Nucleolin-Targeting AS1411-Aptamer-Modified Graft Polymeric Micelle with Dual pH/Redox Sensitivity Designed To Enhance Tumor Therapy through the Codelivery of Doxorubicin/TLR4 siRNA and Suppression of Invasion,Molecular Pharmaceutics

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Nucleolin-Targeting AS1411-Aptamer-Modified Graft Polymeric Micelle with Dual pH/Redox Sensitivity Designed To Enhance Tumor Therapy through the Codelivery of Doxorubicin/TLR4 siRNA and Suppression of Invasion
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-12-18 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b01093
Shudi Yang ₁ , Zhaoxiang Ren ₂ , Mengtian Chen ₁ , Ying Wang ₁ , Bengang You ₁ , Weiliang Chen ₁ , Chenxi Qu ₁ , Yang Liu ₁ , Xuenong Zhang ₁

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In this article, a novel graft polymeric micelle with targeting function ground on aptamer AS1411 was synthesized. The micelle was based on chitosan-ss-polyethylenimine-urocanic acid (CPU) with dual pH/redox sensitivity and targeting effects. This micelle was produced for codelivering Toll-like receptor 4 siRNA (TLR4–siRNA) and doxorubicin (Dox). In vitro investigation revealed the sustained gene and drug release from Dox–siRNA-loaded micelles under physiological conditions, and this codelivery nanosystem exhibited high dual pH/redox sensitivity, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro. Furthermore, the micelles loaded with TLR4–siRNA inhibited the migration and invasion of A549. Excellent tumor penetrating efficacy was also noted in the A549 tumor spheroids and solid tumor slices. In vivo, multiple results demonstrated the excellent tumor-targeting ability of AS1411-chitosan-ss-polyethylenimine-urocanic acid (ACPU) micelle in tumor tissues. The micelles exhibited excellent antitumor efficacy and low toxicity in the systemic circulation in lung-tumor-bearing BALB/c mice. These results conclusively demonstrated the great potential of the new graft copolymer micelle with targeting function for the targeted and efficient codelivery of chemotherapeutic drugs and genes in cancer treatment.

中文翻译：

具有双 pH/氧化还原敏感性的核仁素靶向 AS1411 适体修饰的移植聚合物胶束，旨在通过阿霉素/TLR4 siRNA 的共递送和抑制侵袭来增强肿瘤治疗

本文合成了一种基于适配体AS1411的新型具有靶向功能的接枝聚合物胶束。该胶束基于壳聚糖-SS-聚乙烯亚胺-尿刊酸 (CPU)，具有双重 pH/氧化还原敏感性和靶向作用。该胶束是为共同递送 Toll 样受体 4 siRNA (TLR4–siRNA) 和阿霉素 (Dox) 而生产的。体外研究表明，在生理条件下，负载 Dox-siRNA 的胶束能够持续释放基因和药物，并且这种共递送纳米系统表现出高双 pH/氧化还原敏感性、快速的细胞内药物释放以及体外对 A549 细胞的改善的细胞毒性。此外，负载TLR4-siRNA的胶束抑制A549的迁移和侵袭。 A549 肿瘤球体和实体瘤切片也具有出色的肿瘤穿透功效。体内多项结果表明AS1411-壳聚糖-ss-聚乙烯亚胺-尿刊酸（ACPU）胶束在肿瘤组织中具有优异的肿瘤靶向能力。该胶束在肺肿瘤 BALB/c 小鼠的体循环中表现出优异的抗肿瘤功效和低毒性。这些结果最终证明了具有靶向功能的新型接枝共聚物胶束在癌症治疗中靶向高效地共递送化疗药物和基因的巨大潜力。

更新日期：2017-12-18

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