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.
College of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, People's Republic of China.
Shaoming
S
Jin
Yaonan
Y
Wang
Haimei
H
Zhu
Yuji
Y
Wang
Shurui
S
Zhao
Ming
M
Zhao
Jiawang
J
Liu
Jianhui
J
Wu
Wen
W
Gao
Shiqi
S
Peng
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D001241:Aspirin / Q000008:administration & dosage*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D008297:Male; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005343:Fibrinolytic Agents; D053769:Nanocapsules; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C086684:arginyl-glycyl-aspartyl-valine; D051545:Cyclooxygenase 1; D001241:Aspirin