialdehyde values in the biomass.
Coming to reviews, Mobeen et al. depict an overview of the emerging role of nanotechnology in immunology, highlighting novel theranostic immunological applications of nanomedicine. Yang and Tel , instead, presents recent advancements in global and local signal generators, highlighting their applications in studying temporal and spatial cellular signalling activity.
The third Review in this Research Topic, from Lin et al. , highlights how nanoplatforms can be tailored for targeted delivery to dendritic cells, thus inducing immune tolerance: this approach envisions great perspectives in the treatment of autoimmune diseases, organ transplantation, and allergic diseases.
In the mini-review of Porello and Cellesi , the authors provide a nice overview of the state-of-the-art methods for intracellular protein delivery to mammalian cells, highlighting current challenges, new developments, and future research opportunities.
The Opinion paper of Limongi and Susa is focused on one of the major recent challenge faced by the humankind, i.e. , the COVID-19 pandemic. The Authors focused their attention on how much nanobiotechnology contributed and still is contributing to the development of safe and efficient solutions to prevent, diagnose, and treat COVID-19, and any similar infection or pathology.
Lam et al. describes important translational issues in Nanobiotechnology that can be used as theranostics in neurosurgical oncology, highlighting recent advancements in the application of nanoplatforms for fluorescence image-guided brain tumor resection and treatment.
Concluding, we hope this Research Topic could have provided useful cues and insights to the Readers, shedding lights on the most recent development in the application of nanotechnology to biology and human healthcare.
GC: Conceptualization, Writing–original draft. MM: Writing–review and editing.
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Keywords: stem cells, liposomes, extracellular vesicles (EVs), nanoparticles, immunology, pandemic (COVID-19), neurosurgery
Citation: Ciofani G and Monopoli MP (2023) Editorial: Insights in nanobiotechnology 2022/2023: novel developments, current challenges, and future perspectives. Front. Bioeng. Biotechnol. 11:1331760. doi: 10.3389/fbioe.2023.1331760
Received: 01 November 2023; Accepted: 06 November 2023; Published: 10 November 2023.
Edited and reviewed by:
Copyright © 2023 Ciofani and Monopoli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Gianni Ciofani, [email protected]
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The miniaturization of science and engineering is just one aspect of the many ways that the rapidly expanding ﬁeld of nanotechnology promises to revolutionize the landscape of science, technology, and society. With potential applications stretching across the wide spectrum of research and development in consumer electronics and cosmetics, drug development and delivery in the pharmaceutical industry, medical technologies and therapeutics, energy production and storage, environmental engineering and remediation, industrial manufacturing, and textile production, nanoscience and nanotechnologies have demonstrated breathtaking potential. Some of its most ardent supporters project the future of this technology even more optimistically. Others disagree, suggesting that hype surrounding speculative nanotechnology is well beyond the plausible potential of the technology and seems more at home in science ﬁction novels and ﬁlms. This research paper explores the developing ﬁeld of nanotechnology and given its vast potential considers whether there are inherent concerns or dangers in the utilization of these technologies. Additional attention is given to ethical considerations and implications of these technologies, as well as to policy questions that are raised with respect to regulating nanotechnology for the public good.
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Few areas of research and development have captured the imagination with the potential for such broad impact and implications as has nanoscience and nanotechnology. Applications for nanotechnology cross such disparate ﬁelds of research, development, and production as materials science (with agricultural, industrial/manufacturing, and textile applications), energy production, environmental sciences, information and communication technologies, cosmetics, healthcare (with diagnostics, drug delivery, gene therapy, and potential contributions to regenerative medicine), and the possibility of futuristic applications with nanobots and nanotechnology assemblers. As of late 2014, an inventory by the Woodrow Wilson Center identiﬁed over 1,800 consumer products containing nanoscale materials (Project on Emerging Nanotechnologies 2014).
“Nanoscale technology” or “nanotechnology” generally refers to the products of science and engineering that seek to understand and control matter at the nanoscale level. While deﬁnitions of the terminology are not universally agreed upon, the U.S. National Nanotechnology Initiative (NNI n.d.) deﬁnes the “nanoscale” as the “dimensional range of approximately 1–100 nm” (a nanometer is one-billionth of a meter). Comparatively, a sheet of paper is roughly 100,000 nm thick. The ability to manipulate and control materials at the nanoscale level offers a variety of promising and wide-ranging applications. From enhancements to already existent consumer products to advances in industrial manufacturing to regenerative medicine and the possibility of futuristic applications, nanotechnology has the potential to revolutionize far-reaching aspects of human life. Strong proponents of the future of these technologies offer visions that seem to stretch the limits of credulity and posit applications that may seem more at home in science ﬁction novels and ﬁlms. Such proposals have led others to charge that this very promise has led to unreasonable research hype and speculations, and thus critics within the research and ethics communities increasingly are calling for more chastened projections of potential research deliverables, as well as what they claim are more “realistic” potential beneﬁts.
