Redox Sensitive Hyaluronic Acid-Decorated Graphene Oxide for Photothermally Controlled Tumor-Cytoplasm-Selective Rapid Drug Delivery

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox-sensitive, hyaluronic acid-decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm-specific rapid delivery using near-infrared (NIR) irradiation controlled endo/lysosome disruption and redox-triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox-sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug-loading capacity for aromatic molecules, HA receptor-mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox-dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA-receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm-specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox-triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment.