Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy  

作　　者：Zaigang Zhou Jiashe Chen Yu Liu Chunjuan Zheng Wenjuan Luo Lele Chen Shen Zhou Zhiming Li Jianliang Shen 

机构地区：[1]State Key Laboratory of Ophthalmology,Optometry and Vision Science,School of Ophthalmology and Optometry,School of Biomedical Engineering,Wenzhou Medical University,Wenzhou 325027,China [2]Department of the First Affiliated Hospital of Wenzhou Medical Unaiversity,Wenzhou 325000,China [3]School&Hospital of Stomatology,Wenzhou Medical Untiversity,Wenzhou 325027,China [4]Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325000,China [5]Oujiang Laboratory(Zhejiang Lalb for Regenerative Medicine,Vision and Brain Health),Wenzhou 325000,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第11期4204-4223,共20页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82003697 and 21977081);the Zhejiang Provincial Natural Science of Foundation of China(LZ19H180001);Wenzhou Medical University(KYYW201901,China);Wenzhou Science and Technology Plan Project(Grant No.Y2020827,China);Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province(Grant No:2018E10008,China).

摘　　要：As a promising modality for cancer therapy, photodynamic therapy(PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin(BSA-MHI148) and multi-kinase inhibitor Sorafenib(SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms:(i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory.(ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows:(i) Enhanced immunogenic cell death(ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species(ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability.(ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSAMHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.

关 键 词：Photodynamic immunotherapy SORAFENIB Hypoxia Tumor vessel normalization Mitochondrial oxidative phosphorylation Programmed death ligand-1 

分 类 号：R730.51[医药卫生—肿瘤]