Self-assembled nanoparticles based on the c(RGDfk) peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy.
Self-assembled nanoparticles based on the c(RGDfk) peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy.
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DOI：
10.2147/ijn.s63717
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发表时间：
2014
影响因子：
8
通讯作者：
Ji A
中科院分区：
文献类型：
--
作者：
Liu L;Liu X;Xu Q;Wu P;Zuo X;Zhang J;Deng H;Wu Z;Ji A
小干扰RNA(SiRNA)存在细胞内摄取差、血清稳定性差、不能靶向特异性细胞等缺点，限制了其临床应用。在过去的几十年里，人们致力于探索siRNA传递的材料。在本研究中，由cyclo(Arg–Gly–Asp–d–Phe–Lys)-8–amino–3，6–dioxaoctanoic酸-β-马来酰亚胺丙酸(以下简称RPM)组成的可生物降解的、肿瘤靶向的自组装肽纳米粒在体内外都被发现是一种有效的小干扰RNA载体。利用透射电子显微镜、圆二色谱和动态光散射对纳米颗粒进行了表征。体外分析表明，RPM/VEGFR2-siRNA的细胞毒性可忽略不计，并可诱导有效的基因沉默。将RPM/VEGFR2(斑马鱼)-siRNA导入斑马鱼胚胎可抑制新生血管形成。给荷瘤裸鼠注射RPM/VEGFR2(小鼠)-siRNA可显著抑制肿瘤生长，显著减少肿瘤血管，并下调肿瘤组织中VEGFR2(信使RNA和蛋白质)的表达。此外，通过酶联免疫吸附试验检测小鼠血清中干扰素-α、干扰素-γ、IL-12和IL-6的水平，并未表明RPM/VEGFR2(小鼠)-siRNA在体内具有任何免疫原性。综上所述，RPM为siRNAs在肿瘤治疗中的临床应用提供了一种安全有效的载体。
The clinical application of small interfering RNA (siRNA) has been restricted by their poor intracellular uptake, low serum stability, and inability to target specific cells. During the last several decades, a great deal of effort has been devoted to exploring materials for siRNA delivery. In this study, biodegradable, tumor-targeted, self-assembled peptide nanoparticles consisting of cyclo(Arg–Gly–Asp–d–Phe–Lys)-8–amino–3,6–dioxaoctanoic acid–β–maleimidopropionic acid (hereafter referred to as RPM) were found to be an effective siRNA carrier both in vitro and in vivo. The nanoparticles were characterized based on transmission electron microscopy, circular dichroism spectra, and dynamic light scattering. In vitro analyses showed that the RPM/VEGFR2-siRNA exhibited negligible cytotoxicity and induced effective gene silencing. Delivery of the RPM/VEGFR2 (zebrafish)-siRNA into zebrafish embryos resulted in inhibition of neovascularization. Administration of RPM/VEGFR2 (mouse)-siRNA to tumor-bearing nude mice led to a significant inhibition of tumor growth, a marked reduction of vessels, and a down-regulation of VEGFR2 (messenger RNA and protein) in tumor tissue. Furthermore, the levels of IFN-α, IFN-γ, IL-12, and IL-6 in mouse serum, assayed via enzyme-linked immunosorbent assay, did not indicate any immunogenicity of the RPM/VEGFR2 (mouse)-siRNA in vivo. In conclusion, RPM may provide a safe and effective delivery vector for the clinical application of siRNAs in tumor therapy.