Nanotechnology in Medicine. Группа авторов

(PEI), poly(ε‐caprolactone) (PCL), poly‐N‐(2‐hydroxypropyl) methacrylamide (HPMA), poly(D,L‐lactic acid) (PLA), dextran, poly(D,L‐lactic‐co‐glycolic acid) (PLGA), alongside additional stealth effect offered by most widely used PEG (Utreja et al. 2020). The amphiphilic character allows poorly water‐soluble drugs to be loaded in the core with the shell providing aqueous solubility, colloidal stability, and essential stealth character. Although these nanoformulations offer improved penetrability, solubility, bioavailability, targeting through directing ligand complexed on the surface or combining monoclonal antibodies to the micelle corona, they suffer from poor in vivo stability. This effect is due to dissociation and early drug release below critical micelle concentration succeeding its administration that can also lead to drug‐related toxicity. However, stimuli‐responsive cross‐linked micelles have exhibited micellar stability and have attracted formulation scientists for the delivery of docetaxel, camptothecin, paclitaxel, cisplatin, and oxaliplatin (Ventola 2017).

      The original milled organic nanocrystal, Rapamune®, approved by FDA in 2000 opened new avenues for resourceful NPs that were capable of enhancing solubility and bioavailability. Nanocrystal‐based drugs within the range of 1000 nm are peculiar because they are solely composed of drug derivatives without any carriers bound to them and are typically stabilized using polymeric steric stabilizers or surfactants. The poorly soluble organic or inorganic drugs are rendered enriched pharmacokinetic (PK)/pharmacodynamic (PD) properties by nanostructures known as nanocrystals. Nanocrystals have unique characteristics that allow them to solve problems such as increasing solubility of saturation, increased speed of dissolution, and enhanced surface/cell membrane binding. Saturation solubility increases the forces that, via biological mechanisms, such as the walls of the gastrointestinal tract, drive diffusion‐based mass transfer (Farjadian et al. 2019). The oral absorption process for nanocrystal formulations, however, is not well known and their action is not completely predictable after subcutaneous injection. They are photochemically stable and exhibit a narrow, controllable, symmetric emission spectrum. They consist of an optically energetic core enclosed by a shield that creates a physical barrier to the external environment, rendering them less vulnerable to photo‐oxidation or medium shifts. The methods of preparation of nanocrystals can be divided into top‐down and bottom‐up processes. The bottom‐up method creates nanocrystals from the solution, which requires two basic stages: nucleation and crystal formation. It mainly involves high‐pressure homogenization accompanied by grinding procedures. The top‐down methodologies comprise of high‐energy mechanical powers like milling (NanoCrystals®) or high‐pressure homogenization (IDD‐P®, DissoCubes® and Nanopure®), and the main benefit is that it is adaptable to the manufacturing scale (Lopalco and Denora 2018). Nevertheless, high energy, cost, and time used as well as impurity from grinding media are a downside of this technology, leading to unintended toxic undesirable results. Supercritical fluid (SCF) such as supercritical carbon dioxide exhibits superior physical characteristics, liquid solubilization, diffusivity similar to gas and minimal environmental effect. Thus, nanocrystals are lately prepared using SCF.

