RGD Conjugated Hyperbranched Cationic Amylopectin Nanoparticle as Hypoxia Inducible Factor-1α Targeting Carrier Promotes Neovascularization in Cerebral Infarction

Abstract

Promoting the regeneration of new blood vessels is a crucial treatment in cerebral infarction and hypoxia-inducible factor 1-α (HIF-1α) plays a pivotal role in the regulation of neovascularization. Nevertheless, the degradation of HIF-1α and poor homing into ischemic sites greatly limit its clinical application. In this study, we encapsulated mutant HIF-1α in RGD modified hyperbranched cationic amylopectin derivative conjugated with 3-(dimethylamino)-1-propylamine (RGD-DMAPA-Amyp) nanoparticles. RGD-DMAPA-Amyp nanoparticles exhibited good blood compatibility and low cytotoxicity in hemolysis and MTT assay, and in vivo study showed low concentrations of RGD-DMAPA-Amyp and DMAPA-Amyp had no significant toxicity to zebrafish embryos. Further to investigate the targeting ability of RGD-DMAPA-Amyp in human umbilical vein endothelial cells and rats model of transient middle cerebral artery occlusion, the in vitro and in vivo results showed RGD-DMAPA-Amyp could specifically bind to vascular endothelial cells. Moreover, the RGD-DMAPA-Amyp/HIF-1α administration significantly reduced the incidence of cerebral ischemia in zebrafish. The pro-angiogenic effect of RGD-DMAPA-Amyp/HIF-1α was evaluated on zebra fish model of vascular loss, RGD-DMAPA-Amyp/HIF-1α were found could improve the growth of subintestinal vessels (SIVs). Our results imply that RGD-DMAPA-Amyp/HIF-1α might alleviate cerebral infarction in vivo via promoting neovascularization and could potentially be a very promising approach for cerebral infarction or ischemic diseases.