Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy,Molecular Pharmaceutics

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Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-10-10 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00404
Jinming Zhang ₁ , Yifeng Zheng ₂ , Xi Xie ₃ , Lan Wang ₂ , Ziren Su ₂ , Yitao Wang ₁ , Kam W. Leong ₄ , Meiwan Chen ₁

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Although tumor-targeting nanovehicles for hepatocellular carcinoma (HCC) chemotherapy have attracted great research and clinic interest, the poor cancer penetration, inefficient cellular uptake, and slow intracellular drug release greatly compromise their therapeutic outcomes. In this work, a multifunctional mixed micellar system, consisting of glycyrrhetinic acid (GA) for specific liver-targeting, trans-activator of transcription (TAT) peptide for potent cell penetration, and pH-sensitive poly(β-amino ester) polymers for acidic-triggered drug release, was developed to provide HCC-targeting delivery and pH-triggered release of doxorubicin (DOX). These micelles were hypothesized to efficaciously accumulate in HCC site by the guide of GA ligands, enter into cancer cells facilitated by the activated TAT peptide on the micellar surface, and finally rapidly release DOX in cytoplasm. To demonstrate this design, DOX was initially loaded in micelles modified with both GA and TAT (DOX/[email protected]) with high drug loading efficiency and pH-sensitive drug release profiles. The HCC-targeting cellular uptake and synergetic anticancer efficacy were tested, indicating DOX/[email protected] could be specifically and effectively internalized into HCC cells by the effect of GA targeting and TAT penetrating with enhanced cytotoxicity. In addition, the prolonged circulation time and enhanced accumulation in tumor facilitated its potent tumor growth inhibition activity in vivo. These results demonstrated that the cleavable multifunctional mixed micelles with tumor targeting, controlled TAT peptide activation, and sequential pH-sensitive drug release could be an efficient strategy for HCC treatment.

中文翻译：

具有顺序的pH触发TAT肽活化作用的可切割多功能靶向混合胶束，可提高抗肝细胞癌的疗效

尽管用于肝细胞癌（HCC）化疗的靶向肿瘤纳米载体已经引起了广泛的研究和临床兴趣，但是不良的癌症渗透性，低效率的细胞摄取以及缓慢的细胞内药物释放极大地损害了它们的治疗效果。在这项工作中，一个多功能混合胶束系统组成，该系统由用于特定肝靶向的甘草次酸（GA），用于有效细胞渗透的转录反式激活剂（TAT）以及对pH敏感的聚（β-氨基酯）聚合物组成。开发了酸性触发药物释放以提供HCC靶向递送和pH触发的阿霉素（DOX）释放。假设这些胶束在GA配体的引导下有效地积聚在HCC部位，并通过胶束表面上活化的TAT肽促进进入癌细胞，并最终在细胞质中快速释放DOX。为了证明该设计，将DOX最初加载到经GA和TAT修饰的胶束中（DOX / [电子邮件保护]），并具有较高的药物加载效率和pH敏感的药物释放曲线。测试了靶向HCC的细胞摄取和协同抗癌功效，表明通过GA靶向和TAT穿透的作用增强了细胞毒性，DOX / [电子邮件保护]可以特异性和有效地内化到HCC细胞中。此外，延长的循环时间和增强的肿瘤积累促进了其强大的肿瘤生长抑制活性测试了靶向HCC的细胞摄取和协同抗癌功效，表明通过GA靶向和TAT穿透的作用增强了细胞毒性，DOX / [电子邮件保护]可以特异性和有效地内化到HCC细胞中。此外，延长的循环时间和增强的肿瘤积累促进了其强大的肿瘤生长抑制活性测试了靶向HCC的细胞摄取和协同抗癌功效，表明通过GA靶向和TAT穿透的作用增强了细胞毒性，DOX / [电子邮件保护]可以特异性和有效地内化到HCC细胞中。此外，延长的循环时间和增强的肿瘤积累促进了其强大的肿瘤生长抑制活性体内。这些结果表明，具有肿瘤靶向，可控的TAT肽激活和连续的pH敏感药物释放的可裂解多功能混合胶束可能是HCC治疗的有效策略。

更新日期：2017-10-10

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