pH /组织蛋白酶B层级响应纳米共轭物，可增强肿瘤渗透性和化学免疫治疗。,Advanced Functional Materials

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pH /组织蛋白酶B层级响应纳米共轭物，可增强肿瘤渗透性和化学免疫治疗。
Advanced Functional Materials ( IF 18.5 ) Pub Date : 2020-07-30 , DOI: 10.1002/adfm.202003757
Hongliang Du _{1,

2} , Sui Zhao _{1,

2} , Yaoqi Wang _{1,

2} , Zenghui Wang _{1,

2} , Binlong Chen _{1,

2} , Yue Yan ₂ , Qingqing Yin _{1,

2} , Dechun Liu _{1,

2} , Fangjie Wan _{1,

2} , Qiang Zhang _{1,

2} , Yiguang Wang _{1,

2}

Affiliation

理想的癌症纳米药物应精确地将治疗剂递送至肿瘤细胞内的细胞内靶标。但是，多种生物屏障严重阻碍了它们的递送效率，导致治疗效果不理想。在本文中，据报道，pH /组织蛋白酶B分层反应性纳米共轭物（HRNs）通过顺序响应实体肿瘤中的细胞外和细胞内刺激，以编程性的多西他赛（DTX）递送来克服这些障碍。HRNs在血液循环中具有稳定的纳米结构（≈40nm），可以有效地积聚肿瘤，而肿瘤细胞外的酸性会诱导HRNs快速解离为聚合物结合物（≈5nm），从而促进深层肿瘤的渗透和细胞内在化。被溶酶体困住后组织蛋白酶B裂解偶联物，将生物活性DTX释放到细胞质中并抑制细胞增殖。除直接抑制作用外，HRN还可以通过肿瘤细胞的免疫原性调节，树突状细胞（DC）的激活以及细胞毒性T细胞反应的产生来触发体内抗肿瘤免疫反应。通过与α-PD-1（程序性细胞死亡1）疗法联合使用，可在表达B16的卵白蛋白（B16OVA）肿瘤模型中获得协同的抗肿瘤功效。因此，该策略显示了精确的细胞内化学疗法递送的高效率，并为癌症化学免疫疗法提供了潜在的临床候选者。HRN可以通过肿瘤细胞的免疫原性调节，树突状细胞（DC）的激活以及细胞毒性T细胞反应的产生来触发体内抗肿瘤免疫反应。通过与α-PD-1（程序性细胞死亡1）疗法联合使用，可在表达B16的卵白蛋白（B16OVA）肿瘤模型中获得协同的抗肿瘤功效。因此，该策略显示了精确的细胞内化学疗法递送的高效率，并为癌症化学免疫疗法提供了潜在的临床候选者。HRN可以通过肿瘤细胞的免疫原性调节，树突状细胞（DC）的激活以及细胞毒性T细胞反应的产生来触发体内抗肿瘤免疫反应。通过与α-PD-1（程序性细胞死亡1）疗法联合使用，可在表达B16的卵白蛋白（B16OVA）肿瘤模型中获得协同的抗肿瘤功效。因此，该策略显示了精确的细胞内化学疗法递送的高效率，并为癌症化学免疫疗法提供了潜在的临床候选者。

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pH/Cathepsin B Hierarchical‐Responsive Nanoconjugates for Enhanced Tumor Penetration and Chemo‐Immunotherapy

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 (≈40 nm) in blood circulation for efficient tumor accumulation, while the tumor extracellular acidity induces the rapid dissociation of HRNs into polymer conjugates (≈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 α‐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.

更新日期：2020-09-25

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