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Apolipoprotein E Peptide-Guided Disulfide-Cross-Linked Micelles for Targeted Delivery of Sorafenib to Hepatocellular Carcinoma.
Biomacromolecules ( IF 5.5 ) Pub Date : 2019-12-06 , DOI: 10.1021/acs.biomac.9b01419 Yingwen Li , Jingjing Wei , Yaohua Wei , Liang Cheng , Beibei Guo , Fenghua Meng , Feng Li 1 , Zhiyuan Zhong
Biomacromolecules ( IF 5.5 ) Pub Date : 2019-12-06 , DOI: 10.1021/acs.biomac.9b01419 Yingwen Li , Jingjing Wei , Yaohua Wei , Liang Cheng , Beibei Guo , Fenghua Meng , Feng Li 1 , Zhiyuan Zhong
Affiliation
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Sorafenib (SF) is an FDA-approved molecular-targeted drug for treating hepatocellular carcinoma (HCC). SF, however, suffers from poor water solubility, low bioavailability, dose-limiting side effects, and possible drug resistance. Here, we report on apolipoprotein E peptide-decorated disulfide-cross-linked micellar SF (ApoE-Ms-SF) as a targeted and intelligent formulation for HCC therapy. ApoE-Ms-SF was prepared with a good SF loading of 7.0 wt %, small size (37 nm), high stability, and reduction-triggered drug release from poly(ethylene glycol)-b-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate (PEG-P(CL-DTC)-MA) and ApoE-modified ApoE-PEG-P(CL-DTC) block copolymers. MTT assays in low-density lipoprotein receptors (LDLRs) overexpressing SMMC-7721 human liver cancer cells showed ApoE density-dependent antitumor potency of ApoE-Ms-SF, in which 7.5% ApoE led to the best antitumor effect (IC50: 8.5 vs 23.3 μg/mL for free SF). Confocal studies, flow cytometry, western blot, and apoptotic assays illustrated clearly a more efficient uptake of ApoE-Ms than nontargeted Ms by SMMC-7721 cells as well as lower phosphorylated extracellular signal-regulated kinase protein level and better cell apoptosis caused by ApoE-Ms-SF compared with Ms-SF and free SF. ApoE-Ms-SF revealed a long circulation time (elimination half-life = 6.8 h). DiR-loaded ApoE-Ms showed a significantly higher accumulation in SMMC-7721 tumor than the nontargeted counterpart. The therapeutic outcomes in the orthotopic SMMC-7721 tumor models demonstrated that ApoE-Ms-SF reduced SF-associated side effects and brought about enhanced angiogenesis inhibition and tumor apoptosis compared to free SF and Ms-SF controls, leading to a better treatment of HCC.
中文翻译：
载脂蛋白E肽引导的二硫键交叉连接的胶束，用于将索拉非尼靶向递送至肝细胞癌。
索拉非尼（SF）是FDA批准的用于治疗肝细胞癌（HCC）的分子靶向药物。但是，SF具有水溶性差，生物利用度低，剂量限制的副作用以及可能的耐药性的问题。在这里，我们报告载脂蛋白E肽装饰的二硫键交联的胶束SF（ApoE-Ms-SF）作为针对HCC治疗的靶向和智能制剂。制备的ApoE-Ms-SF具有7.0 wt％的良好SF负载，小尺寸（37 nm），高稳定性以及从聚（乙二醇）-b-聚（ε-己内酯-co-co-二硫杂环戊烷碳酸三亚甲基酯）-甲芬那酸酯（PEG-P（CL-DTC）-MA）和ApoE改性的ApoE-PEG-P（CL-DTC）嵌段共聚物。在过表达SMMC-7721人肝癌细胞的低密度脂蛋白受体（LDLR）中进行的MTT分析显示，ApoE-Ms-SF的ApoE密度依赖性抗肿瘤效力，其中7.5％ApoE导致最佳的抗肿瘤作用（IC50：8.5 vs 23.3）游离SF的微克/毫升）。共聚焦研究，流式细胞术，蛋白质印迹和凋亡分析清楚地表明，SMMC-7721细胞比非靶向Ms更有效地吸收ApoE-Ms，并且磷酸化的细胞外信号调节激酶蛋白水平更低，并且由ApoE-引起的细胞凋亡更好Ms-SF与Ms-SF和游离SF的比较。ApoE-Ms-SF显示循环时间长（消除半衰期= 6.8小时）。负载DiR的ApoE-Ms在SMMC-7721肿瘤中的蓄积明显高于未靶向的对应物。
更新日期：2019-12-07
中文翻译：
载脂蛋白E肽引导的二硫键交叉连接的胶束，用于将索拉非尼靶向递送至肝细胞癌。
索拉非尼（SF）是FDA批准的用于治疗肝细胞癌（HCC）的分子靶向药物。但是，SF具有水溶性差，生物利用度低，剂量限制的副作用以及可能的耐药性的问题。在这里，我们报告载脂蛋白E肽装饰的二硫键交联的胶束SF（ApoE-Ms-SF）作为针对HCC治疗的靶向和智能制剂。制备的ApoE-Ms-SF具有7.0 wt％的良好SF负载，小尺寸（37 nm），高稳定性以及从聚（乙二醇）-b-聚（ε-己内酯-co-co-二硫杂环戊烷碳酸三亚甲基酯）-甲芬那酸酯（PEG-P（CL-DTC）-MA）和ApoE改性的ApoE-PEG-P（CL-DTC）嵌段共聚物。在过表达SMMC-7721人肝癌细胞的低密度脂蛋白受体（LDLR）中进行的MTT分析显示，ApoE-Ms-SF的ApoE密度依赖性抗肿瘤效力，其中7.5％ApoE导致最佳的抗肿瘤作用（IC50：8.5 vs 23.3）游离SF的微克/毫升）。共聚焦研究，流式细胞术，蛋白质印迹和凋亡分析清楚地表明，SMMC-7721细胞比非靶向Ms更有效地吸收ApoE-Ms，并且磷酸化的细胞外信号调节激酶蛋白水平更低，并且由ApoE-引起的细胞凋亡更好Ms-SF与Ms-SF和游离SF的比较。ApoE-Ms-SF显示循环时间长（消除半衰期= 6.8小时）。负载DiR的ApoE-Ms在SMMC-7721肿瘤中的蓄积明显高于未靶向的对应物。
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