Blind Spots in Development of Nanomedicines

Abstract

The field of nanomedicine demonstrates immense advantages and noteworthy expansion compared to conventional drug delivery systems like tablet, capsules, etc. Despite the innumerable advantages, it holds certain shortcomings in the form of blind spots that need to be assessed before the successful clinical translation. This perspective highlights the foremost blind spots in nanomedicine and emphasizes the challenges faced before the entry into the market, including the need for provision of safety and efficacy data by the regulatory agencies like FDA. The significant revolution of nanomedicine in the human life, particularly in patient well-being, necessitates to identify the blind spots and overcome them for effective management and treatment of ailments.

Conceptual Essay

According to the National Cancer Institute and the regulatory agencies across the globe (FDA, EMA, etc), nanotechnology is defined as the knowledge and control of matter up to 100 nanometre (nm) in dimension where unique phenomenon results in novel applications. The National Nanotechnology Initiative (NNI) mirrors a similar definition ¹ but in pharmaceutical applications, nanoparticles are with a size up to 1000 nm. Medicinal application of nanotechnology in the form of nanomedicine is the transition between conventional macroparticulate (tablet, capsule, pills, etc) and picosize (therapeutic carbon spheres, powders, etc) drug delivery systems. Currently no ideal drug transporters are available due to limitations like insignificant absorption at the target site, poor bioavailability, high first-pass metabolism, inconvenience in preparation of actives, etc. Recently, unprecedented advances in the field of healthcare technology accompanied with nanomedicine is revolutionized owing to the modulation of physiochemical properties of actives such as surface area, surface functional properties, shape, and submicron-dimensional network. Moreover, the field of nanomedicine illustrates noteworthy expansion post-1980 upto 2022, with 234 completed clinical trial studies of nanostructured drug delivery products as per USFDA. ²

Nanotechnology exhibits the ability to transform medical science for various benefits especially in pre-programmed drug delivery systems, rapid computing devices mainly integration with AI, 3D printing, and DNA barcoding techniques for real-time health analysis of patient. ³ Despite innumerable advantages, it holds certain shortcomings like blind spots that are required to be addressed for the development of advanced and novel products with regulatory compliance. Therefore, this perspective will aid researchers to quickly identify the principle blind spots in nanomedicine and provide an overview to advance in the field of nanotechnology-based medicinal products.

Foremost blind spots for clinical translation in field of nanomedicine encompasses following: 1) Practical feasibility for acceptance of physicians’ willingness to shift from conventional oral therapy to parenteral dosing, 2) Lack of viable commercialization and marketability for better patient outcome and quality of life with lesser risks, 3) Inability to achieve clinical potential benefit, 4) Inefficient predictability due to issues of therapeutic efficiency and accurate response rate variation that lead to greater dependence on nanoparticles’ intrinsic properties viz. non-specific interaction with cellular protein, penetration (EPR effect), target localization, bioaccumulation and biodistribution, 5) Preferential accumulation in lymphoid organs and kidney leading to immunotoxicity, hypersensitive reactions, etc and 6) Challenge in monitoring critical key quality attributes for up-scaling and robust manufacturing process in accordance to global/local guidelines.

Submicron-dimensional particulate system of nanomedicines displays diverse accumulation in the tumor. However, insufficient clinical outcomes are often observed due to their inability to overcome intra/inter-patients variability with physiological transport barriers. Significant accumulation of cancer therapeutics in the microenvironment of tumor may be achieved via stimuli-responsive or with active targeting of nanoparticles by using targeted ligands like aptamers (eg Aptamers-based on RNA for HIV glycoprotein), monoclonal antibodies (eg anti-EGFR, anti-Her2), proteins (eg lectins, transferrin), peptides (eg RGD, Arg-Gly-Asp), etc. Despite breakthroughs in therapeutic nanoparticle targeting technology to the tumor tissue, less than 1% injected nanoparticles normally reach the tumor via intravenous route. Nonetheless, advancement in nanoparticulate systems for targeting only a single specific molecular moiety overexpressed on the surface of cancer cells disregard the tumor heterogeneity and promote the development of tumor resistance. Hence, combination of different targeting moieties (ie polyfunctional) to the nanoparticles may improve effectiveness of the system. Moreover, major factors like physicochemical characteristics of nanoparticles, selection of ligand/s for surface functionalization, and the response of biological systems attribute to the efficacy of drug ultimately affecting the clinical outcome of the nanoparticulate system. ⁴ Regardless of the advancements in the disease-driven approach of nanomedicine, there exists a gap in clinical translation that requires a thorough assessment of the data, and in-depth understanding about efficacy, biodistribution, retention, toxicity along with in-vivo correlation of human versus animal models of nanoparticles. Despite this, certain techniques exist for real-time evaluation of localization of nanomaterials such as magnetic resonance imaging, electron imaging, computed tomography, etc However, the ability of these techniques to analyse the data qualitatively and quantitatively for assessing the real-time results at cellular and/or whole-organ levels, but mostly accompanied with advantages and drawbacks. Research studies for in-vivo distribution of nanoparticles by utilization of other advanced modalities are currently being explored. ⁵ Recently, Dong and co-workers developed a hydrophilic (IR783) organic dye-hydrophobic (Ce6) organic dye self-assembly for the delivery of paclitaxel for the treatment of pancreatic cancer with the aid of ultrasound in photoacoustic imaging. The self-assembled system resulted in enhancement of tumor accumulation via the enhanced permeation and retention (EPR) effect for photoacoustic imaging. ⁶ Nevertheless, some challenges in assessment techniques like no standardized analytical sampling method for the detection of biodistribution, lack of significant reproducibility, laborious assessment, interference in detection accuracy, and negative effect on physiochemical properties of nanoparticles do exist. Additionally, the determination of biodistribution of nanoparticles using NIR fluorophores for whole body imaging varies based on the concentration and content of the dye. Meng et al, fabricated DiR-loaded poly(lactic-co-glycolic acid) nanoparticles with surface modification (folate conjugated polyethylene glycol) to compare the distribution of fluorescence signals in a mouse model expressing tumor via NIR whole body imaging. Surprisingly, the fluorescence patterns altered significantly with DiR loading in comparison to surface ligand, and led to conflicting results due to variability in dye content in nanoparticulate systems. ⁷ Thus, these challenges act as a major setback for the transformational development of nanomedicine in futuristic therapy.

Recent studies revealed encapsulated drug molecules altered the clearance mechanism and phagocytosis of the particles. FDA approved supermagnetic nanoparticles (Feridex™) are discontinued as results proved to exhibit Fenton and Haber–Weiss reactions responsible for cellular DNA damage, genotoxicity and inflammatory reactions. ⁸ Currently, emergency FDA approval for COVID mRNA vaccines of Pfizer-BioNTech exhibited significant instability issues. ⁹ Owing to the challenges faced before entry in the market, numerous challenges are associated with nano-carriers particularly for their efficient development, meeting the ethical/regulatory requirements, toxicity assessment, and clinical translational assessment techniques. Considerations for both patients and manufacturers, and to the wider environment remains ambiguous due to the complexities of safety and risk ratios. This ambiguity presents a significant challenge to establishing a robust framework for estimation, particularly concerning nano-carrier-based products, where comprehensive pre-clinical and clinical guidance is imperative. ¹⁰ While nanomedicine holds promise in drug delivery advancements, thorough research is essential to grasp its pharmacological, toxicological, and immunological implications. The ability of nano-products to cross blood–brain barrier, cell membranes, placenta, and more, increases the probability of non-specific interaction, that may ultimately cause their unwanted accumulation at tumor site with potential issues like cellular toxicities. ¹¹ One of the most common challenges associated in determination of safety and risk of nanoparticles relates to inherent intrinsic properties of nanoparticles. Despite progress in predicting nanotoxicology, the linkage of inherent physical and chemical features (shape, size, surface charge, pH of membrane, etc) impact on their uptake in the body, and remains as a fundamental problem for determining nanomaterial biotransformation. The complex nature of nanomedicines particularly their size, form, structure with clinical applications, challenges the regulatory bodies to characterise and categorize nanomaterials. For example, dynamic light scattering for characterization of hydrodynamic size of particulate matter associates with the scattering of light in spherical forms however, in rod shaped materials no exact metrology technique is defined. Moreover, the size determination can be impeded by the presence of dust or small amounts of large aggregates. Nanoparticle tracking analysis (NTA) and imaging systems address these challenges and determine the particle size of nanoparticles based on the refractive index and morphology of the particles. NTA enables visualisation and recording of the nanoparticles’ real time due to the presence of charge-couple device camera (CCD) along with light scattering microscopy. ¹²

