Codelivered Chemotherapeutic Doxorubicin via a Dual-Functional Immunostimulatory Polymeric Prodrug for Breast Cancer Immunochemotherapy.

Abstract

Immunochemotherapy is viewed as a promising approach for cancer therapy via combination treatment with immune-modulating drugs and chemotherapeutic drugs. A novel dual-functional immunostimulatory polymeric prodrug carrier PEG2k-Fmoc-1-MT was developed for simultaneously delivering 1-methyl tryptophan (1-MT) of an indoleamine 2,3-dioxygenase (IDO) inhibitor and chemotherapeutic doxorubicin (DOX) for breast cancer immunochemotherapy. DOX/PEG2k-Fmoc-1-MT micelles were more effective in cell proliferation inhibition and apoptosis induction in 4T1 cells. PEG2k-Fmoc-1-MT prodrug micelles presented enhanced inhibition ability of IDO with decreased kynurenine production and increased the proliferation in dose-dependent manners of effector CD4+ and CD8+ T cells. DOX/PEG2k-Fmoc-1-MT micelles exhibited prolonged blood circulation time and superior accumulation of DOX and 1-MT in tumors compared to that of DOX and 1-MT solutions. A significantly enhanced immune response of the DOX/PEG2k-Fmoc-1-MT micelles was observed with the decreasing tryptophan/kynurenine ratio in blood and tumor tissue, promoting effector CD4+ and CD8+ T cells while reducing regulatory T cell (Tregs) expression. Meanwhile, the coreleased DOX-triggered immunogenic cell death action combined with the cleaved 1-MT promoted the related cytokine secretion of tumor necrosis factor-α, interleukin-2, and interferon-γ, further facilitating the T cell-mediated immune responses. More importantly, the DOX-loaded micelles led to a significantly improved inhibition on tumor growth and prolonged animal survival rate in a 4T1 murine breast cancer model. In conclusion, DOX codelivered by a PEG2k-Fmoc-1-MT immunostimulatory polymeric prodrug showed a maximum immunochemotherapy efficacy against breast cancer.