Development and activity evaluation of Arg-Gly-Asp-containing antithrombotic conjugate

Publication date: Available online 16 July 2019Source: Journal of Molecular StructureAuthor(s): Shuangling Chen, Zidong Peng, Yuji Wang, Jianhui Wu, Ran An, Rongrong Miao, Ming Zhao, Shiqi PengAbstractPoly-α,β-D,L-aspartic acid (PD) is highly susceptible to the degradation of lysosomal enzyme and produce monomeric aspartic acid as the product. Exogenous RGD-containing sequences could inhibit platelet aggregation and formation of thrombosis by competitively binding to activated platelet membrane GPIIb/IIIa receptors. Poly-α,β-D,L-aspartyl-Arg-Gly-Asp-Ser (PD-RGDS) was synthesized by conjugating anti-thrombotic RGDS to the highly biodegradable poly-α,β-D,L-aspartic acid molecules (PD) and its structure was confirmed. PD-RGDS existed as the nanoparticles of 60–108 nm at 10−6 M by TEM and SEM. In vitro anti-platelet aggregation assay showed that PD-RGDS could preferentially inhibit platelet aggregation induced by PAF (IC50 33.5 nM). In vivo antithrombotic activity of PD-RGDS was evaluated with a rat model of carotid artery and venous bypass cannulation. PD-RGDS had increased antithrombotic activity (1 nmol/kg by ig.) compared with RGDS(5 μmol/kg). Furthermore, to measure blood concentration of PD-RGDS in rats, FITC-PD-RGDS was prepared and had an elimination half-life of 240.3 ± 49.6 min by intragastric administration of 50 mg/kg. Therefore PD-RGDS could be built as a novel oral antithrombotic agent.Graphical abstract
Source: Journal of Molecular Structure - Category: Molecular Biology Source Type: research