Spatial targeting of tumor-associated macrophage and tumor cells with a designer nanocarrier for cancer chemo-immunotherapy.

Abstract

Chemo-immunotherapy which combines chemotherapeutics with immune-modulating agents represents an appealing approach to improving cancer therapy [1, 2]. To maximize its efficacy, differential and precise targeting of the multiple therapeutics into corresponding cells is desirable. Here we develop an immunostimulatory nanocarrier that simultaneously loads platinum (Pt)-based chemotherapeutic prodrug and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of tumor-associated macrophages (TAMs) [3], to spatially target tumor cells and TAMs for cancer chemo-immunotherapy. The nanoparticles (denoted as BLZ-945SCNs/Pt) undergo supersensitive structure collapse through responding to tumor acidity, along with instantaneous release of BLZ-945 and Pt-prodrug conjugated small particles. The extracellularly released BLZ-945 could be taken up by TAMs, which locate preferentially in the perivascular region [4], to directly disturb CSF-1/CSF-1R signaling pathway to suppress TAMs and modulate the tumor immune microenvironment, while the released small particles carrying Pt-prodrug could penetrate deeply into bulk tumor to kill more cancer cells [5], realizing synergistic antitumor effect of chemo- and immunotherapy (Fig. 1). Our in vivo studies demonstrate that the co-delivery nanocarrier outperforms monotherapy in varying tumor models.