pH‐Responsive Multicomponent Nanocomposite for Enhanced Reactive Oxygen Species Generation and Targeted Apoptosis‐Induced Synergistic Cancer Treatment

In recent years, various cancer treatment methods have been investigated and additional strategies have been introduced into treatment. Among these strategies, cancer targeting and drug delivery systems have emerged as essential aspects of chemotherapy, one of the most fundamental cancer therapies. Nanoparticle-based cancer therapy has numerous advantages, such as improved biocompatibility, enhanced permeability and retention (EPR) effect, large surface area, and convenience of surface modification. Thus, numerous studies in cancer-targeted drug delivery systems have been conducted using nanoparticles. In this study, glucose oxidase (GOx) encapsulated pH-responsive nanocomposites are developed. The nanocomposites are composed of hyaluronic acid (HA) and chitosan (CS)-stabilized platinum nanoparticles (HA-CS@PtNP-GOx, HCPG). The HA specifically conjugated to the CD44 membrane receptor forms a nano-sized complex with CS through electrostatic interactions, enhancing both the biocompatibility of the nanocomposite and the stability of the encapsulated GOx. The platinum nanoparticles (PtNPs) can generate the hydroxyl radicals (·OH) through a cascade reaction with GOx under acidic conditions to induce apoptosis. Furthermore, the hydroxyl radical acted as an initiator in the lipid peroxidation (LPO) process, and PtNPs oxidized the intracellular glutathione. These results may lead to the inhibition of glutathione peroxidase 4 (GPX4)-mediated LPO degradation, resulting in enhanced apoptosis.