Thermo-sensitive hydrogel-mediated locally sequential release of doxorubicin and palbociclib for chemo-immunotherapy of osteosarcoma

Abstract

Traditional cytotoxic drugs induce immunogenic cell death (ICD) of tumor cells to trigger anti-tumor immunity. Unfortunately, the presence of immunosuppressive cells such as regulatory T cells (Tregs) in tumor microenvironment offsets part of anti-tumor immunity. In this work, we engineered a methoxy poly(ethylene glycol)-block-poly(l-alanine) (mPEG − PLAla)-based thermo-sensitive hydrogel by ring-opening polymerization as a vehicle for locally sequential delivery of doxorubicin (DOX) and palbociclib (PAL) to induce the antitumor immunity in osteosarcoma. The copolymer exhibited an appropriate sol–gel transition behavior triggered by physiological temperature. Meanwhile, the superior rheological properties, the uniform morphology and the suitable biodegradability were also investigated in the hydrogel. Interestingly, codelivery of gel and DOX + PAL displayed sequential drug release behavior and exhibited improved antitumor effect toward the K7 orthotopic osteosarcoma mouse model. The DOX-induced immunogenic cell death (ICD) and PAL-mediated suppression of regulatory T cells jointly facilitate antitumor immunity in osteosarcoma. Furthermore, the dual drug codelivery hydrogel showed reduced lung metastasis and enhanced biosafety than free drugs in mouse models of osteosarcoma. Therefore, the locally sequential drug delivery system to induce antitumor immunity will have great potential in future tumor therapy.