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首页> 外文期刊>Advanced Functional Materials >pH/Cathepsin B Hierarchical-Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo-lmmunotherapy
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pH/Cathepsin B Hierarchical-Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo-lmmunotherapy

机译：pH /组织蛋白酶B分层响应纳米缀合物，用于增强肿瘤渗透和化学Lmmun疗法

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摘要

An ideal cancer nanomedicine should precisely deliver therapeutics to its intracellular target within tumor cells. However, the multiple biological barriers seriously hinder their delivery efficiency, leading to unsatisfactory therapeutic outcome. Herein, pH/cathepsin B hierarchical-responsive nanoconjugates (HRNs) are reported to overcome these barriers by sequentially responding to extra- and intracellular stimuli in solid tumors for programmed delivery of docetaxel (DTX). The HRNs have stable nanostructures (approximate to 40 nm) in blood circulation for efficient tumor accumulation, while the tumor extracellular acidity induces the rapid dissociation of HRNs into polymer conjugates (approximate to 5 nm), facilitating the deep tumor penetration and cellular internalization. After being trapped into the lysosomes, the conjugates are cleaved by cathepsin B to release bioactive DTX into cytoplasm and inhibit cell proliferation. In addition to the direct inhibition effect, HRNs can trigger the in vivo antitumor immune responses via the immunogenic modulation of tumor cells, activation of dendritic cells (DCs), and generation of cytotoxic T-cell responses. By employing a combination with alpha-PD-1 (programmed cell death 1) therapy, synergistic antitumor efficacy is achieved in B16 expressing ovalbumin (B16OVA) tumor model. Hence, this strategy demonstrates high efficiency for precise intracellular delivery of chemotherapeutics and provides a potential clinical candidate for cancer chemo-immunotherapy.
机译：理想的癌症纳米胺应在肿瘤细胞内精确地将治疗剂送入其细胞内靶标。然而，多种生物障碍严重阻碍了其输送效率，导致治疗结果不令人满意。这里，据报道，pH /组织蛋白酶B分层响应纳米缀合物（HRNS）克服这些屏障通过顺序响应固体瘤中的特性和细胞内刺激而被用于编程的多西紫杉醇（DTX）。 HRNS在血液循环中具有稳定的纳米结构（近似为40nm），以获得有效的肿瘤积累，而肿瘤细胞外酸会诱导HRNs进入聚合物缀合物（近似为5nm），促进深肿瘤渗透和细胞内化。在被困成溶酶体后，缀合物被组织蛋白酶B切割，以将生物活性DTX释放到细胞质中并抑制细胞增殖。除了直接抑制效果之外，HRN可以通过肿瘤细胞的免疫原调制来引发体内抗肿瘤免疫应答，树突细胞（DC）的激活，以及细胞毒性T细胞应答的产生。通过使用与α-PD-1（编程细胞死亡1）治疗的组合，在表达卵烧（B16OVA）肿瘤模型的B16中实现协同抗肿瘤功效。因此，该策略表明了精确的细胞内递送化学治疗剂的高效率，并为癌症化学免疫疗法提供了潜在的临床候选物。

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  • 来源
    《Advanced Functional Materials》 |2020年第39期|2003757.1-2003757.14|共14页
  • 作者

    Du Hongliang; Zhao Sui; Wang Yaoqi; Wang Zenghui; Chen Binlong; Yan Yue; Yin Qingqing; Liu Dechun; Wan Fangjie; Zhang Qiang; Wang Yiguang;

  • 作者单位

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

    Peking Univ State Key Lab Nat & Biomimet Drugs Beijing 100191 Peoples R China|Peking Univ Sch Pharmaceut Sci Beijing Key Lab Mol Pharmaceut & New Drug Deliver Beijing 100191 Peoples R China;

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  • 正文语种 eng
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  • 关键词

    acidic tumor microenvironment; chemo-immunotherapy; nanoconjugates; programmed intracellular delivery; tumor penetration;

    机译：酸性肿瘤微环境;化学免疫疗法;纳米缀合物;编程的细胞内递送;肿瘤渗透;

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