**7. Hyaluronic Acid-Based Nanoparticles**

Hyaluronic acid (HA) is an anionic polysaccharide with repeating units of N-acetyl-D glucosamine and disaccharides of D-glucuronic acid linked via β-1,4- or β-1,3-glycosidic bonds [121,122]. HA also is known as hyaluronan, present in the synovial fluids, in the extracellular matrix, in the skin and uniformly distributed in vertebrate tissues of the body [123]; the structure is shown in Figure 8. HA has good biocompatibility, greater viscoelasticity, biodegradability and the capacity to combine with the receptor cell surface. The presence of receptors such as CD44 on the surface of HA makes it a site-specific drug delivery system for anticancer drug release and its capacity for cellular uptake [124,125].

Modification of HA with hydrophobic macromolecules occurs because of hydroxyl and carboxylic functional groups and its negatively charged surface. Based on nanocarriers, HA can be divided into different drug delivery systems such as gel and cationic drug delivery systems, a polyelectrolyte microcapsule release system, a nano-emulsion delivery system, and a nano-carriers drug delivery system [126]. HA nanocarriers are not only used for cancer drug therapy but also as photosensors, for photo imaging, and gene plasmids [127]. Various modification steps can be used to enhance its properties for drug delivery systems, such as conjugation with the nanocarriers as a targeting moiety, with dendrimers, quantum dots, and graphene oxide [35,128]. Modification of HA is important due to

its accumulation in the liver; hence, Choi et al. [129] synthesized polyethylene glycol-modified HA nanoparticles. By varying the degree of PEGlation, negatively charged self-assembled nanoparticles were formed. Although PEGlation of HA-NPs decreased their cellular uptake in vitro, nanoparticles having CD44HA receptor were taken in huge amount by cancer cell as compared to normal fibroblast cells. Using in vivo images, it was established that PEGlation of HA reduces the accretion of HA nanoparticles in the liver and enhances its cellular uptake. Characterization results showed the maximum accumulation of PEGylated HA nanoparticles in tumour cells. Lee and Na [130] also synthesized the sustainable drug release to reduce the toxic effect and avoid an accumulation of HA in healthy organs. The authors modified HA with a Polycaprolacton (PCL) copolymer, HA cross-linking is carried out by disulfide bond. Doxorubicin (DOX), selected as a sample anticancer drug, was successfully encapsulated into the nanoparticles with greater drug loading ability. The DOX-loaded in the modified HA significantly delayed the drug release in physiological environments. However, the drug release rate was significantly improved in the occurrence of glutathione, a thiol-containing tripeptide capable of reducing disulfide bonds in the cytoplasm. Moreover, DOX-HA-ss-NPs could efficiently transport the DOX into the tumour cell. Overall, the characterization results indicate that this modification can act as a potential carrier for a drug delivery system. In another study [131], photo-crosslinked hyaluronic acid nanoparticles (c-HANPs) were prepared for involuntary burst release of the drug into the blood. They were readily synthesized via UV-triggered chemical cross-linking with the acrylate groups in the polymer backbone. High sustainability of c-HANPs enabled their large circulation in the body. Owing to the constant discharge of the drug and improved tumour-targeting capacity, c-HANPs showed higher healing ability compared to uncrosslinked HANPs. These data imply the promising potential of c-HANP as a tumour-targeting drug carrier and have established the extraordinary effect of better stability upon the biodistribution and therapeutic ability of drug-loaded nanoparticles.

**Figure 8.** The structure of hyaluronic acid.
