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Tumor-targeted self-assembled micelles reducing PD-L1 expression combined with ICIs to enhance chemo-immunotherapy of TNBC

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Chinese Chemical Letters 2024年第2期35卷 305-310页

作者： Hongda Zhu Kai Ma Rui Ruan Chaobo Yang Aqin Yan Jing Li Qi Yu Hongmei Sun Mingxing Liu Hongmei Zheng Jing Gao Xiaofang Guan Zhu Dai Yao Sun Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province) Key Laboratory of Fermentation Engineering (Ministry of Education)National “111” Center for Cellular Regulation and Molecular PharmaceuticsSchool of Food and Biological EngineeringHubei University of TechnologyWuhan 430068China Hubei Cancer Hospital Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430079China National Key Laboratory of Green Pesticide College of ChemistryCentral China Normal UniversityWuhan 430079China Key Laboratory of Medical Optics Suzhou Institute of Biomedical Engineering and TechnologyChinese Academy of SciencesSuzhou 215163China Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science Ministry of EducationQingdao University of Science and TechnologyQingdao 266000China

Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of ***,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive *** results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of *** micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.

关键词： Immunotherapy Tumor-targeted self-assembled micelles Metformin Reducing PD-L1 expression TNBC

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Redox-responsive self-assembly polymeric micelles based on mPEG-β-cyclodextrin and a camptothecin prodrug as drug release carriers

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Journal of Chinese Pharmaceutical Sciences 2021年第12期30卷 941-955页

作者： Yiben Lu Miao Zhang Yongjun Zheng Xinyu Hou Muye He Kaiyan Lou Feng Gao Shanghai Key Laboratory of Functional Materials Chemistry East China University of Science and TechnologyShanghai 200237China Shanghai Key Laboratory of New Drug Design East China University of Science and TechnologyShanghai 200237China Department of Pharmaceutics School of PharmacyEast China University of Science and TechnologyShanghai 200237China

Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-β-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin(CPT) in a reductive environment inside cancer cells. The host-guest supramolecular micelles utilized a simple β-CD modified PEG, mPEG-β-cyclodextrin(mPEG-β-CD), as the polymeric host with the ease of synthesis and purification. The guest prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against He La cells comparable to the free drug. The host-guest polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment.

关键词： mPEG-β-cyclodextrin Camptothecin prodrug self-assembled micelles Redox-responsive Supramolecular

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