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Branched Polymer‐Based Redox/Enzyme‐Activatable Photodynamic Nanoagent to Trigger STING‐Dependent Immune Responses for Enhanced Therapeutic Effect

Qiang LuoHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaZhenyu DuanHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaXiaoling LiHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaLei GuHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaLong RenHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaHongyan ZhuHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaXiaohe TianFunctional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 ChinaRongjun ChenDepartment of Chemical Engineering Imperial College London South Kensington Campus London SW7 2AZ UKHu ZhangAmgen Bioprocessing Centre Keck Graduate Institute Claremont CA 91711 USAQiyong GongFunctional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 ChinaZhongwei GuHuaxi MR Research Center (HMRRC) Department of Radiology National Clinical Research Center for Geriatrics Frontiers Science Center for Disease‐Related Molecular Network State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaKui LuoFunctional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of Psychoradiology Chinese Academy of Medical Sciences Chengdu 610041 China

2021en

ABI

Annotatsiya

Abstract Immune response in the tumor microenvironment (TME) is an essential therapeutic factor for antitumor therapy. Herein, to improve immunostimulatory effects, photodynamic therapy (PDT) is combined with AZD2281 to trigger the stimulator of interferon genes (STING)‐dependent immune responses. A synthetic branched polymer‐pyropheophorbide a (Ppa) conjugate (BGSSP) is designed and developed in response to redox/cathepsin B of the TME. This conjugate with a unique structure and a large molecular weight (MW) can self‐assemble into a compact structure via hydrophilic and hydrophobic forces, inducing self‐quenching of conjugated Ppa. AZD2281 is encapsulated in BGSSP to obtain a TME‐activatable photodynamic nanoagent, AZD@BGSSP. AZD@BGSSP with a stable assembly structure accumulates effectively in tumors and enters lysosomes through endocytosis pathways. Polymer degradation, Ppa activation, and AZD2281 release are achieved after exposure of AZD@BGSSP to highly expressed cathepsin B and glutathione in tumor cells. After laser irradiation, AD2281 inhibits the repair of damaged DNA caused by ROS from PDT and promotes generation of cytosolic DNA, which activates the cGAS‐STING pathway and further induces interferons‐mediated immune responses and a long‐term immune memory effect for immunotherapy. This nanoagent opens a new door to combination PDT and immune response for anti‐cancer treatment.

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Identifikatorlar

DOI: 10.1002/adfm.202110408

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