Thermosensitive Polypeptide Hydrogels Co-Loaded with Two Anti-Tumor Agents to Reduce Multi-Drug Resistance and Enhance Local Tumor Treatment

Localized tumor treatment with hydrogels co-loaded with two or more drugs is an emerging approach offering superior anti-tumor efficacy and reduced systemic toxicity. Nevertheless, the development of multi-drug resistance (MDR) during sustained local treatment with hydrogel depots has not been studied. In this study, a strategy is developed for local tumor combination therapy using a polypeptide hydrogel co-loaded with doxorubicin (DOX) and cisplatin (CDDP) for evaluation in both drug-sensitive A549 and CDDP-resistant A549 (A549/CDDP) tumor models. It is found that the combination of DOX and CDDP synergistically inhibits both A549 and A549/CDDP cells in vitro, accompanying increased inhibition of the expression of the MDR and anti-apoptosis B-cell lymphoma 2 (Bcl-2) genes. After a single peritumoral injection into nude mice bearing A549 or A549/CDDP xenografts, the DOX/CDDP co-loaded hydrogels exhibit remarkably high anti-tumor efficiency, compared with a dual-drug solution or single drug-loaded hydrogels. The development of MDR genes in both tumor models is inhibited by the hydrogel-based combination therapy. This study presents an efficient strategy for long-acting treatment of both drug-sensitive and drug-resistant tumors.