Enzyme-Induced Transformable Peptide Nanocarriers with Enhanced Drug Permeability and Retention to Improve Tumor Nanotherapy Efficacy
Enzyme-Induced Transformable Peptide Nanocarriers with Enhanced Drug Permeability and Retention to Improve Tumor Nanotherapy Efficacy
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DOI：
10.1021/acsami.1c17917
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发表时间：
2021-12-01
影响因子：
9.5
通讯作者：
Bai, Jingkun
中科院分区：
文献类型：
--
作者：
Gong, Zhongying;Zhou, Baolong;Bai, Jingkun
对于纳米载体来说，时间持久性与空间准确性一样重要。然而，由于化疗药物在肿瘤中的聚集不足和滞留时间短，极大地限制了其临床应用。依赖于对肿瘤微环境中存在的酶的敏感性的药物递送方法被设计为在不同部位表现出不同的尺寸，从而实现增强的药物渗透性和保留，以提高肿瘤纳米治疗的功效。在这项工作中，我们报告了一个小分子肽药物传递系统，含有肿瘤靶向基团和酶反应位点。该系统能够将肽纳米载体靶向递送至肿瘤细胞，并对肿瘤微环境中的碱性磷酸酶（ALP）产生独特的响应，以激活形态转化和药物释放。两亲性肽AYR在包封脂溶性模型药物阿霉素（DOX）后自聚集成球形纳米颗粒结构，并通过ALP的诱导迅速转化为纳米纤维。这种向高纵横比的形态学转变允许快速且有效的药物释放到肿瘤位置，同时增强对肿瘤细胞的特异性毒性。有趣的是，这种“Transformer”样的药物递送策略可以增强局部药物蓄积并有效抑制药物外排。体外沿着体内实验进一步证明，抗肿瘤药物在肿瘤细胞和组织中的渗透和滞留显著增强，毒副作用降低，治疗效果较不变形载药肽纳米载体显著提高。开发的AYR纳米颗粒具有原位形态转化的能力，可以改善肿瘤部位的局部药物聚集和保留时间。我们的研究结果为新型癌症治疗中的纳米载体形态转化提供了一种新的简单方法。
Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.