As an area of emerging technology, nanotechnology (at least in its formal use of nanoscience) and the corresponding ﬁeld of nanotechnology ethics (or nanoethics) are relatively recent developments of the 1990s with much of their growth occurring within the early years of the twenty-ﬁrst century. The purpose of this research paper is to explore the historical background leading to contemporary research, development, and product release of nanotechnologies; clarify key terminology; examine recent, near future, and speculative applications of these technologies; and conclude with a discussion of various ethical considerations raised by nanotechnologies.
“Nanotechnology” was ﬁrst coined in 1974 by the Japanese researcher Norio Taniguchi “to mean precision machining with tolerances of a micrometer or less” (Voss 1999). While this marked the ﬁrst known usage of the term, the formal discipline of nanoscience is indebted to the work of Richard Feynman, a physicist who speculated in a 1959 presentation “There’s Plenty of Room at the Bottom.” In his talk, Feynman (1960) explored the possibility of printing the entire 24 volumes of the Encyclopedia Britannica on the head of a pin, thus requiring the equivalent of an electron microscope to read the nanometer-scale transcription. Feynman speculated on the ability to manipulate material at the atomic and molecular level to create what would later be referred to as nanoscale devices or nanomachines utilizing a “bottom-up approach” (O’Mathúna 2009). This “bottom-up approach” of nanoscale assembly is often contrasted with a “top-down approach” that seeks to apply larger-scale manufacturing techniques and principles at increasingly smaller scales (Navarro and Planell 2012; Mitchell et al. 2007). Feynman’s 1959 presentation advanced possibilities that would characterize both approaches.
Eric Drexler’s 1986 volume Engines of Creation was instrumental in introducing nanotechnology into public awareness and the ensuing policy discourse. In his work, Drexler revisited the two approaches to the miniaturization of research by contrasting “bulk technology”– similar to a “topdown approach” – with that of “molecular technology” – similar to a “bottom-up approach” and interchangeable with the term “nanotechnology” (Drexler 1990). In describing these two technologies, Drexler notes that previous technologies that moved “room-sized computers” to silicon chips relied upon the older model of bulk technology, while molecular technology will allow for the possibility of precision devices made of “nanocircuits and nanomachines” (Drexler 1990). Within the nanoscience and nanotechnology research community, Drexler’s promotion of nanobots and self-replicating nanoassemblers has had a polarizing effect resulting in a division between those who focus on the near-term potential of nanotechnology (based upon strides that have already been made and are perceived to be likely outcomes from current research capabilities) and those who take a more futuristic or speculative approach to nanotechnologies. Such speculative approaches often advance the idea of increasing convergence of emerging technologies to promote such possibilities as radical life extension, human enhancement and augmentation, cryonics, and attempts to guide the future of human evolution (O’Mathúna 2009).
One of the oldest known applications of nanotechnology dates back to the fourth-century Roman Lycurgus Cup made of dichroic glass. Housed in the British Museum, this cup contains metal nanoparticles in the glass which alter its color when held up to a light source (O’Mathúna 2009; Khan 2012). Little is known about how the glassmakers came to utilize these nanoparticles. Later applications throughout history included use of nanoparticles on glass windows (Ireland, mid-ﬁfth century), ceramics (Islamic world and later Europe, ninth to seventeenth centuries), and traditional medicines in South Asia. Furthermore, weapons metallurgy of the thirteenth to eighteenth centuries used carbon nanotubes and cementite nanowires in the making of “Damascus” saber blades (Khan 2012).
A major breakthrough in contemporary nanotechnology research occurred in 1985 with the creation of a new form of carbon known as the buckminsterfullerene or more commonly a “buckyball” (also bucky-ball) due to its resemblance to a soccer ball. The buckyball was followed in 1991 with the related development of carbon nanotubes. Due to their unique structure, carbon nanotubes were viewed as a major development for materials science, as they are approximately “60 times stronger than steel and capable of conducting electricity 1,000 times better than copper” (Khan 2012).
