环状 RGD 肽修饰脂质体给药系统：增强体外细胞摄取并改善大鼠药代动力学。,International Journal of Nanomedicine

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环状 RGD 肽修饰脂质体给药系统：增强体外细胞摄取并改善大鼠药代动力学。
International Journal of Nanomedicine ( IF 6.6 ) Pub Date : 2012-07-18 , DOI: 10.2147/ijn.s33541
Zhongya Chen ₁ , Jiaxin Deng , Yan Zhao , Tao Tao

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背景整合素α(v)β(3) 和α(v)β(5)，两者都特异性识别Arg-Gly-Asp (RGD) 基序，在许多实体瘤和肿瘤新血管系统中过度表达。因此，将 RGD 基序耦合到脂质体表面以实现主动靶向可能是治疗肿瘤的有前途的策略。方法环（Arg-Gly-Asp-D-Phe-Cys）（cRGD）与脂质体膜表面共价偶联，然后使用后插入技术用聚（乙二醇）（PEG）包被。确定了 cRGD 的偶联效率。使用硫酸铵梯度法将多柔比星作为模型抗癌药物加载到脂质体中，以研究封装效率、体外过表达整合素的人神经胶质瘤细胞系 U87MG 的细胞摄取以及 Sprague-Dawley 大鼠的药代动力学特性。结果 cRGD 通过硫醇-马来酰亚胺偶联反应偶联到脂质体表面。耦合效率达到98%。阿霉素在脂质体中的包封率达98%以上。流式细胞仪检测结果表明，与非靶向脂质体（DXRL-PEG）相比，cRGD修饰的脂质体（RGD-DXRL-PEG）对U87MG细胞的细胞摄取更高。在过量游离 cRGD 的存在下，细胞摄取被显着抑制。靶向（t(1/2) = 24.10 小时）和非靶向（t(1/2) = 25.32 小时）脂质体在大鼠血浆中均显示出长循环特性。靶向和非靶向脂质体的曲线下面积分别比阿霉素溶液高 6.4 倍和 8.3 倍。

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Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats.

BACKGROUND Integrins α(v)β(3) and α(v)β(5), both of which specifically recognize the Arg-Gly-Asp (RGD) motif, are overexpressed on many solid tumors and in tumor neovasculature. Thus, coupling the RGD motif to the liposomal surface for achieving active targeting can be a promising strategy for the treatment of tumors. METHODS Cyclo(Arg-Gly-Asp-D-Phe-Cys) (cRGD) was covalently coupled with the liposomal membrane surface, followed by coating with poly(ethylene glycol) (PEG) using the post-insertion technique. The coupling efficiency of cRGD was determined. Doxorubicin as a model anticancer drug was loaded into liposomes using an ammonium sulfate gradient method to investigate the encapsulation efficiency, cellular uptake by the integrin-overexpressing human glioma cell line U87MG in vitro, and pharmacokinetic properties in Sprague-Dawley rats. RESULTS cRGD was conjugated to the liposomal surface by a thiol-maleimide coupling reaction. The coupling efficiency reached 98%. The encapsulation efficiency of doxorubicin in liposomes was more than 98%. The flow cytometry test result showed that cRGD-modified liposomes (RGD-DXRL-PEG) had higher cell uptake by U87MG cells, compared with nontargeted liposomes (DXRL-PEG). The cellular uptake was significantly inhibited in the presence of excess free cRGD. Both the targeted (t(1/2) = 24.10 hours) and non-targeted (t(1/2) = 25.32 hours) liposomes showed long circulating properties in rat plasma. The area under the curve of the targeted and nontargeted liposomes was 6.4-fold and 8.3-fold higher than that of doxorubicin solution, respectively. CONCLUSION This study indicates preferential targeting and long circulating properties for cRGD-modified liposomes in vivo, which could be used as a potential targeted liposomal drug delivery system to treat human glioma.

更新日期：2019-11-01

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