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Tumor Microenvironment-Activatable Nanoenzymes for Mechanical Remodeling of Extracellular Matrix and Enhanced Tumor Chemotherapy

机译：肿瘤微环境 - 活化纳米酶，用于机械重塑细胞外基质和增强肿瘤化疗

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摘要

Increased tissue stiffness is a hallmark of cancer and promotes tumor progression. It is hypothesized that decreased tumorous stress may aid or sensitize chemotherapies. To overcome extracellular matrix (ECM) stiffening and fulfill sensitized chemotherapy in one nanosystem, a reactive oxygen species-activatable nanoenzyme (SP-NE) based on a dendritic polyglycerol scaffold, integrating collagenase and paclitaxel (PTX) prodrug, is constructed. The dense and tough ECM is highly remitted by SP-NE in the tumor microenvironment (TME) mimicking gelatin hydrogel models, which causes cell shrinkage, disorders cytoskeletal constructions, and subsequently enhances chemotherapeutic efficacy. ECM softening via SP-NE downregulates mechanotransduction signaling pathways of integrin-focal adhesion kinase (FAK)-Ras homolog family member A (RhoA) implicated in cytoskeletal assembly, and integrin-FAK-phosphorylated extracellular signal regulated kinase (pERK 1/2) mediating mitosis. Notably, this programmed nanosystem in human breast MCF-7 tumor-bearing mice models displays a significant relief of ECM stress from 4300 to 1200 Pa and results in 87.1% suppression of tumor growth at a low PTX dosage of 3 mg kg(-1). The attenuated expression of the key players RhoA and pERK 1/2 involved in cellular mechano-sensing is further verified in vivo. This study thus provides a new and potential nanoplatform to selectively decrease TME stiffness for enhanced chemotherapy.
机译：增加的组织僵硬是癌症的标志，促进肿瘤进展。假设膜压力降低可能有助于或敏化化疗。为了克服细胞外基质（ECM）加强和满足一个纳米系统中的敏化化疗，构建基于树突式聚甘油支架，整合胶原酶和紫杉醇（PTX）前药的反应性氧物质可活化的纳米酶（SP-NE）。通过SP-NE在肿瘤微环境（TME）中的致密和强烈的ECM在模仿明胶水凝胶模型中高度汇编，这导致细胞收缩，疾病细胞骨骼结构，随后提高了化疗效果。通过SP-NE软化ECM软化，下调整合素焦粘连激酶（FAK）的机械调节信号通路（FAK） - 同源物家庭成员A（RHOA）涉及细胞骨骼组件，整合素-FAK-磷酸化细胞外信号调节激酶（PERK 1/2）中介有丝分裂。值得注意的是，该编程的人乳房MCF-7肿瘤小鼠模型的纳米系统显示出4300至1200Pa的ECM应激的显着缓解，并导致87.1％的肿瘤抑制在3mg kg（-1）的低ptx剂量下。在体内进一步验证了涉及细胞机械传感的关键球员RhoA和Perk 1/2的衰减表达。因此，该研究提供了一种新的和潜在的纳米片，以选择性地降低增强化疗的TME刚度。

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  • 来源
    《Advanced Functional Materials》 |2021年第3期|2007544.1-2007544.11|共11页
  • 作者

    Zhong Yinan; Zhang Jianguang; Zhang Junmei; Hou Yong; Chen Enping; Huang Dechun; Chen Wei; Haag Rainer;

  • 作者单位

    China Pharmaceut Univ Dept Pharmaceut Engn Nanjing 211198 Peoples R China|Free Univ Berlin Inst Chem & Biochem Takustr 3 D-14195 Berlin Germany;

    China Pharmaceut Univ Dept Pharmaceut Engn Nanjing 211198 Peoples R China|Free Univ Berlin Inst Chem & Biochem Takustr 3 D-14195 Berlin Germany;

    China Pharmaceut Univ Dept Pharmaceut Engn Nanjing 211198 Peoples R China|Free Univ Berlin Inst Chem & Biochem Takustr 3 D-14195 Berlin Germany;

    Free Univ Berlin Inst Chem & Biochem Takustr 3 D-14195 Berlin Germany;

    China Pharmaceut Univ Dept Pharmaceut Engn Nanjing 211198 Peoples R China;

    China Pharmaceut Univ Dept Pharmaceut Engn Nanjing 211198 Peoples R China;

    China Pharmaceut Univ Dept Pharmaceut Engn Nanjing 211198 Peoples R China;

    Free Univ Berlin Inst Chem & Biochem Takustr 3 D-14195 Berlin Germany;

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  • 正文语种 eng
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  • 关键词

    mechanical remodeling; nanomedicine; sensitized chemotherapy; tumor microenvironment; tumor stiffness;

    机译：机械重塑;纳米医生;敏化化疗;肿瘤微环境;肿瘤僵硬;

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