Poly(lactic-co-glycolic acid) nanoparticle-mediated interleukin-12 delivery for the treatment of diabetic retinopathy

Abstract

Lina Zeng,1,* Wenbei Ma,1,* Lingyu Shi,1 Xiaohong Chen,1 Rong Wu,1 Yingying Zhang,2 Huaiwen Chen,2 Hui Chen11Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People’s Republic of China; 2Sunlipo Biotech Research Center for Nanomedicine, Shanghai 201507, People’s Republic of China*These authors contributed equally to this workBackground: Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes and vision. It is a leading cause of visual impairment and blindness in working-age people. Vascular endothelial growth factor-A (VEGF-A) is a primary initiator and potential mediator of DR. Matrix metalloproteinase-9 (MMP-9) plays a progressive role in the onset and severity of DR. Interleukin-12 (IL-12) is a cytokine of the chemokine family that could reduce the levels of MMP-9 and VEGF-A and suppress tumor angiogenesis. We hypothesize that IL-12 may also have superior therapeutic efficacy against DR. However, protein drugs are prone to degradation by various proteases after drug injection. Therefore, they have short half-lives and low blood concentrations. The objective of this study was to develop IL-12-loaded nanoparticles for long-term and sustained DR treatment.Methods: IL-12-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IL-12-PNP) were developed by double emulsion. The characteristics, anti-DR activity, and mechanisms of IL-12-PNP were examined in vitro and in vivo.Results: The nanoparticles had suitable particle size (∼132.8 nm), drug encapsulation efficiency (∼34.7%), and sustained drug release profile. Compared with IL-12 and blank nanoparticles, IL-12-PNP showed better inhibitory efficacy against VEGF-A and MMP-9 expression in rat endothelial cells and DR mouse retina. Intraocular IL-12-PNP administration significantly reduced retinal damage in DR mice as they presented with increased thickness and decreased neovascularization after treatment.Conclusion: These data indicate that IL-12-PNP is an effective drug delivery platform for DR therapy. It restores the thickness and reduces neovascularization of the retinas of DR mice.Keywords: interleukin-12, nanoparticles, angiogenesis, controlled release, diabetic retinopathy

Keywords

• interleukin-12
• nanoparticles
• angiogenesis
• controlled release
• diabetic retinopathy