Nanotechnology Themes In Fiction
Given the potential of nanotechnology, it is no surprise that it has also captured the attention of science ﬁction authors. The value of ﬁction and ﬁlm to philosophy, ethics, and medicine has been on the rise in the past decade with increased attention given to the contributions of the medical humanities and its role in education. Examples of nanotechnology in science ﬁction range from cautionary tales such as Michael Crichton’s 2002 novel Prey of an uncontrolled nanotech swarm to classic works such as Isaac Asimov’s Fantastic Voyage with its miniaturized machines (O’Mathúna 2009). Likewise, William Gibson’s The Peripheral (2014) explores two futures in which the technology of 3-D printing gives way to the proliferation of self-replicating nanoassemblers, demonstrating an interesting progression of possible technological evolution.
Perhaps the most direct connection between science ﬁction and bioethics is that nanotechnology and similar technologies offer “science ﬁction authors the opportunity to make predictions about what is to come and to issue warnings” (O’Mathúna 2009). Such “speculative ethics” may project and support either dystopian or utopian conceptions of the future. Nordmann (2007) and others counter that such speculative approaches treat imagined futures as if they already exist and thereby displace actual presenting issues. Balancing ethical reﬂection of existing nanotechnologies with anticipating futuristic applications of nanotechnologies is a delicate task. As with all rapidly evolving arenas of emerging technologies, merely setting aside the speculative dimension of potential applications seems to ignore the length of deliberation necessary to implement appropriate policy and regulatory regimes so as to avoid both conceptual and policy vacuums. Technology assessment and ethical analysis of emerging technologies such as nanotechnologies are perhaps necessarily speculative endeavors. However, an appropriate caution must be raised to prevent the conﬂation of hypotheticals with presenting technologies in such ethical discourse.
Funding And International Research And Development
The U.S. government took an early lead in funding research and development of nanoscience and nanotechnology, launching what would eventually become the NNI in the late 1990s during the administration of President Bill Clinton. Recognizing the value of a coordinated federal effort for nanotechnology research and development, in 2003 President George W. Bush signed into law the 21st Century Nanotechnology Research and Development Act (NNI n.d.). Initial U.S. government funding of $464 million in 2001 quickly grew to nearly $2 billion in 2010, with 2015 budget allocations for the NNI set at more than $1.5 billion (NNI n.d.). In addition to the federal funding provided by the NNI, both state-level and private funding are substantial supplements to U.S. research initiatives in nanotechnology. Cumulative NNI investment from 2001 to 2015 is estimated at approximately $21 billion.
The European Commission has likewise taken “a leading and coordinating role in nanoscience and nanotechnology development in Europe,” as well as individual governmental support from several EU member states that invest directly in research and development such as the United Kingdom, Germany, France, and others (Malsch and Emond 2014). The European Commission in 2007 had allocated approximately EUR 600 million through its Seventh Framework Programme (FP7) for research in the areas of nanomedicine and nanomaterials (Navarro and Planell 2012). Similarly, signiﬁcant research initiatives in Australia, Japan, and South Korea as well as in numerous emerging economies such as Brazil, Argentina, Russia, India, and China demonstrate the global involvement of research investment in nanoscience and nanotechnology research, infrastructure, and development.
As noted earlier, “nanotechnology” refers to the products of science and engineering that seek to understand and control matter at the nanoscale level. The interest of studying and manipulating materials at the nanoscale level is that such materials exhibit novel properties that are distinct from larger scales of the same materials.
While the upper limit of 100 nanometers (nm) is commonly used, some have noted the lack of scientiﬁc evidence to justify such a demarcation in that some materials exhibit similar properties at larger scales and, thus, have proposed an alternative dimensional range of 1–1,000 nm (O’Mathúna 2009). The U.S. Food and Drug Administration (FDA) in a 2014 industry guidance suggests the consideration of those materials with dimensions outside of the nanoscale but which may demonstrate “novel properties and phenomena similar to those seen in materials with dimensions in the nanoscale range” and thus proposes an upper limit of 1 mm (1,000 nm) for regulation (FDA 2014). Others such as the European Commission have proposed more functional deﬁnitions that focus on controlling “the structure and behaviour of matter at the level of atoms and molecules” rather than emphasizing speciﬁc size ranges (European Commission 2014; Khan 2012). As O’Mathúna (2009) notes, part of the challenge to precisely deﬁning the boundaries of nanotechnology is that within the nanoscale range, “a unique combination of quantum and macroscale effects converge to give nanoparticles their unique and interesting properties,” particularly as they interact with cells and living tissues to “permeat[e] the impermeable.”
