## 4 Biomedical Applications
### Drug/Gene Delivery Carriers  
A challenge in cancer treatment is targeting anticancer drug delivery to increase the efficiency of drugs. Because HA interacts with CD44, overexpressed in cancer cells, HA-based hydrogels as drug/gene delivery carriers have been developed for anticancer drug therapy. The catechol groups in HA can act as coating and crosslinking moieties to achieve sustained drug release. For instance, HA-catechol/chitosan composite nanoparticles containing the anticancer drug doxorubicin (DOX), with a high loading capacity of 250 \(\upmu\)g/mg, exhibited a controlled release of DOX, in comparison to the administration of free DOX [63]. In addition, the nanoparticles showed mucoadhesive properties; over 60% of the nanoparticles remained on the buccal mucosa after washing with artificial saliva, while only 10% remained when dextran was used as a control. In addition, these nanoparticles showed enhanced cellular uptake and accumulation in HN22 cells. Furthermore, treatment using DOX nanoparticles led to extensive apoptosis (22% of the apoptotic rate), which was higher than that observed using free DOX (16%). HA-catechol hydrogels containing amine-functionalized graphene oxide (GO) are prepared by covalent reactions involving the catechol groups of HA and the amine groups of GO [53]. DOX is noncovalently bound to GO in hydrogels by hydrophobic interactions and \(\uppi\)-\(\uppi\) stacking. In addition, controlled DOX release profiles have been obtained using HA-catechol/GO hydrogels. HA-catechol hollow nanoparticles have also been developed to deliver anticancer drugs. Silica nanoparticles are coated with HA-catechol, and the inner silica particles are removed to fabricate hollow HA-catechol particles to load anticancer drugs, such as DOX [65]. The hollow HA-catechol particles showed drug-loading efficiency (\(\sim\)20 wt%) with different drug-release profiles between pH 5.5 and 7.4. At pH 5.5, 67% of DOX was released from the particles within 8 h, while 25% of DOX release occurred at pH 7.4 after 60 h. Considering the pH of the physiological conditions and the cancer microenvironment, these particles can effectively lead to cancer cell death after pH-triggered DOX release. In addition, HA-catechol-coated Au nanorods have been fabricated for cancer therapy via the interaction of catechol and Au [66]. DOX was covalently conjugated to HA-catechol, which has an acid-labile hydrazone linkage. The release of DOX from the HA-catechol-coated Au nanorods was controlled by two stimuli, namely, pH and NIR (near-infrared) light, and was found to be successful in inhibiting the growth of breast cancer cells.  
HA-catechol-based gene delivery has been performed using calcium phosphate (CaP)-containing plasmid DNA or siRNA [45]. HA-catechol has been used as a binder for CaP and cancer-targeting materials. Stabilized CaP/siRNA/HA-catechol nanoparticles are prepared by the simple mixing of solutions and involve specific interactions between calcium and catechol. The nanoparticles deliver siRNA to cancer cells via endocytosis. In the HT29-luc tumor xenograft model, the nanoparticles showed no sign of hepatic toxicity after systemic administration and successfully inhibited cancer growth through the gene silencing effect of siRNA. In addition, CAP nanoparticles stabilized by HA-catechol have been designed to enhance the transfection of hMSCs in a gene delivery system, as shown in Figure 6[41]. The CAP nanoparticles stabilized by HA-catechol showed efficient gene delivery of both pBMP-2 as a plasmid DNA and mir148b as a microRNA to stem cells via CD44-specific receptor-mediated endocytosis.