Tumor Microenvironmental pH and Enzyme Dual Responsive Polymer-Liposomes for Synergistic Treatment of Cancer Immuno-Chemotherapy.

ABSTRACT

Despite recent advances in tumor treatment through cancer immunotherapy, the efficacy of this approach remains to be improved. Looking forward to high rates of objective clinical response, cancer immunotherapy combined with chemotherapy has gained increasing attention recently. Here, we constructed liposomes with matrix metalloproteinases (MMPs) responsive moiety and PD-L1 inhibitor conjugate combine with low dose chemotherapy to achieve enhanced antitumor efficacy. Upon introduction of the pH-responsive polymer to LPDp, the coassembly could be almost stable in physiological conditions and tumor microenvironments and release the loaded cargos at the lysosome. MMP-2 enzyme extracellularly secreted by the B16F10 cells could cleave the cross-linker and liberate the PD-L1 inhibitor effectively disrupting the PD-1/PD-L1 interaction in vitro. Low dose DOX encapsulated in the LPDp was capable of sensitizing B16F10 cells to CTLs by inducing overexpression of M6PR on tumor cell membranes. In comparison with free PD-L1 inhibitor, LPDp improved the biodistribution and on-demand release of the peptide inhibitor in tumor regions following administration. LPDp achieved the optimal tumor suppression efficiency (∼78.7%), which demonstrated the significantly enhanced antitumor effect ( P < 0.01) than that of LPp (∼57.5%) as well as that of LD (<40%), attributing to synergistic contribution from the substantial increase in M6PR expression on tumor cells and the blockade of immune checkpoints. This strategy provides a strong rationale for combining standard-of-care chemotherapy with relative nontoxic and high specific immunotherapy.