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

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Tan et al, Biomaterials 2021_Accepted Manuscript.pdfFile embargoed until 26 August 20221.15 MBAdobe PDF    Request a copy
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Title: Enhanced chemo-photodynamic therapy of an enzyme-responsive prodrug in bladder cancer patient-derived xenograft models
Authors: Tan, P
Cai, H
Wei, Q
Tang, X
Zhang, Q
Kopytynski, M
Yang, J
Yi, Y
Zhang, H
Gong, Q
Gu, Z
Chen, R
Luo, K
Item Type: Journal Article
Abstract: 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 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.
Issue Date: Oct-2021
Date of Acceptance: 4-Aug-2021
DOI: 10.1016/j.biomaterials.2021.121061
ISSN: 0142-9612
Publisher: Elsevier BV
Start Page: 1
End Page: 13
Journal / Book Title: Biomaterials
Volume: 277
Copyright Statement: © 2021 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: RDF01
Keywords: Bioinformatics analysis
Bladder cancer
Chemo-photodynamic therapy
PDX models
Photo-chemical internalization
Polymer-paclitaxel prodrug
Biomedical Engineering
Publication Status: Published
Embargo Date: 2022-08-26
Article Number: 121061
Online Publication Date: 2021-08-27
Appears in Collections:Chemical Engineering
Faculty of Engineering

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