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A dendritic polymer-based nanosystem mediates drug penetration and irreversible endoplasmic reticulum stresses in tumor via neighboring effect.

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机构： [1]Huaxi MR Research Center (HMRRC), Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. [2]Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, and Core Facility of West China Hospital, West China Hospital, Sichuan University, Chengdu, 610041, China. [3]Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, United Kingdom. [4]Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA, 91711, USA. [5]Functional and molecular imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China.

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Nanoparticles (NPs)-based cancer therapeutics is generally impeded by poor drug penetration into solid tumors due to their dense tumor extracellular matrix (ECM). Herein, we develop pH/redox-responsive dendritic polymer-based NPs to amplify the neighboring effect for improving drug penetration and driving cell apoptosis via combination therapy. Pyropheophorbide a (Ppa) is conjugated with PEGylated dendritic peptides via disulfide bonds and doxorubicin (DOX) encapsulated in the conjugate to construct dual-responsive NPs, PDPP@D. Delayed released DOX and Ppa from PDPP@D exert their combination therapeutic effect to induce cell apoptosis, and then they are liberated out of dying cells to amplify the neighboring effect, resulting in their diffusion through the dense ECM and penetration into solid tumors. Transcriptome studies reveal that PDPP@D leads to irreversible stress on the endoplasmic reticulum and inhibits cell protection through blocking the IRE1-dependent survival pathway and unleashing the DR5-mediated caspase activity to promote cell death. The strategy of amplifying the neighboring effect of NPs through combination therapy may offer great potential in enhancing drug penetration and eradicating solid tumors. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.

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出版当年[2022]版：

大类 | 1 区

材料科学

小类 | 1 区材料科学：综合 1 区物理化学 1 区物理：凝聚态物理 1 区化学：综合 1 区纳米科技 1 区物理：应用

最新[2023]版：

大类 | 1 区

材料科学

小类 | 1 区化学：综合 1 区物理化学 1 区材料科学：综合 1 区纳米科技 1 区物理：应用 1 区物理：凝聚态物理

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第一作者机构： [1]Huaxi MR Research Center (HMRRC), Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.

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通讯机构： [1]Huaxi MR Research Center (HMRRC), Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. [5]Functional and molecular imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China.

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