A dual-responsive hyaluronic acid nanocomposite hydrogel drug delivery system for overcoming multiple drug resistance

Abstract

Chemotherapy is restricted by efficient drug outflow due to the multiple drug resistance (MDR) in heterogenous nature of tumor. Herein, we present a dual-responsive hyaluronic acid (HA) nanocomposite hydrogel that can not only response to the tumor microenvironment but also enhance chemotherapy. This HA hydrogel consists of a core-shell SiO2 (GOD@SiO2-Arg) and mesoporous silica nanoparticles (MSNs) with doxorubicin (DOX) as the cargo (DOX@MSN). It could rapidly release the GOD@SiO2-Arg nanoparticles at the low pH tumor-specific environment due to the cleavage of imine bond. GOD@SiO2-Arg activated by over-expressed glutathione (GSH) in tumor cells releases GOD due to the cleavage of disulfide bonds, which could oxidize glucose to produce hydrogen peroxide (H2O2) for in situ NO generation via reaction between Arg and H2O2. The validity of this study might provide a method to modulate the tumor microenvironment for enhancing chemotherapy.