Nanotechnology in Medicine. Группа авторов

and Kim 2016).

      It has been reported that AuNPs possibly move through a mother's placenta to the fetus. During the neonatal phase, these NPs can act as allergens, activating the immune system. NPs can communicate with diverse immune cell networks found inside and under epithelial surfaces. The proficient gastrointestinal tract uptake of NPs also been well recorded in oral feeding and forced feeding studies. Despite the clinical approval, the dermal toxicity of nanosilver‐based surgical dressings and sutures is yet a matter of concern (El‐Ansary and Al‐Daihan 2009). While beneficial control of wound infection is accomplished, their dermal toxicity is even of concern. In epidemiological trials, adverse cardiovascular effects attributable to exposure to NPs have been identified (De Jong and Borm 2008). Oxidative damage to DNA is exhibited by the titanium dioxide and zinc oxide NPs in in vitro tests and cultured human fibroblasts. Nano‐sized particles inhaled can increase bloodstream access and can then be spread to other organs. There is a good likelihood that, via the lungs, skin, and gastrointestinal tract, NPs may be assimilated into the bloodstream. Besides, fluids representing the liver, blood, and airway environment are exploited to conduct experiments concerning the dissolution of NPs in artificial body fluids and classify harmful influences. NPs also have access to the brain, exhibiting toxic effects on BBB, especially high concentrations of anionic and cationic NPs, although, neutral NPs and low concentrations of anionic NPs were found not to affect the integrity of BBB (Teleanu et al. 2019). The development of reactive oxygen species and oxidative stress are caused by NPs. Further, these have shown to be involved in the development of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases (Armstead and Li 2016).

      The dominant role of protein–nanoparticle interactions has begun to appear in nanomedicine and nanotoxicity. The “corona” nanoparticle protein is a dynamic coating of proteins and other biomolecules that adsorbs to the surfaces of the nanoparticle (Dickinson et al. 2019). Protein corona is a nanoparticle's biological identity since it is what the cell “sees and communicates.” At any given time, the structure of the corona protein can be determined by the concentrations of over 3700 plasma proteins. When exposed to a biological fluid, this corona may not achieve equilibrium automatically. The nanoparticle surface would initially be dominated by proteins with high concentrations and elevated interaction rate constants. They can also easily dissociate to be swapped by reduced concentration, leisurely exchange, and greater affinity proteins. Small NPs may cause protein malfunction, with their wide surface area as a binding interface, which may lead to pathogenesis and adverse health effects (Sukhanova et al. 2018; Singh et al. 2019).

There are two standard approaches adopted to study NPs’ toxic effects on human health: in vitro studies on model cell lines and in vivo experiments on experimental animals. There are unique benefits and drawbacks of both cell culture and animal laboratory models for testing NP toxicity (Osman et al. 2020). The former offers a deeper insight into the molecular processes of toxicity and describes the key targets of NPs; however, it does not take into account the patterns of the delivery of NPs in the body and their transfer to various tissues and cells (Guadagnini et al. 2015). The study of NP toxicity in animal laboratories makes it possible to predict the delayed effects of in vivo NPs action. The general pattern of manifestations of toxicity, however, is so complex that it is difficult to establish which of them is the major cause of the result observed and which are the effects thereof. The long‐term consequences of prolonged exposure to these NPs in humans must be analyzed. For all of the therapeutic NPs, methods must be built for detecting NPs in situ. Biotransformation of therapeutic NPs in the human body, their association with biological processes, and adsorption, delivery, digestion, transformation, degradation, and excretion in living systems should be studied by the characterization of NPs in terms of distribution of size, surface properties, persistence, and stabilization of initial and modified NPs (Zhao and Castranova 2011; Dickinson et al. 2019).

      The latest toxicological approaches utilized for the detection of NP hazards are based on conventional toxicology approaches or complementary techniques. These tools for safety assessment of the rapidly budding list of nanomaterials have innate restrictions. There is a rising demand for strategies that could be adopted for screening by industries during the advancement of nanoproducts. These products may have to be handled on a case‐by‐case basis and require costly evaluations. Usually, acute and chronic toxicity is assessed in the pharmaceutical industry. The acute toxicity incorporates mitochondrial activity hemolysis, oxidative stress, inflammation, or complement activation. The chronic toxicity investigation is arduous, and it is more perplexing to scrutinize the results (Zhao and Castranova 2011). An epitome alteration has been proposed by toxicologists in using in vitro and small animal models with high‐throughput capability. The molecular and cellular pathways extrapolative to probable pathology conditions in whole organisms are the foundation. The authentication of such analytical toxicity testing methods of nanoproducts, although, would present a challenge for the scientific society (Armstead and Li 2016). Effective methods and state‐of‐the‐art techniques to research biological behaviors and the transformation of nanomaterials in vivo and in vitro are important for the evaluation of safety and therapeutic efficacy. Systemic and quantitative proteomics, genomics, transcriptomics, and metabolomics data can also capture improvements in metabolism, mechanisms of signaling, and biological functions (Wolfram et al. 2015; Pelaz et al. 2017).

1.6 Safety Issues and Regulations

      A number of nanomedicines have been approved for cancer treatment by the FDA and the European Medicines Agency (EMA). The FDA, EMA, and other regulatory agencies have not yet explicitly adopted recommendations for drug products containing not so hard materials (Wu et al. 2020). In the absence of guidelines for the review of nanomedicine therapeutics, regulatory decisions can be taken only on the basis of an individual evaluation of benefits and risks. The regulatory process is therefore laborious and involves a sophisticated specialist in emerging technology, which could result in regulatory delays (Juillerat‐Jeanneret et al. 2015; Singh et al. 2019). Also, regulatory concerns are critical for the production of cutting‐edge technology to define and monitor, in addition to clinical trials and the approval process, the safety of nanomedicine products. There is an immediate need for comprehensive characterization and quality control protocols. It is important to build more sophisticated and multifunctional tools for assessing the safety of nanotherapeutics, even as the difficulty of the approval process may be increased. To date, understanding has not been reached about how to determine the safety of nanomaterials using efficient approaches and standards that are approved by regulatory bodies. There are several explanations for this: lack of established reference material for benchmarking the effects of the material being tested, lack of clarity on predictive endpoints for human toxicity, technological shortcomings of nanomaterial testing, and batch‐to‐batch variations due to inadequate control over the development process. Many government and nongovernment groups have been attempting to find out how to handle this topic for the past two decades (Fadeel et al. 2007; Oberdorster 2010; Pelaz et al. 2017).

In clinical trials, nanomedicine drugs should have a desirable pharmacology and toxicity profile and show safety and efficacy. In order to further link the physicochemical assets of nanomedical systems with biological consequences, successful incorporation of capital from academia, business, government organizations, and hospitals would be critical. To leverage each partner's specific strengths, it is important to cultivate collaborations between major pharmaceuticals, smaller firms, and academia early in preclinical growth (Havel et al. 2016). The definitions, quality requirements, recommendations and regulatory concerns of nanomedicine should be defined and reciprocated by health authorities (Zhao and Castranova 2011; George et al. 2015). Although any new drug conceptually needs to meet comparable challenges, the basic sophistication and multicomponent existence of nanomedicines contributes to a vast range of additional variables that may raise further concerns considerably. Nanomedicine will go on to the next step and bring practical and meaningful benefit to human medicine and healthcare by rationally planned and systematic approaches to overcome various safety issues and solve the problems.

1.7 Conclusion and Future Perspectives

      Nanomedicine has raised exhilarating prospects for many medical issues. It has