纳米级阿司匹林-Arg-Gly-Asp-Val：将阿司匹林通过靶载体Arg-Gly-Asp-Val四肽传递至血栓。,ACS Nano

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纳米级阿司匹林-Arg-Gly-Asp-Val：将阿司匹林通过靶载体Arg-Gly-Asp-Val四肽传递至血栓。
ACS Nano ( IF 15.8 ) Pub Date : 2013-08-29 00:00:00 , DOI: 10.1021/nn402171v
Shaoming Jin,Yaonan Wang,Haimei Zhu,Yuji Wang,Shurui Zhao,Ming Zhao,Jiawang Liu,Jianhui Wu,Wen Gao,Shiqi Peng

对阿司匹林的抗药性和无反应性会大大降低其治疗功效。为了克服这个问题，通过将Arg-Gly-Asp-Val四肽与阿司匹林共价连接，开发了一种靶向阿门汀-Arg-Gly-Asp-Val（阿司匹林-Arg-Gly-Asp-Val）的小分子药物递送系统。二维ROESY NMR和ESI-MS光谱支持A-RGDV四聚体的分子模型。透射电子显微镜图像表明，四聚体在水中自发组装成纳米颗粒（直径为5至50 nm）。扫描电子显微镜图像和原子力显微镜图像表明，A-RGDV的较小纳米颗粒进一步组装成在大鼠血液中稳定的较大颗粒。传递研究表明，在大鼠血液中，A-RGDV能够保持其分子完整性，而在血栓中，它会释放阿司匹林。这体外抗血小板凝集试验表明，A-RGDV选择性抑制花生四烯酸诱导的血小板凝集。作用机制可能包括释放阿司匹林，修饰环氧化酶和降低GPIIb / IIIa的表达。在体内测定证明，A-RGDV的有效的抗血栓形成剂量为16700倍阿司匹林的非响应剂量低。

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Nanosized Aspirin-Arg-Gly-Asp-Val: Delivery of Aspirin to Thrombus by the Target Carrier Arg-Gly-Asp-Val Tetrapeptide

Resistance and nonresponse to aspirin dramatically decreases its therapeutic efficacy. To overcome this issue, a small-molecule thrombus-targeting drug delivery system, aspirin-Arg-Gly-Asp-Val (A-RGDV), is developed by covalently linking Arg-Gly-Asp-Val tetrapeptide with aspirin. The 2D ROESY NMR and ESI-MS spectra support a molecular model of an A-RGDV tetramer. Transmission electron microscopy images suggest that the tetramer spontaneously assembles to nanoparticles (ranging from 5 to 50 nm in diameter) in water. Scanning electron microscopy images and atomic force microscopy images indicate that the smaller nanoparticles of A-RGDV further assemble to bigger particles that are stable in rat blood. The delivery investigation implies that in rat blood A-RGDV is able to keep its molecular integrity, while in a thrombus it releases aspirin. The in vitro antiplatelet aggregation assay suggests that A-RGDV selectively inhibits arachidonic acid induced platelet aggregation. The mechanisms of action probably include releasing aspirin, modifying cyclic oxidase, and decreasing the expression of GPIIb/IIIa. The in vivo assay demonstrates that the effective antithrombotic dose of A-RGDV is 16700-fold lower than the nonresponsive dose of aspirin.

更新日期：2013-08-29

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