A pH-responsive injectable hydrogel for enhanced chemo-chemodynamic synergistic therapy

Abstract

Cisplatin (cis-diammine-dichloro-platinum II, CDDP) is one of the most commonly used chemotherapeutic agents for the treatment of esophageal cancer, and its clinical application has been greatly limited due to non-specific administration, severe systemic toxicity, and reduced efficacy due to drug resistance. The special physicochemical properties of hydrogels enable them to achieve a sustained controlled release of CDDP and to maintain high local drug concentrations over a long period, but the problem of drug resistance still needs to be addressed. Herein, CS-BA-PVA, a pH-responsive hydrogel is used to co-load CDDP and divalent copper ion (Cu2+) for constructing a drug delivery system CS-BA-PVA@Cu/CDDP to achieve controlled and sustained drug release. Once reaching the acidic tumor microenvironment (TME), CS-BA-PVA@Cu/CDDP specifically responds and disassembles to release CDDP for chemotherapy against cancer. Besides, the simultaneous release of Cu2+ can deplete the intracellular glutathione (GSH) for increased toxicity of CDDP as well as catalyzing the decomposition of intra-tumoral H2O2 into highly toxic •OH for chemodynamic therapy (CDT). Moreover, the substantially reduced GSH can also protect the yielded •OH from scavenging and thus greatly improve the •OH-based CDT effect. In addition to providing a new drug delivery system CS-BA-PVA@Cu/CDDP, this study is also expected to establish a new form of TME-responsive carrier for highly efficient tumor-specific GSH-depletion-enhanced synergistic chemotherapy/chemodynamic therapy.