Mixed Nanosized Polymeric Micelles as Promoter of Doxorubicin and miRNA-34a Co-Delivery Triggered by Dual Stimuli in Tumor Tissue.
Mixed Nanosized Polymeric Micelles as Promoter of Doxorubicin and miRNA-34a Co-Delivery Triggered by Dual Stimuli in Tumor Tissue.
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DOI：
10.1002/smll.201600925
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Torchilin VP
中科院分区：
文献类型：
--
作者：
Salzano G;Costa DF;Sarisozen C;Luther E;Mattheolabakis G;Dhargalkar PP;Torchilin VP
双刺激敏感的混合聚合物胶束 (MM) 被开发用于将内源性肿瘤抑制因子 miRNA-34a 和化疗药物阿霉素 (Dox) 共同递送到癌细胞中。该系统的新颖性在于两种刺激敏感的前药，一种是基质金属蛋白酶2（MMP2）敏感的Dox缀合物，另一种是还原剂（谷胱甘肽，GSH）敏感的miRNA-34a缀合物，它们自组装在单个颗粒中，并用聚乙二醇冠装饰以延长寿命，并用细胞穿透肽（TATp）来增强细胞内递送。与低表达 MMP2 的 MCF7 细胞相比，该系统对 MMP2 的敏感性导致过表达 MMP2 的 HT1080 细胞的细胞毒性高出 3 倍。将 TATp 添加到配方中后，Dox 的细胞内化增加了 70% 以上。 MMP2 敏感的 MM 还抑制 HT1080 细胞的增殖和迁移。此外，GSH 敏感的 MM 可以有效下调 HT1080 细胞中的 Bcl2、survivin 和 notch1（分别为 65%、55% 和 46%）。双敏感 MM 中两种缀合物的组合可将 HT1080 细胞活力降低至 40%，并降低 Bcl2 和生存素的表达。最后，在肿瘤块的 3D 模型中观察到 50% 的细胞死亡。结果证实了 MM 在肿瘤组织固有的双重刺激下共同递送 miRNA-34a 和阿霉素的潜力。设计的系统由两种刺激敏感的缀合物组成，它们组装在装饰有 PEG 冠和细胞穿透肽的颗粒中。它在细胞外蛋白酶和细胞内还原环境裂解后选择性地将阿霉素和 miRNA-34a 释放到靶组织中，从而促进细胞活力下降和肿瘤进展相关基因的下调。
Dual stimuli-sensitive mixed polymeric micelles (MM) are developed for co-delivery of the endogenous tumor suppressor miRNA-34a and the chemotherapeutic agent doxorubicin (Dox) into cancer cells. The novelty of the system resides in two stimuli-sensitive prodrugs, a matrix metalloproteinase 2 (MMP2)-sensitive Dox conjugate and a reducing agent (glutathione, GSH)-sensitive miRNA-34a conjugate, self-assembled in a single particle decorated with a polyethylene glycol corona for longevity and a cell-penetrating peptide (TATp) for enhanced intracellular delivery. The MMP2-sensitivity of the system results in 3-fold higher cytotoxicity in MMP2-overexpressing HT1080 cells compared to low MMP2-expressing MCF7 cells. Cellular internalization of Dox increases by more than 70% after inclusion of TATp to the formulation. MMP2-sensitive MM also inhibits proliferation and migration of HT1080 cells. Moreover, GSH-sensitive MM allows for an efficient downregulation of Bcl2, survivin, and notch1 (65%, 55% and 46%, respectively) in HT1080 cells. Combination of both conjugates in dual sensitive MM reduces HT1080 cell viability to 40% and expression of Bcl2 and survivin. Finally, 50% cell death is observed in 3D models of tumor mass. The results confirm the potential of the MM to co-deliver miRNA-34a and doxorubicin triggered by dual stimuli inherent of tumor tissues. The designed system is composed of two stimuli-sensitive conjugates assembled in a particle decorated with a PEG corona and a cell-penetrating peptide. It selectively releases doxorubicin and miRNA-34a into the target tissue after cleavage by extracellular proteinases and an intracellular reductive environment, which promotes decrease in cell viability and downregulation of genes involved in tumor progression.
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影响因子：
11.2
作者：
Bader AG;Brown D;Winkler M
通讯作者：
Winkler M
来自人神经胶质瘤细胞系的多细胞球体的建立和表征；对肿瘤治疗的影响。
影响因子：
7.4
作者：
Khaitan, D;Chandna, S;Arya, MB;Dwarakanath, BS
通讯作者：
Dwarakanath, BS
影响因子：
4.9
作者：
Navarro G;Pan J;Torchilin VP
通讯作者：
Torchilin VP
影响因子：
8
作者：
Lees, J. G.;Bach, C. T. T.;O'Neill, G. M.
通讯作者：
O'Neill, G. M.
DOI：
10.1007/978-1-4939-2806-4_24
发表时间：
2015-01-01
期刊：
CELL-PENETRATING PEPTIDES: METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Salzano, Giuseppina;Torchilin, Vladimir P.
通讯作者：
Torchilin, Vladimir P.