cRGD Peptide-Modified Nanocarriers for Targeted Delivery of Angiogenesis Inhibitors to Attenuate Advanced Atherosclerosis

Neovascularization in plaque is the main driving factor for the formation of vulnerable plaque. It is an effective strategy to alleviate atherosclerosis by intervening neovascularization. Herein, we constructed a cRGD peptide (cyclo­(Arg–Gly–Asp–d-Phe–Cys))-modified nanodelivery systems (RNPs) for targeted delivery of an antiangiogenesis drug pigment epithelium-derived factor (PEDF), which is known as the strongest endogenous angiogenesis inhibitor. PEDF RNPs have a suitable size and good stability, which is conducive to passive target and long-term blood circulation. In vitro cell uptake study showed that cRGD on the surface of nanoparticles could bind to the overexpressed α_νβ₃ integrin in HUVECs, resulting in an increased uptake of PEDF RNPs by HUVECs. In vivo targeting experiments indicated that PEDF RNPs could be effectively enriched in plaques by an EPR effect and a cRGD peptide. In an apoE^–/– mice model of advanced atherosclerosis, we evaluated the therapeutic efficacy of PEDF RNPs by ultrasound imaging. The result indicated that PEDF RNPs can inhibit intimal thickening. Oil Red O (ORO) staining of isolated aorta showed that PEDF RNPs can reduce the area of plaque, compared with free PEDF treatment. H&E (hematoxylin–eosin) and Masson staining of the vessel cross section further proved that PEDF RNPs had a nice curative effect. CD31 staining suggested that the therapeutic effect of PEDF RNPs was related to the inhibition of angiogenesis. This study provides a targeting delivery system for inhibition of vasa vasorum in plaque, which has the potential of clinical application for future atherosclerosis treatment.