RGD-modified multifunctional nanoparticles encapsulating salvianolic acid A for targeted treatment of choroidal neovascularization

Junxiu Zhang,Qing Gu,Ke Mao,Dongli Li,Jinhua Zhao,Xingwei Wu,Jingyi Zhu,Lingzhou Zhao

doi:10.1186/s12951-021-00939-9

Abstract

BackgroundThe development of alternative anti-angiogenesis therapy for choroidal neovascularization (CNV) remains a great challenge. Nanoparticle systems have emerged as a new form of drug delivery in ocular diseases. Here, we report the construction and characterization of arginine-glycine-aspartic acid (RGD)-conjugated polyethyleneimine (PEI) as a vehicle to load antioxidant salvianolic acid A (SAA) for targeted anti-angiogenesis therapy of CNV. In this study, PEI was consecutively modified with polyethylene glycol (PEG) conjugated RGD segments, 3-(4′-hydroxyphenyl) propionic acid-Osu (HPAO), and fluorescein isothiocyanate (FI), followed by acetylation of the remaining PEI surface amines to generate the multifunctional PEI vehicle PEI.NHAc-FI-HPAO-(PEG-RGD) (for short, RGD-PEI). The formed RGD-PEI was utilized as an effective vehicle platform to load SAA.ResultsWe showed that RGD-PEI/SAA complexes displayed desirable water dispersibility, low cytotoxicity, and sustainable release of SAA under different pH conditions. It could be specifically taken up by retinal pigment epithelium (RPE) cells which highly expressed ɑvβ5 integrin receptors in vitro and selectively accumulated in CNV lesions in vivo. Moreover, the complexes displayed specific therapeutic efficacy in a mouse model of laser induced CNV, and the slow elimination of the complexes in the vitreous cavity was verified by SPECT imaging after 131I radiolabeling. The histological examinations further confirmed the biocompatibility of RGD-PEI/SAA.ConclusionsThe results suggest that the designed RGD-PEI/SAA complexes may be a potential alternative anti-angiogenesis therapy for posterior ocular neovascular diseases.Graphic abstract

Highlights

Age-related macular degeneration (AMD) is the leading cause of blindness and visual loss among elderly patients [1, 2]
We revealed that Oxidized low-density lipoproteins (ox-LDL) could induce chronic oxidative damage and inflammation to the retinal pigment epithelium (RPE) layer and exacerbate choroidal neovascularization (CNV) progression, which could be reversed by salvianolic acid A (SAA) [27, 28]
The targeting specificity of the RGD-PEI/SAA complex was evaluated by confocal laser scanning microscopy (CLSM), flow cytometry in human retinal pigment epithelium cell line (ARPE-19) cells and a laser-induced CNV mouse model in vivo

Summary

Results

We showed that RGD-PEI/SAA complexes displayed desirable water dispersibility, low cytotoxicity, and sustainable release of SAA under different pH conditions. It could be taken up by retinal pigment epithelium (RPE) cells which highly expressed ɑvβ integrin receptors in vitro and selectively accumulated in CNV lesions in vivo. The complexes displayed specific therapeutic efficacy in a mouse model of laser induced CNV, and the slow elimination of the complexes in the vitreous cavity was verified by SPECT imaging after 131I radiolabeling. The histological examinations further confirmed the biocompatibility of RGD-PEI/SAA

Conclusions

Introduction

Results and discussion