The UK’s Royal Society and Royal Academy of Engineering have emphasized the distinction between “nanoscience” and “nanotechnology.” The former is “the study of phenomena and manipulation of materials at atomic, molecular and macromolecular scales, where properties differ signiﬁcantly from those at a larger scale” (The Royal Society and The Royal Academy of Engineering 2004; ten Have 2007). The latter is “the design, characterization, production and application of structures, devices and systems by controlling shape and size at nanometer scale.” Furthermore, given the range of disciplines and applications covered by nanoscience and nanotechnology research, ten Have (2007) and others suggest that “nanotechnologies” is a more accurate term to designate the ﬁeld. With their potential impact, nanotechnologies have been deemed by many to be not only enabling technologies but also transformative or disruptive technologies, capable of altering a disciplinary landscape or aspect of technology and society (Jotterand 2008).
Nanotechnologies are available in a variety of applications, of which nanoparticles, carbon nanotubes, and nanobiosensors are some of the most common. As noted earlier, one of the oldest and most widely utilized nanotechnologies is nanoparticles. Some of the most commonly used types of nanoparticles are gold nanoparticles, magnetic nanoparticles, and a semiconductor nanocrystal referred to as a quantum dot (Navarro and Planell 2012). In contrast to their bulk material counterparts (generally those materials larger than 1 mm), nanoparticles exhibit novel properties (e.g., color, reactivity, conductivity, melting point, hardness, etc.) that introduce potential uses beyond those of their bulk counterparts. Nanoparticles are being utilized or researched for use in cosmetics, surface coatings for manufacturing and textiles, diagnostics, environmental remediation, energy production, as well as numerous medical applications.
One of the early developments in contemporary nanotechnology was the creation of carbon nanotubes (CNTs). In addition to their strength and conductivity, CNTs demonstrate an impressive ﬂexibility in the structures that may be formed and thus the diversity of types that may be created. CNTs have shown signiﬁcant potential for advances in materials science, electronics, energy production and storage, environmental remediation, and medical applications, particularly drug delivery and bone tissue engineering. Despite their promise, the unique structure of CNTs raises concerns about potential toxicity issues, particularly the potential for respiratory contamination (Malsch and Emond 2014; O’Mathúna 2009). Broader adoption of CNT technology will depend upon further research to examine under what conditions, if any, CNTs pose a serious risk to the health of humans and/or other living organisms.
Nanobiosensors are a nanoscale detection tool for biological or chemical materials. One category of nanobiosensors includes MEMS (microelectromechanical sensors), which have been proposed as a kind of smart dust for military and environmental applications, or even medical monitoring. MEMS also may refer to the broader category of nanotechnologies referred to as microelectromechanical systems, which include sensor technologies. Nanobiosensors or MEMS could be set to wirelessly transmit information allowing for the possibility of real-time detection or tracking capabilities. Other types of nanoscale sensors include nanoﬂuidic arrays and protein nanochips for analysis of chemical materials or even DNA.
MEMS and the broader category of nanobots (or nanorobotics) and nanites or nanoassemblers represent futuristic forms of nanotechnologies. Speculative uses envision nanobots injected into the bloodstream as medical diagnostics, releasing drugs on demand, and performing nanoscale surgeries to repair the body. Self-replicating nanoassemblers are posited as the future of materials science for construction and product manufacturing, disrupting contemporary models through the nanoscale equivalent of 3-D printing. At present, these potential applications remain the purview of speculative nanotechnologies, despite their popular adoption in many science ﬁction works.
Current And Potential Applications
Given that nanotechnologies are so wide ranging in their impact and applications, what follows is merely a sampling of the various developments in recent years with relevant comments to areas of active inquiry.
A number of the early advances due to nanoscience and nanotechnology were actually the result of the development of nanoscale instrumentation. New instruments capable of measurements at the subcellular level have led to expansion in the understanding of fundamental biological processes (Navarro and Planell 2012). Developments in instrumentation include the 1981 invention of the scanning tunneling microscope (STM). STM permitted images of individual atoms 5 nm in size and was the ﬁrst of several scanning probe microscopes signiﬁcantly to improve the power of instrumentation to study materials at the nanoscale level, leading to later developments such as the atomic force microscope (O’Mathúna 2009; ten Have 2007).
Medical And Pharmaceutical
Nanodelivery systems that utilize encapsulation or coatings with additives allow for increased absorption of pharmaceutical drugs or nutrients such as vitamins, which permits lower dosages and potentially fewer side effects. Due to their ability to pass through cell membranes, carbon nanotubes in particular have demonstrated promise as drug delivery mechanisms (Navarro and Planell 2012; Malsch and Emond 2014). Carbon nanotubes also are generating research interest as potential scaffold material for tissue engineering (Malsch and Emond 2014).
One of the novel properties of nanoparticles, with various medical applications, involves electromagnetic spectrum reactions that result in the vibration or heating of nanomaterials. One such application would be a type of precision tumor surgery involving gold nanoparticles injected directly into a tumor or delivered as part of a drug dosage to enter cancer cells. Several studies have demonstrated the potential for such delivery mechanisms, and when coupled with low-energy laser pulses, the gold nanoparticles caused the cancer cells to explode while leaving surrounding cells unharmed (Evans 2008).
