Source: Based on Makvandi et al. (2020).
1.4 Clinical Translation of Nanomedicine
Prof. Kinam Park of Purdue University has precisely pointed out that “It is time to review the progress made in nanomedicine, and examine the sources of difficulty in clinical translation, and move forward” in the cover story “The beginning of the end of the nanomedicine hype” in Journal of Controlled Release (Park 2019a). The research world of nanomedicine has produced abundant research articles with proof of concept aiming towards the same admirable endings of countless possibilities of nanomedicine. But the enigma around the quantitative data proving its clinical efficacy still prevails. It is time to understand that what we desire is not equivalent to what we have. At this phase, it is also obligatory to shift exorbitant prejudiced focus from smart nanoformulations for treatment of tumors toward investigative endeavors for discovering remedies for other types of diseases like CVS diseases, Parkinson's disease, Alzheimer's disease to name a few. It is necessary to allow and back the clinical production of new, promising formulations for diseases that are not linked to oncology. It is the time to promote the incorporation of nanomedicines into clinical trials of new promising formulations (Park 2019b). Nevertheless, there are numerous and nuanced problems in the clinical translation of nanomedicine (Wu et al. 2020). These include lack of business management education, especially at the academic level; difficulties in carrying out early‐stage preclinical characterization and safety evaluations; absence of protocols and access to characterization facilities; barriers in scale‐up and GMP production; reproducibility and stability of batch‐to‐batch engineered nanocarriers; the absence of adequate controls and badly specified essential quality characteristics; lack of cutting‐edge harmonizing assays and standard principle for toxicity estimation of nanomedicine products; the low quality and durability of the preclinical research that has been published; shortage of appropriate animal models for extrapolating the immunotoxicity data to humans; and complexity and heterogeneity within the regulatory framework (Gabizon et al. 2020; Martins et al. 2020). A key component of an effective clinical translation is the identification of the right patient and matching with the right nanoformulation.
1.5 Nanotoxicological Challenges
Nanoparticles have been commonly used in medicine in recent years, making it important to resolve human health toxicity concerns. These nanostructures generally directly enter into the human body and do not undergo the normal absorption process. The nanocarriers themselves may exhibit toxicity, penetrate the biological membrane barriers, interact with biomacromolecules, and get accumulated in organs or tissues in the human body. This stresses the fact that the toxicological evaluation of nanomaterials is an essential step in the advancement of nanomedicine (SCENIHR 2006). It has been almost more than a decade since the importance of nanotoxicology is realized in nanomedicine just as toxicology in medicine. Nanotoxicology is a developing subfield of toxicology that can be defined as the science of engineered nanodevices and nanostructures that studies the interaction between the physical and chemical properties of nanostructures and biological systems and develops means to prevent such deleterious effects (Oberdörster et al. 2005, 2009). Nanotoxicology research cannot only offer data for the safety evaluation of advanced nanostructures and materials but can also help advance the field of nanomedicine by providing awareness of their hazardous properties and methods of avoiding them. Nanotoxicological issues of nanomedicine include its physicochemical parameters at nanoscale, biological behavior, mechanisms of toxicity, and toxic effects that can be produced within the human body (Gatoo et al. 2014; Warheit and Sayes 2015; Sukhanova et al. 2018) as illustrated in Table 1.2.
Table 1.2 Diverse nanotoxicological concerns of nanomaterials.
Sources: Based on Gatoo et al. (2014), Warheit and Sayes (2015) and Sukhanova et al. (2018).
| Sr. No. | Nanotoxicological issues of nanomaterials | Associated parameters |
|---|---|---|
| 1. | Physicochemical properties of nanocarriers | Particle size and surface area, particle shape, aspect ratio, chemical composition, hydrophilicity and hydrophobicity, surface coating, surface roughness, aggregation and concentration, degradability |
| 2. | Biological behavior of nanomaterials | Protein corona effects, metabolism, distribution, clearance mechanisms, toxicity against cells and tissues of the reticuloendothelial system, therapeutic efficacy, safety |
| 3. | Toxic effects of nanoparticles | Renal toxicity, spermatotoxicity, hepatotoxicity, cardiovascular toxicity, dermal toxicity, neurotoxicity, pulmonary toxicity |
| 4. | Mechanisms of nanoparticle toxicity | Oxidative stress, cell membrane damage, disturbance of intracellular/intercellular transport, accelerate mutagenesis, cell energy imbalance, apoptosis, hindered cell division, disruption of cell, tissue and organ metabolism |
Figure 1.3 Consequences of environmental contact of nanoparticles.
Nanoecotoxicology is a subdiscipline of ecotoxicology that is primarily designed to define and forecast the impact of nano‐sized materials on ecosystems. The quantitative risk assessment of NPs is inadequate owing to unsatisfactory research on the toxicity of nanomaterials to environmentally important organisms. It is indistinct that the structure, aspect ratio, morphology, and various other physicochemical properties have a greater impact on toxicity (Klaine et al. 2008). It must be mandatory to evaluate the NPs for their possible hazard to the environment before their use in products (Oberdörster et al. 2009; Viswanath and Kim 2016; Gaur et al. 2020). To accomplish this aim, to identify exposure, nanoecotoxicology requires taking into account the entry routes and consequences of environmental contact of NPs as shown in Figure 1.3.
Numerous critical toxic characteristics are closely associated with the nano‐size/surface area of the nanomaterials. These include surface properties, physical absorption potential, chemical reactivity, and so on, all of which strongly dominate in vivo nanotoxicological behavior (Fubini et al. 2010). NPs and their biologics, such as proteins, peptides, antibody fragments, and nucleic acids, can act as bases of antigens that can induce an immune response. Its immunogenicity can be influenced by the physicochemical properties of NPs, such as size, surface area, surface charge, hydrophobicity, and solubility. An exceptional type of toxicity owing to surface modification is of distinct apprehension. The capacity for inflammatory activity and oxidative stress is shown to be largely dependent on NPs’ surface chemistry and surface modifications (Azarnezhad et al. 2020). NPs’ toxicity also strongly depends on their shape and chemical composition. Spherical NPs are more susceptible to endocytosis than nanotubes and nanofibers. The calcium channels are commendably blocked by single‐walled carbon nanotubes than spherical fullerenes. The degradation of NPs has been shown to occur, and its magnitude depends on the conditions of the environment, such as pH or ionic strength. The toxicity also relies on the composition of the NPs’ core. Leaking metal ions from the NPs’ core is the most common source of the toxic impact of NPs reacting with cells. Indeed, the toxicity of NPs is determined to a large degree by their chemical