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

Background: The 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. 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 specifically taken up by retinal pigment epithelium (RPE) cells which highly expressed alpha(v)beta(5) 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 I-131 radiolabeling. The histological examinations further confirmed the biocompatibility of RGD-PEI/SAA. Conclusions: The results suggest that the designed RGD-PEI/SAA complexes may be a potential alternative anti-angiogenesis therapy for posterior ocular neovascular diseases.

Automated summary

The designed RGD-PEI/SAA complexes show potential therapeutic efficacy for targeted anti-angiogenesis therapy of CNV with good biocompatibility and specificity. The complexes exhibit controlled drug release properties in vivo and demonstrate specific therapeutic effects in a mouse model, indicating their potential as an alternative treatment for posterior ocular neovascular diseases.