Combinational Chemoimmunotherapy for Breast Cancer by Codelivery of Doxorubicin and PD-L1 siRNA Using a PAMAM-Incorporated Liposomal Nanoplatform.

Abstract

Chemoimmunotherapy can synergistically enhance the therapeutic effects and decrease the side effects by a combined method. However, the effective targeted codelivery of various chemotherapeutic agents and siRNAs remains challenging. Although nanomedicine-based chemoimmunotherapy has shown great potential in cancer treatment in recent years, further effort is needed to simplify the nanocarrier designs and maintain their effective functions. Here, we report a simple but robust multifunctional liposomal nanocarrier that contains a pH-sensitive liposome (LP) shell and a dendritic core for tumor-targeted codelivery of programmed cell death ligand 1 (PD-L1) siRNA and doxorubicin (DOX) (siPD-L1@PM/DOX/LPs). siPD-L1@PM/DOX/LPs had a suitable particle size and zeta potential, excellent stability in serum, and pH-sensitive drug release in vitro. They exhibited significant cell proliferation inhibition compared to free DOX and DOX-loaded LPs and could escape endosomes, effectively release siRNA into the cytoplasm of MCF-7 cells, and significantly reduce the PD-L1 expression on tumor cells. In vivo imaging confirmed high accumulation of siPD-L1@PM/DOX/LPs at the tumor site. More importantly, compared with siPD-L1@PM/LPs or DOX alone, siPD-L1@PM/DOX/LPs were more effective in inhibiting tumor growth and activating cytotoxic T cells in vivo. In conclusion, this nanocarrier may hold promise as a codelivery nanoplatform to improve the treatment of various solid tumors.