Association of inherent complex properties (eg, rigidity, particle size, zeta potential, etc) of nanomaterials to biological responses are quintessential for the fabrication of safer nanoparticles with qualitative and quantitative frameworks. Moreover, it results in incompetence for creating a link between intricate aspects of nanostructures in biosystems as well as inadequate efficiency in analysis of biopharmaceutical parameters. As in case of in-vitro toxicity studies, neglection of human body complexities may limit the best-fit model of nanomaterials due to interaction with reagents or interference with detection mechanism. As nanomaterials properties like optical property, catalytic efficiency, magnetic property and absorption efficiency, etc may promote interaction and ultimately lead to generation inaccurate data. Thus, the results required for regulatory guidelines on nanomedicine toxicity studies are impacted. The FDA cites the lack of safety, and efficacy data of nanomedicines to analyze the effect of nanomaterials on the humans, environment, etc for the development of more efficacious and safe nano-technology-based products. ¹³ Major challenges for regulatory bodies in regulation of nanomedicines involves inability of proving safety and efficacy data in bulk for pharmacodynamics and pharmacokinetics studies; and no significant correlation exists between safety and efficacy data collected from studies along with data after marketing authorization. Classification of nanomedicine either as medical devices or medicine is another task and may led to inconsistence across the globe as adherence of guidelines for nanomedicine varies day-to-day according to change in classification of nanomedicine. The complexities associated with nanostructures like physicochemical properties with respect to route, manufacturing process are not yet defined to obtain nanocarriers of reliable, strong quality, stability, efficacy, with safety standards. Hence, clinical trials for risk assessment in terms of extrapolation of in-vivo studies in human studies are found to be detrimental. Moreover, the ambiguous explanation of Cost-of-Quality (COQ) attributes for analysis in small-scale manufacturing aids in understanding the manufacturing process on large-scale. However, to meet the standard regulatory requirement of laboratories, sophisticated instrumentation, infrastructure, together with clinicians and technical expertise must be considered for up-scaling during the development of nanotechnology at manufacturing level.

Nanoparticles possess the drawback of environmental accumulation potentially affecting the ecosystems, in case of metal nanoparticles, silver especially exerts toxicity to aquatic life hampering the microbial flora and soil fertility. Owing to nano-dimensional nature, they penetrate facilely via water, soil and air; continue to be present in the environment for longer duration. Thus, it is critical to understand the effects nanoparticles in environment and to formulate techniques to reduce their detrimental potential. Several strategies are employed like preparing biodegradable nanoparticles with decreased toxicity, remodeling waste management practices to inhibit its release in the environment with implementation of stringent guidelines ensuring nanoparticles safe usage and disposal. The regulations pertaining to usage of nanoparticles are currently under development and leading to doubts that only a few nanoparticles may evade regulatory gaps. Absence of specific regulations and guidelines leads to lack of reliability regarding the safety and efficacy of some nanoparticles like metallic or polymeric nanomaterials associated with greater risk of pulmonary toxicities and carcinogenicities.

Advances in nanotechnology possess the ability to transform detection, treatment in medicine along with material science and energy intensifying the prevailing societal problems such as healthcare access, disparity in income and job displacement. With the advancement and surge of nanomedicine, understanding the influence to ensure equitable distribution of benefits is essential. Increasing demand of nanotechnology requires surge in manufacturing ultimately resulting in the job displacement for workers with insufficient skill set to perform this technology. The production and manufacturing are expensive and complicated procedures, indicating the development of newer simpler techniques with cost-effectiveness. Although nanotechnology possess an ability to significantly revolutionize all aspects of life for ensuring patient well-being, however, it is necessary to identify the existing blind spots and accordingly strategize approaches to overcome the same. Lastly, awareness of the potential negative effects of existing blind spots and strategies to overcome the same may enable the scientists for the development of safe and effective nanomedicines for futuristic trend in multiple applications.

Future Perspectives

The influence of nanomedicine in drug delivery systems is undeniable. With adequate evaluation of blind spots, and constant nanotechnological innovations corresponding to complex diseases like cancer, the number of nanomedicine-based materials like carbon nanotubes, quantum dots, etc hold a promising potential in the near future by integrating with AI, ML, and 3D printing technologies.