Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance

Journal of Nanobiotechnology

Zhiyi Zhou¹  Shuling Liu²  Meng Ao³  Lei Su³  Chen Cheng³  Junrui Wang³  Zhuoyan Xie³  Pan Li³  Xun Guo³  Xingyue Wang³  Jianli Ren³  Yuanli Luo³  Yang Cao³  Haitao Ran³  Weixi Jiang³  Zhigang Wang³ 

[1] Department of General Practice of Chongqing General Hospital, University of Chinese Academy of Sciences, 401147, Chongqing, People’s Republic of China;Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, 400010, Chongqing, People’s Republic of China;Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical University, 400010, Chongqing, People’s Republic of China;

关键词: Multidrug resistance;    Endo/lysosomal escape;    Tumor homing-penetrating peptide;    Chemotherapy enhancement;    PD-L1 blockade;   

DOI  :  10.1186/s12951-021-00947-9

来源: Springer

【 摘 要 】

BackgroundRecent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents.ResultsIn this study, we fabricated a “combo” nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors.ConclusionThis work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel.Graphic Abstract

【 授权许可】

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