Beyond individual therapeutic interventions, much optimism surrounds the potential of nanotechnology to advance the ﬁeld of regenerative medicine. In the goal to repair, replace, or regenerate damaged tissues, William Haseltine and others argue that nanotechnology will play a pivotal role (Navarro and Planell 2012). The inclusion of nanotechnology is often seen as the ﬁnal phase of regenerative medicine, permitting nanoscale examination and analysis of biological structures as well as bottom-up construction of artiﬁcial organs and tissues. Research in this area is often classiﬁed as “nanobiotechnology” and deﬁned as a ﬁeld of inquiry that “applies the nanoscale principles and techniques to understand and transform biosystems (living or non-living) and which uses biological principles and materials to create new devices and systems integrated from the nanoscale” (Navarro and Planell 2012). In this respect, nanobiotechnology shares similarities in the application of engineering methodologies employed in genetic engineering (or, more recently, gene therapy) and synthetic biology.
Agricultural And Environmental
Agricultural and environmental applications hold the promise of promoting global equity both in food production, sanitation, and availability of clean water. Additives and engineered nanomaterial (ENM) coatings have the potential to serve as delivery mechanisms for fertilizers, pesticides, and veterinary medicine. Furthermore, such coatings could be applied on packing materials (e.g., silver nanoparticles for antimicrobial protection) to increase longevity of food storage and reduce spoilage (Malsch and Emond 2014). Other potential applications include nanobiosensors – sometimes referred to as “labon-a-chip” technology – to detect food spoilage for improved process monitoring or the presence of environmental contaminants. The combination of nanobiosensors with other technologies such as RFID (radio-frequency identiﬁcation technology) to tag materials or other data communication technologies would allow for such technologies to work in nanosensor networks. Such interaction between technologies would permit the nanobiosensors to report the quality of food products throughout the entire distribution process including at the checkout counter or even a refrigerator (Malsch and Emond 2014).
Another prospective application is environmental remediation to remove pollutants. One such example would be the utilization of various nanotechnologies to assist in water puriﬁcation (Evans 2008) or the removal of air pollutants such as carbon dioxide (Malsch and Emond 2014). Particularly promising for water puriﬁcation are nanoﬁltration membranes, nanomagnets, and magnetite nanoparticles (Evans 2008; see also Street et al. 2014; Malsch and Emond 2014). Other environmental applications could include nanobiosensors as air or water monitoring systems to identify contaminants.
Like nanotechnology, nanoethics (or nanotechnology ethics) is a relatively recent development within the realm of applied ethics. Similar to other bioethical subspecialties (e.g., neuroethics, genetic ethics), scholars debate if nanoethics represents the development of a distinct subﬁeld of bioethical inquiry with unique considerations. Some have argued that it is merely a topical specialization that overlaps in its ethical considerations with several other emerging technologies and developments in biotechnology. Robert McGinn, for instance, has responded with skepticism that current evidence does not suggest that nanotechnology raises qualitatively new ethical issues and thus is best regarded as a “subﬁeld of bioethics” (Khan 2012). Similarly, ten Have (2007) and others have noted that only further developments in nanotechnologies will clarify whether nanoethics emerges as a unique “subdiscipline.”
Hype And Scientific Promise
Particularly within Western countries, the current academic research environment has resulted in criticisms of ethics and research practices. One of these criticisms includes the increasing challenges presented by hype in individual research applications or budgetary proposals for entire ﬁelds of inquiry due to the increasingly competitive environment to procure grants and other funding. This activity may take multiple forms, such as exaggerating “a project’s feasibility, likely results or signiﬁcance” with regard to beneﬁts (McGinn 2010). Such hyping of research may also lead to media distortion in coverage of new technologies. While media distortion is not solely the result of hype within the research community, continued “researcher participation in or endorsement of media coverage of scientiﬁc or engineering developments that turns [sic] out to be distorted can dilute public trust and foster public misunderstanding of science and engineering” (McGinn 2010; see also Jotterand 2008; Cameron and Mitchell 2007). Such activities become counterproductive to active public engagement of such complex emerging technologies by impeding ethical considerations in the public deliberation process.
