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

Abstract

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 epitheliumderived 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 ν β 3 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.

Advances in Atherosclerosis Theranostics Harnessing Iron Oxide‐Based Nanoparticles

“…[ 16 , 43 ] Numerous biomarkers, including VEGF, ανβ3, and hypoxia‐inducible factors, participate in neovascularization, making them potential targets for plaque visualization and treatment. [ 44 ] The extracellular matrix, enriched in collagen, serves as a critical component of the fibrous cap, primarily responsible for maintaining its structural integrity. Consequently, several studies centered on IONPs have focused on stabilizing plaques by delivering nanomedicines targeted to type IV collagen.…”

Nanomedicine for Diagnosis and Treatment of Atherosclerosis

“…established cRGD‐modified polymeric nanoparticles that specifically deliver angiogenesis inhibitors pigment epithelium‐derived factor (PEDF) with 91.7 ± 2.6% entrapment efficiency to endothelial cells to stabilize plaques. [ 215 ] In addition, the multiple sites on the surface of the polymer make it easy to construct intelligent responsive delivery systems, which can stably and continuously release loaded drugs under stimulation, thereby effectively reducing off‐target effects. [ 216 ] Furthermore, folic acid‐modified lipid‐polymeric nanoparticles encapsulating naringenin (Nrg) were found to effectively overcome the intestinal mucosal barrier and accumulate in atherosclerotic macrophages to exert an anti‐inflammatory effect.…”

Multifunctional liposomes Co-encapsulating epigallocatechin-3-gallate (EGCG) and miRNA for atherosclerosis lesion elimination

“…Nano-drug delivery systems have been applied for AS treatment because of the permeability and retention (EPR) effect developed during the formation of atherosclerotic lesions. 21,22 Liposomes are a widely applied nano-drug delivery system, which have the advantages of high biocompatibility, excellent drug-loading capacity, and controllable size. 23,24 Moreover, as nanoparticles composed of lipid molecules, they have a natural ability to spontaneously accumulate in AS, making them an ideal drug-delivery system for AS treatment.…”