Inorganic nanocarriers have recently been used to create powerful nanocarriers for drug delivery applications attributable to easy alteration, high drug loading capability, and stability. A significant variety of inorganic materials can be used to produce NPs, such as silica, metal oxide, or metal. In particular, NPs of metal and metal oxide are being intensively studied for simultaneous therapeutic as well as imaging purposes. They are used and developed for an investigative picture of the diseased area because of the special magnetic and plasmonic properties. However, only a few inorganic NPs have been approved for clinical use, although others are still in the clinical testing stage. They are composed of a core containing the inorganic portion such as silica, gold, iron oxide, or quantum dots. A shell region consisting mostly of organic polymers (or metals) offers an adequate surface functionalization substrate or a way to protect from redundant physicochemical interactions with the biological microenvironment. Particle modification is usually done to strengthen the interaction with the biological membranes. In spite of these benefits, however, inorganic NPs have demonstrated only modest effectiveness in the treatment of disease tissues due to the crucial problems associated with the limited quantity of drug substances delivered and extreme toxicity (Lombardo et al. 2019). Gold NPs, silver NPs, and iron oxide NPs have been extensively studied in the biomedical field due to their special biochemical properties and high electron conductivity. With the approval of Abraxane® in 2005, which incorporates 130‐nm albumin NPs conjugated with paclitaxel, a shift occurred from the use of unmodified proteins to engineered particle complexes originated to enable active targeting. Protein‐based NPs include protein‐conjugated medications, formulations where the protein itself is the active therapy, and complex combined platforms that utilize proteins for targeted delivery. Generally, natural proteins are preferred to reduce toxicity. In the last decade, albumin has gained the attention of research scientists as a drug carrier due to the facilitation of cellular uptake mechanisms and accumulation via EPR effect (Ventola 2017). Mesoporous silica NPs, quantum dots, and carbon nanotubes have also registered their applications in biomedical and nanomedicine fields. Moreover, nanocarriers that are equipped with complex surface functionalization of inorganic nanocarriers with organic materials or through the use of organic colloids as a template for the regulated growth of inorganic materials have recently attracted considerable global interest. For example, surface coating of mesoporous silica NPs with polyethyleneimine improves cellular uptake and enables siRNA and DNA constructs to be transported safely (Paris and Vallet‐Regí 2020). Lately, lipid‐coated mesoporous silica NPs have also been employed to achieve stimuli‐responsive drug release, promote drug loading, prevent premature release of drug, avoid multidrug resistance, stability, and biocompatibility.

      1.3.3 Tissue Engineering and Regenerative Medicine

Nanomaterials of low toxicity, contrasting agent properties, customizable characteristics, targeted/stimuli distribution ability, and accurate behavioral regulation via external stimulus are valuable tools for achieving unparalleled efficiency in driving and overcoming barriers in tissue engineering. The extraordinary mechanical strength and electrochemical properties of carbon nanostructures corresponding to graphene, carbon nanohorns, fullerenes, nanodiamonds, single/multi‐walled carbon nanotubes; the fluorescence properties of quantum dots; the antimicrobial effect of silver and other metal/metal oxide NPs; and surface conjugation as well as surface conductive properties of gold NPs have made them quite successful in different tissue engineering and regenerative medicine applications (Makvandi et al. 2020) as seen in Figure 1.2.

These residing nanomaterials must unveil biocompatibility, boost the growth of cells, promote the proliferation of various types of cells, provide regulated means for delivery of bioactive and contrast agents to manage and track the engineered tissues. Furthermore, nanodiamond–polymer composites are also seen as a promising medium for repairing damaged tissues due to their unique mechanical properties, fluorescence capability, and biocompatibility (Hasan et al. 2018). The emerging field of nanoneedles for intracellular distribution, intracellular pH estimation, probing, and cell‐interfacing is currently growing promptly and displays abundant potential. Nanotechnology proposes innovative culture approaches to resolve the prevalent problem of cell‐based therapy with minimal retention in target tissues. It has got the ability to generate smart surfaces that renders intermittent adhesive properties to cells. This makes detachment of cell patches from cell culture substrate feasible for further transplantation (Kubinova and Sykova 2010). Cell sheet patch therapies have paved the way for possible cell and tissue engineering therapies for patients suffering from various disorders such as cardiomyopathy, osteoarthritis, and periodontal reconstruction. Nanomedicine is now emerging as a powerful tool to mitigate organ donor shortages. The formation of in vitro whole organs is a present‐day requirement in the field of biomedicine. This is fulfilled by nanomaterials enabling the production of artificial organs for regenerative medicine as well as organs‐on‐a‐chip applications.