Risk, Unintended Consequences, And The Precautionary Principle
While the potential for nanotechnologies is vast, they pose threats similar to that of other realms of biotechnology and emerging technologies (e.g., gene therapy, genetically modiﬁed organisms, synthetic biology, and artiﬁcial life). With each of these ﬁelds, there is a threat potential for catastrophic consequences such as the mass destruction of nature and/or human life (Mitchell et al. 2007). Given the scale in which nanotechnology functions, disasters involving environmental contamination with an impact upon the water and food supply could be particularly damaging and may prove difﬁcult to resolve. While we should not equate science ﬁction with plausible outcomes, such scenarios (as, for instance, Neal Stephenson’s novel Diamond Age) regularly project futures in which environmental nanotechnology pollution has become the norm. Risk assessment for effects on environment, health, and safety (EHS) must be carefully considered and guarded against given the challenges for both detecting and removing nanotechnology materials (Khan 2012).
Potential futuristic applications of nanobots and nanoassemblers have given rise to concerns among even the most ardent supporters of nanotechnologies. The potential of an accident with self-replicating nanotechnologies could lead to something that “could easily be too tough, small, and rapidly spreading to stop” (Drexler 1990). Often referred to as the gray goo problem (or grey goo scenario), widespread environmental disasters resulting from an accident with nanotechnology have generally been “downplayed as an unlikely concern” (Mitchell et al. 2007). The potential for environmental contamination remains, however, and subsequent regulations and policies should be examined that promote due diligence on the part of individuals and corporations before releasing such materials publicly.
Such considerations may entail the need for strategies on containment, detection, and inactivation of nanotechnologies (Mitchell et al. 2007). At the very least, efforts must be made to facilitate open dialogue between governmental bodies, the general public, as well as those individuals and corporations pursuing release of nanotechnology. Such parties need to be actively engaged in discussions of “risk analysis, risk management, and acceptable options for risk transfer” (Cameron and Mitchell 2007). Nanotechnology presents particular challenges for constructing accurate threat matrices due to uncertainty regarding potential toxicity and pollution and for the near future will continue to present particular challenges for risk management and insurers. Clear priority must be given in nanoscience to study these aspects of potential risks, alongside traditional emphasis on discovery. Most models of risk analysis and risk management are based on “evolutionary developments” within a given ﬁeld. In emerging areas such as nanotechnology that mark “revolutionary” or transformative changes in which “potential for damage cannot be assessed,” one must carefully distinguish between those “potential risks related to events attributable to a cause” (i.e., real risks) as opposed to “those whose causality merely cannot be excluded” – so-called phantom risks (Cameron and Mitchell 2007; cf. Jotterand 2008).
Deb Newberry suggests several factors that must be assessed to determine potential harm “to humans, ﬂora, and fauna” (Khan 2012). Those factors include (1) Element Type: the primary compositional elements and their impact or toxicity on living organisms, (2) Object Size: the mass and/or volume of the material that may be present, (3) Total Number of Objects: total amount of the material present, (4) Object Shape: may determine the potential harm to certain organs even if the element type is compatible, (5) Time in System: length of interaction within a living system, (6) Life Cycle and Length of Exposure: life cycle of the material, (7) Method of Entry: how the material enters the life system (e.g., air, ﬂuid, injected, absorbed), and (8) Purity: residual chemicals or artifacts that remain on or in the material that result from the manufacturing process (Khan 2012). Each of these factors may assist in determining the potential harm or beneﬁt that may result from the presence of nanomaterial within a life system provided that the impact of such factors is established in the relevant research.
The importance of thorough knowledge of the effects of nanomaterials on living systems and the relative infancy of this ﬁeld demonstrates the need for caution. Furthermore, given the novel properties that exist at the nanoscale level, previous knowledge of bulk properties or the properties of microor macroscale materials may offer little guidance with respect to potential toxicity or harm (Malsch and Emond 2014). One example would be gold, which at the macro level (e.g., in jewelry) offers very low toxicity, good stability, low reactivity, and well-established properties. In contrast, the properties of gold nanoparticles are still being established, with variable melting temperature and higher reactivity, and thus may pose risks for human health (Khan 2012; Malsch and Emond 2014; O’Mathúna 2009). Given the size of nanoparticles, a potential health concern is the possibility that if they enter the human bloodstream, their size would enable them to cross the blood–brain barrier. This is not just an idle concern as buckyballs have been shown to cause damage in the brains of some aquatic animals (O’Mathúna 2009).
Unintended consequences are often examined with respect to short-term effects, but long-term consequences also may result that are not properly anticipated or thoroughly considered. One such example of an unintended consequence is that nanoparticles may exit the body of animals or humans as waste and be introduced into the environment indirectly. Environmental contamination could result both from direct release of nanoparticles having an unintended consequence or through indirect means such as being introduced as a waste by-product. Indirect means of contamination have important parallels with certain pharmaceutical drugs in which trace amounts have made their way into water supplies. Environmental public health is an emerging ﬁeld that is leading the way in studying the effects of these developments and may play an increasingly important role with the release of rising numbers of products involving nanomaterials. Of course, not all consequences are necessarily harmful, and an unintended consequence of a new material may be beneﬁcial.
