Chemo-Photodynamic Therapy With Light-Triggered Disassembly Of Theranostic Nanoplatform In Combination With Checkpoint Blockade For Immunotherapy Of Hepatocellular Carcinoma

Objective:Hepatocellular carcinoma(HCC)is the third leading cause of cancer death in the world.Vast majority of patients are diagnosed at advanced stage that lose the chance of radical surgery,and the high probability of recurrence and metastasis leading to more than 90%of cancer-caused deaths is the major challenge in clinical treatment of HCC.The current treatment strategies still cannot achieve satisfactory therapeutic effect,especially in unresectable HCC patients.Therefore,how to effectively eradicate the primary tumor and suppress recurrence and metastasis is the key to improve the efficacy of HCC.Although immune checkpoint blockade(ICB)has emerged as a promising type of immunotherapy in advanced HCC,treatment with ICB alone achieves an objective remission rate less than 20%.Thus,combination therapy strategies is needed to improve the treatment response rate and therapeutic effect.Methods:In this study,we designed and synthesized an active tumor targeting lighttriggered disassembly of nano-micelle.The nanocarrier originates from a ROS-sensitive thioketal(TK)linkage-bridged diblock copolymer of PEG with polylactic acid-glycolic acid(PLGA)(PEG-TK-PLGA).The cRGD peptide is coupled with NHS-PEG-TK-PLGA through an amidation reaction,and then through the self-assembly of cRGD-PEG-TKPLGA and PEG-TK-PLGA,excellent tumor targeting can be obtained on the prepared micelles of cRGD-modified PEG-TK-PLGA.The light-triggered disassembly of nanoplatform(TB/PTX@RTK)co-loaded an aggregation induced emission(AIE)photosensitizer(TB)and paclitaxel(PTX)for on-command drug release and synergistic chemo-PDT.Nano-micelles were characterized for drug loading content,hydrodynamic size,absorption and emission spectra,reactive oxygen species production,and PTX release from micelles.The targeted fluorescence imaging of TB/PTX@RTK micelles and the synergistic anti-tumor efficacy of TB/PTX@RTK micelles-mediated chemo-PDT combined with anti-PD-L1 were assessed both in vitro and in vivo.Results:The TB/PTX@RTK micelles could specifically accumulate at the tumor site through cRGD-mediated active target and facilitate image-guided PDT for tumor ablation.Once irradiated by light,the AIE photosensitizer of TB could produce ROS for PDT,and the thioketal linker could be cleaved by ROS to precise release of PTX in tumor cells.Chemo-PDT could not only synergistically inhibit tumor growth,but also induce immunogenic cell death and elicit anti-tumor immune response.Meanwhile,chemo-PDT significantly upregulated the expression of PD-L1 on tumor cell surface which could efficiently synergize with anti-PD-L1 monoclonal antibodies to induce an abscopal effect.Conclusion:Our results suggest that the combination of TB/PTX@RTK micelle-mediated chemo-PDT with anti-PD-L1 monoclonal antibodies can synergistically enhance systemic anti-tumor effects,and provide a novel insight into the development of new nanomedicine with precise controlled release and multimodal therapy to enhance the therapeutic efficacy.