Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release
Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release
复制标题
基质金属蛋白酶敏感的尺寸可收缩纳米粒子，用于深度肿瘤渗透和 pH 触发阿霉素释放。
DOI：
10.1016/j.biomaterials.2015.05.006
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发表时间：
2015-08-01
期刊：
影响因子：
14
通讯作者：
Gao, Huile
中科院分区：
文献类型：
--
作者：
Ruan, Shaobo;Cao, Xi;Gao, Huile
纳米载体广泛用于向肿瘤输送药物，并呈稳定发展趋势。增强渗透性和保留（EPR）效应一直是开发针对实体瘤的刺激响应性纳米载体的关键原理。在本研究中，我们开发了一种新型纳米载体G-AuNPs-DOX-PEG，它是由可收缩明胶纳米颗粒包被、阿霉素（DOX）束缚的金纳米颗粒和长链聚乙二醇（PEG）构建而成。 G-AuNPs-DOX-PEG的粒径为186.5 nm，zeta电位为-4.21 mV，DOX负载量为9.22%。在体外，G-AuNPs-DOX-PEG可以被MMP-2蛋白降解，尺寸从186.5 nm缩小到593 nm。 G-AuNPs-DOX-PEG 中 DOX 的释放具有 pH 值和时间依赖性。在pH 5.0时，DOX的释放比高pH值时快得多，G-AuNPs-DOX-PEG中DOX的累积释放率接近90.9%。细胞摄取表明 G-AuNPs-DOX-PEG 可以通过内体介导的途径内化。肿瘤球体穿透和胶原凝胶扩散表明，G-AuNPs-DOX-PEG与MMP-2预孵育可显着提高其穿透效率。体内和离体成像表明，G-AuNPs-DOX-PEG 能够以最高强度分布到 4T1 和 B16F10 肿瘤中。相应地，用G-AuNPs-DOX-PEG治疗的4T1和B16F10荷瘤小鼠显示出最低的肿瘤生长率。综上所述，肿瘤微环境敏感的尺寸收缩G-AuNPs-DOX-PEG可以递送至肿瘤深部区域，然后释放DOX，从而产生最佳的抗肿瘤效果。 (C) 2015 Elsevier Ltd. 保留所有权利。
Nanocarriers are widely used for delivering drugs to tumors and are progressing in a stable trend. The enhanced permeability and retention (EPR) effect has been a key rationale for the development of stimulus-responsive nanocarriers to solid tumor. In this study, we developed a kind of novel nanocarrier, G-AuNPs-DOX-PEG, which was constructed with shrinkable gelatin nanoparticles coated, doxorubicin (DOX) tethered gold nanoparticles and long chain polyethylene glycol (PEG). The particle size of G-AuNPs-DOX-PEG was 186.5 nm with a zeta potential of -4.21 mV and the DOX loading capacity was 9.22%. In vitro, the G-AuNPs-DOX-PEG could be degraded by MMP-2 proteins with a size shrink from 186.5 nm to 593 nm. The release of DOX from G-AuNPs-DOX-PEG was in a pH- and time-dependent manner. At pH 5.0, the release of DOX was much quicker than that at high pH value and the cumulative release rate of DOX from G-AuNPs-DOX-PEG was approach 90.9%. Cellular uptake demonstrated that G-AuNPs-DOX-PEG could be internalized via the endosome-mediated pathway. Tumor spheroid penetration and collagen gel diffusion showed G-AuNPs-DOX-PEG with pre-incubation with MMP-2 could significantly enhance its penetrating efficiency. In vivo and ex vivo imaging exhibit that G-AuNPs-DOX-PEG could distribute into 4T1 and B16F10 tumor at a highest intensity. Correspondingly, 4T1 and B16F10 tumor bearing mice treated with G-AuNPs-DOX-PEG displayed the lowest tumor growth rate. In summary, the tumor microenvironment sensitive size-shrinkable G-AuNPs-DOX-PEG could deliver into deep tumor region and then release DOX, resulting in a best anti-tumor effect. (C) 2015 Elsevier Ltd. All rights reserved.