Crizotinib prodrug micelles co-delivered doxorubicin for synergistic immunogenic cell death induction on breast cancer chemo-immunotherapy.

Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG-b-PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG-b-PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG-b-PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG-b-PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration, concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG-b-PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.