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Enhanced chemo-photodynamic therapy of an enzyme-responsive prodrug in bladder cancer patient-derived xenograft models.

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机构： [a]Department of Urology, Institute of Urology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, China [b]Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China [c]State Key Laboratory for Environment-friendly Energy Materials, Southwest University of Science and Technology, Mianyang, 621010, China [d]State Key Laboratory Cultivation Base for Nonmetal Composite and Functional Materials, Southwest University of Science and Technology, Mianyang, 621010, China [e]Amgen Bioprocessing Centre, Keck Graduate Institute, CA, 91711, USA [f]Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, United Kingdom

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Patient-derived xenograft (PDX) models are powerful tools for understanding cancer biology and drug discovery. In this study, a polymeric nano-sized drug delivery system poly (OEGMA)-PTX@Ce6 (NPs@Ce6) composed of a photosensitizer chlorin e6 (Ce6) and a cathepsin B-sensitive polymer-paclitaxel (PTX) prodrug was constructed. The photochemical internalization (PCI) effect and enhanced chemo-photodynamic therapy (PDT) were achieved via a two-stage light irradiation strategy. The results showed that the NPs@Ce6 had great tumor targeting and rapid cellular uptake induced by PCI, thereby producing excellent anti-tumor effects on human bladder cancer PDX models with tumor growth inhibition greater than 98%. Bioinformatics analysis revealed that the combination of PTX chemotherapy and PDT up-regulated oxidative phosphorylation and reactive oxygen species (ROS) generation, blocked cell cycle and proliferation, and down-regulated the pathways related to tumor progression, invasion and metastasis, including hypoxia, TGF-β signaling and TNF-α signaling pathways. Western blots analysis confirmed that proteins promoting apoptosis (Bax, Cleaved caspase-3, Cleaved PARP) and DNA damage (γH2A.X) were up-regulated, while those inhibiting apoptosis (Bcl-2) and mitosis (pan-actin and α/β-tubulin) were down-regulated after chemo-PDT treatment. Therefore, this stimuli-responsive polymer-PTX prodrug-based nanomedicine with combinational chemotherapy and PDT evaluated in the PDX models could be a potential candidate for bladder cancer therapy.Copyright © 2021 Elsevier Ltd. All rights reserved.

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出版当年[2021]版：

大类 | 1 区

工程技术

小类 | 1 区工程：生物医学 1 区材料科学：生物材料

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大类 | 1 区

医学

小类 | 1 区工程：生物医学 1 区材料科学：生物材料

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第一作者机构： [a]Department of Urology, Institute of Urology, Huaxi MR Research Center (HMRRC), National Clinical Research Center for Geriatrics, Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, China

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