In the midst of uncertain risk, the precautionary principle is typically invoked. In its common understanding, this principle “demands the proactive introduction of protective measures in the face of possible risks, which science at present (in the absence of knowledge) can neither conﬁrm nor deny” (Cameron and Mitchell 2007). Care must be taken in the invocation of the precautionary principle so as to avoid stiﬂing technological innovation. However, in the case of revolutionary technologies, the precautionary principle offers a conceptual framework to advance cautiously in their research, development, and commercialization until real risks can be distinguished from phantom risks and such real risks are analyzed and appropriately managed.
Role Of Technology Assessment
Beyond the more narrow areas of risk assessment and analyses to assess effectiveness and economic impact, emerging technologies such as nanotechnologies should also account for the broader context of technology assessment. Accordingly, ten Have (2007) has noted that technology assessment should include a “broader conception” that takes into consideration “the social and ethical consequences of technologies.” This broader conception may include an examination of “the value judgments at play in recommendations and determine if and how those recommendations were not simply scientiﬁc but also normative” (ten Have 2007). Such considerations go beyond the technology itself in its technical dimensions to examine values that are underlying or inherent within the technologies or to assess whether the technologies are “justiﬁed in the light of moral values” (ten Have 2007).
In the case of nanotechnologies, some bioethicists have raised concerns similar to those of genetic engineering and synthetic biology, in that the attempt to control or manipulate nature at the atomic or molecular level instrumentalizes nature, emptying nature of any intrinsic value or ontological reality. Through this instrumentalization, nature becomes mere artiﬁce. Those aspects of nanotechnology that exhibit a drive for mastery and control of nature and/or human nature, and particularly those that seek convergence with other emerging technologies as part of a transhumanist or posthumanist paradigm, may be open to such critiques. Nanotechnologies themselves need not be guilty of such critiques, particularly those that emerge from a top-down approach. Yet, given the engineering model that is applied to areas such as synthetic biology, nanotechnologies that emerge from a bottom-up approach may be vulnerable to such concerns.
Donald Evans (2008) suggests the relevance of two articles from UNESCO’s Universal Declaration on Bioethics and Human Rights for assessing nanotechnologies, particularly their impact on future generations and protection of the environment in human interactions. Article 16 of the Declaration states, “The impact of life sciences on future generations, including on their genetic constitution, should be given due regard” (UNESCO 2006). Article 17 goes on to note, “Due regard is to be given to the interconnection between human beings and other forms of life, to the importance of appropriate access and utilization of biological and genetic resources, to respect for traditional knowledge and to the role of human beings in the protection of the environment, the biosphere and biodiversity” (UNESCO 2006). Both articles point to the importance of broader considerations in the assessment of emerging technologies such as nanotechnologies.
Informed Consent And Privacy
While the issues of informed consent are not unique to nanotechnology, they do raise important considerations for how such technologies will be introduced for human use. Given the potential for environmental contamination and other public health risks, such consent discussions often include the importance of engaging the general public at least through education but also through public commenting and deliberation. Informed consent presents particular challenges when so little is understood on toxicity, particularly for early experimental use in humans or the widespread commercial use of nanoparticles, the long-term effects of which are not well understood. One need only look to the introduction of titanium dioxide and zinc oxide nanoparticles in sunscreen as an example of when nanotechnologies are introduced into a consumer product without adequate public education or without fully exploring potential risks.
Additional considerations for diagnostic nanotechnologies such as biosensors involve the issue of privacy and control of information that may result. Again, while not unique to nanotechnologies, the potential for the ubiquity of such sensors (e.g., smart dust or medical monitoring) raises important considerations regarding data privacy, data protection, and other issues such as a potential “right to know” or “right to not know” (Jotterand 2008). When combined with DNA detection and analysis, these diagnostics introduce all of the privacy considerations relevant to genetic testing and screening.
Nanotechnologies, Converging Technologies, Regenerative Medicine, And Human Enhancement
Nanotechnologies and convergence frequently appear together in discussions of emerging technologies. In 2002, the National Science Foundation and U.S. Department of Commerce commissioned the report Converging Technologies for Improving Human Performance that introduced the acronym NBIC (nanotechnology, biotechnology, information technology, and cognitive science). The report argued that these previously disparate technologies were increasingly converging and would coalesce to improve health, overcome disability, and even permit human enhancement and posthuman technologies. Other convergence proposals include GRIN (genetic, robotic, information, and nano processes) and some variation of the preceding ﬁelds in conjunction with neuroscience and/or artiﬁcial intelligence research.
