RESUMEN
Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments, but its clinical implementation has been restricted by the low host antitumor response rate. Recently, chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication. The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism. Herein, a synergistic antitumor platform (designated as BMS/RA@CC-Liposome) was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug (RA-V) and PD-1/PD-L1 blockade inhibitor (BMS-202) to remarkably enhance antitumor immunity. In this study, the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem. To achieve the cell-specific targeting drug delivery, the combination therapy nanosystem was functionalized with cancer cell membrane camouflage. The biomimetic drug delivery system perfectly disguised as endogenous substances, and realized elongated blood circulation due to anti-phagocytosis capability. Moreover, the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells. The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response, RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells. Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically, demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.
RESUMEN
BACKGROUND: Natural cyclopeptide RA-XII, isolated from Rubia yunnanensis, is a promising chemotherapeutic agent for colon cancer. The photosensitizer protoporphyrin-IX attached with triphenylphosphonium (TPP) could possess mitochondria targeting capacity and exert photodynamic therapy (PDT) by inducing oxidizing damage to the mitochondria and cell apoptosis eventually. In this work, pH-sensitive liposomes were constructed to simultaneously deliver RA-XII as a chemotherapeutic drug and modified porphyrin as a mitochondria-targeting photosensitizer to treat colon cancer, and verified its mechanism of action and antitumor therapeutic efficacy. METHODS: The colon cancer targeting liposome nanoparticle RA/TPPP-Lip was synthesized using thin film hydration. The therapeutic effect and targeting ability of RA/TPPP-Lip was investigated in vitro. And use HCT116 cell allogeneic subcutaneous transplantation tumor model to investigate the anti-tumor and targeting effects of RA/TPPP-Lip in vivo. RESULTS: RA/TPPP-Lip gained the targeting ability through surface-modified HA to increase the accumulation of RA-XII and TPPP in colon cancer cells. A series of in vitro experimental results showed that TPPP produced cytotoxic ROS under laser irradiation to directly damage cell mitochondria and played a combined role with RA-XII, making RA/TPPP-Lip the best colon cancer cell growth inhibitory effect. Furthermore, in vivo antitumor experiments showed that the RA/TPPP-Lip substantially accumulated at the tumor site and efficiently repressed tumor growth in nude mice. CONCLUSION: We have successfully designed a new cancer-targeted nanomedicine platform (RA/TPPP-Lip) for the collaborative treatment of colon cancer, which can achieve the targeted continuous release of multiple therapeutic drugs. This work provides a new strategy for precise combination therapy, which may promote the further development of collaborative cancer treatment platforms.