Aptamer-functionalized peptide H3CR5C as a novel nanovehicle for codelivery of fasudil and miRNA-195 targeting hepatocellular carcinoma.
Aptamer-functionalized peptide H3CR5C as a novel nanovehicle for codelivery of fasudil and miRNA-195 targeting hepatocellular carcinoma.
复制标题
适体功能化肽 H3CR5C 作为一种新型纳米载体，用于共同递送法舒地尔和 miRNA-195 靶向肝细胞癌。
DOI：
10.2147/ijn.s108128
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发表时间：
2016
影响因子：
8
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Liu Y;Wu X;Gao Y;Zhang J;Zhang D;Gu S;Zhu G;Liu G;Li X
肝癌是第五大常见的恶性肿瘤，其中肝细胞癌是最常见的组织亚型。针对血管内皮生长因子(VEGF)的抗血管生成治疗显示出良好的临床前景，但由于血管生成拟态是一种高度图案化的血管通道，有别于内皮依赖的血管，它可能在包括肝癌在内的侵袭性肿瘤中发挥血供网络的作用。在本研究中，我们使用了一种新型的阳离子多肽--二硫化硬脂酸化组氨酸修饰的聚精氨酸肽(H3R5)作为还原载体，与肝癌细胞特异结合的穿透性多肽修饰适配子(ST21)作为靶向探针，miRNA-195(MiR195)作为抑制血管内皮生长的强大基因药物，法舒地尔通过阻断ROCK2来抑制血管生成拟态，所有这些都同时被包裹在相同的纳米粒中。法舒地尔通过硫酸铵诱导的跨膜电化学梯度负载，miR195通过静电相互作用进行缩合。ST21-H3R5-聚乙二醇对法舒地尔和miR195均表现出良好的载药能力，给药比例可调。Western印迹分析表明，FasudilST21-H3R5-PEGmiR195与FasudilH3R5-PEGmiR195相比，具有较强的ROCK2和VEGF沉默活性。体外和体内实验证实，ST21修饰的纳米颗粒在肿瘤细胞或肿瘤组织中的细胞摄取率和治疗效果明显高于未修饰的纳米颗粒。这些发现表明，适配子结合的多肽在同时输送化学药物和基因药物以对抗肝癌方面具有很大的前景。
Liver cancer is the fifth most commonly diagnosed malignancy, of which hepatocellular carcinoma (HCC) represents the dominating histological subtype. Antiangiogenic therapy aimed at vascular endothelial growth factor (VEGF) has shown promising but deficient clinical prospects on account of vasculogenic mimicry, a highly patterned vascular channel distinguished from the endothelium-dependent blood vessel, which may function as blood supply networks occurring in aggressive tumors including HCC. In this study, we used a new cationic peptide, disulfide cross-linked stearylated polyarginine peptide modified with histidine (H3R5), as a reducible vector, cell penetrating peptide-modified aptamer (ST21) with specific binding to HCC cells to conjugate to peptide H3R5 as the targeting probe, miRNA-195 (miR195) as a powerful gene drug to inhibit VEGF, and fasudil to suppress vasculogenic mimicry by blocking ROCK2, all of which were simultaneously encapsulated in the same nanoparticles. Fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient and miR195 was condensed through electrostatic interaction. ST21-H3R5-polyethylene glycol (PEG) exhibited excellent loading capacities for both fasudil and miR195 with adjustable dosing ratios. Western blot analysis showed that FasudilST21-H3R5-PEGmiR195 had strong silencing activity of ROCK2 and VEGF, as compared with FasudilH3R5-PEGmiR195. In vitro and in vivo experiments confirmed that ST21-modified nanoparticles showed significantly higher cellular uptake and therapeutic efficacy in tumor cells or tumor tissues than the unmodified counterparts. These findings suggest that aptamer-conjugated peptide holds great promise for delivering chemical drugs and gene drugs simultaneously to overcome HCC.