The convergence of such emerging technologies may open exponential leaps forward in regenerative medicine but more modestly will exacerbate already existing medical challenges regarding the distinction between therapies and enhancements. One particular issue is the challenge to clearly distinguish when nanotechnology is therapeutic and when it would be an enhancement. The traditional role of medicine has been to use biomedical technologies and interventions to repair or restore, rather than to enhance or make one “better than well.” The goals of regenerative medicine open the possibility for remarkable medical interventions, but such interventions will likely have inherent capacity for dual use, permitting both therapeutic and enhancement use. Speculative proposals for nanotechnology use extend these medical interventions to include radical life extension research and cryonics. Beyond the speculative proposals for nanotechnology, O’Mathúna (2009; ten Have 2007) and others have raised the concern that nanomedicine will contribute to the increasing challenges already presented by trends toward medicalization.
The role of nanotechnologies along with other converging technologies raises important considerations into the ontological status of living organisms and living systems, including human beings. Possibilities of convergence between nanotechnologies and neuroscience or nanotechnologies and genetics raise important considerations of human identity, the limits of human nature, and ultimately what constitutes the status of being human or, in other words, human nature itself (Jotterand 2008). Considerations such as discussion of the common good, human ﬂourishing, and human futures should be brought to bear in an analysis of converging technologies and human enhancement. While perhaps speculative in nature, the possibility of such futuristic technological outcomes should be included as part of a broader analysis of technology assessment when applied to nanotechnologies. These speculative analyses may be distinct from analyses of presenting technologies but should not be ignored in a more complete analysis of nanotechnologies as such.
Nanotechnologies And The Global Context
Finally, within the global context, questions must be raised with respect to just development and use of nanotechnologies, particularly within existing global inequities. Considerations should be given to how such advances in nanotechnologies will help resolve or exacerbate long-standing inequities. The prospect of nanotechnologies to revolutionize the availability of clean water and to expand the shelf life and availability of food and the decreasing expense of improved manufacturing may yield signiﬁcant gains for developing economies with reciprocal potential to improve the median standard of living in such contexts. Yet, these technologies also appear more likely to beneﬁt economically developed countries with respect to intellectual property development and rights from increased patents and further expand such disparities. Additional beneﬁts from nanotechnologies, however, might be seen through signiﬁcant cost reductions in the creation and availability of devices and delivery mechanisms for medical therapeutics and advances in industrial manufacturing. The rapid adoption of mobile communication technologies drastically improving access to global data and communication networks serves as an example of closing a disparity, which global development of nanotechnologies may well follow. Global justice considerations also have been a key component of nanoethics with a common proposal that research funding should privilege those areas of nanotechnology research and development that will have the most signiﬁcant impact for developing countries. Unfortunately, realization of such funding priorities has been modest at best.
Relevant regulatory regimes are also implicated. Setting appropriate regulatory regimes and policy guidelines within individual countries presents particular challenges given the typically slow regulatory and legislative processes and the rapid pace of technology development. Furthermore, the international context for developing such guidelines or regulatory protocols presents even more vexing challenges. Self-regulation presents substantive challenges with respect to the nature of the public risks that may be involved. While guidelines for adequate models of risk management and responsibility of risk have slowly emerged, they are not universally agreed upon. Important parallels for such models may be found with the research, development, and commercialization of genetically modiﬁed organisms (particularly genetically modiﬁed produce). Effort for global governance of nanotechnologies has met with minimal results, though international committees and organizations such as UNESCO, the International Bioethics Committee, and the World Commission on the Ethics of Scientiﬁc Knowledge and Technology continue to play important roles in monitoring developments in nanotechnology research for potential beneﬁts and harms, as well as playing signiﬁcant roles in facilitating public education and discourse (ten Have 2007).
Nanotechnologies have demonstrated the potential to transform the landscape of industrial manufacturing, energy production, environmental sciences, information and communication technologies, and medical research. As one of several emerging technologies, nanotechnologies must be carefully examined for their potential beneﬁts, while closely monitoring the temptations of research hype. Careful consideration must also be given to immediate concerns for potential risks as well as examinations of the broader impact of such technologies for considerations of human nature and human futures both in their individual and global dimensions. Proper technology assessment of these technologies must explore not only important considerations of risk assessment for safety and efﬁciency with respect to individual applications but should raise broader considerations so as to anticipate and address conceptual vacuums that may exist within a rapidly evolving ﬁeld of research and development.
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