Nanogel-Incorporated Injectable Hydrogel for Synergistic Therapy Based on Sequential Local Delivery of Combretastatin-A4 Phosphate (CA4P) and Doxorubicin (DOX).

Abstract

Drug combination therapies employing dual-drug delivery systems offer an effective approach to reduce disadvantages of single-drug therapy, such as high dose and easy generation of drug resistance. Herein, a dual-drug delivery system based on nanogel-incorporated injectable hydrogel (NHG) was designed for sequential local delivery of combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) for antiangiogenesis and anticancer combination therapy. The injectable hydrogel was prepared for loading and quick release of hydrophilic drug CA4P, while the pH and redox stimuli-responsive nanohydrogels were incorporated into the injectable hydrogel by pH-responsive boronate ester bond for sustained long-term DOX delivery. The dual-drug-loaded NHG system released CA4P and DOX sequentially and exhibited high inhibitory activities on the cancer cell proliferation in vitro. It displayed superior therapeutic efficacy in vivo with only one single injection. Immunohistochemistry analyses suggested a synergistic therapeutic effect through tumor vascular collapse caused by CA4P and tumor cell apoptosis induced by DOX. The combination therapy of antiangiogenic and cytotoxic drugs using NHG delivery system offers a promising approach for improved cancer therapeutic efficacy. The nanogel-embedded injectable hydrogel can be employed as a universal drug carrier for local dual-drug delivery with sequential release behaviors by simple injection.