Abstract

Overactivation of PI3K signaling has been identified in prostate cancer. ZSTK is an effective pan-PI3K inhibitor, but it was withdrawn from early-phase clinical trials because of its poor solubility, on-target/off-tumor toxicity, and recruitment and polarization of tumor-associated macrophages (TAMs). Indomethacin (IND) reduces the polarization of TAMs, increases the proinflammatory macrophage (M1 phenotype) ratio in the tumor microenvironment, and enhances the immune response in tumor cells. Herein, we developed ZSTK carrier-free nanoparticle (ZNP)-loaded biomimetic hybrid indomethacin liposomes ( [email protected] ) with PC3 cell membranes (termed ZNPs/ [email protected] ). ZNPs/ [email protected] displayed amplified synergistic therapeutic effects on zebrafish and nude mouse PC3 xenograft models. Their homologous targeting ability can deliver ZSTK to tumor tissue and elicit effective antiproliferative effects on PC3 cancer cells. Meanwhile, the released IND improved the immunosuppressive microenvironment, inducing immunological activation against cancer cells. Additionally, ZNPs/ [email protected] did not cause liver toxicity compared with other treatment groups, as shown by histological analysis, suggesting their improved safety. Our data demonstrate that biomimetic hybrid liposome-coated carrier-free nanoparticles are a promising nanoplatform for amplifying the antitumor efficacy of kinase-inhibiting therapeutics with immunotherapy, but more preclinical and clinical evidence is required.