Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV

Abstract

Choroidal neovascularization (CNV) leads to loss of vision in age-related macular degeneration (AMD), the leading cause of blindness in adult population over 50 years old. In this study, we developed intravenously administered, nanoparticulate, targeted nonviral retinal gene delivery systems for the management of CNV. CNV was induced in Brown Norway rats using a 532 nm laser. We engineered transferrin, arginine-glycineaspartic acid (RGD) peptide or dual-functionalized poly-(lactideco-glycolide) nanoparticles to target delivery of anti-vascular endothelial growth factor (VEGF) intraceptor plasmid to CNV lesions. Anti-VEGF intraceptor is the only intracellularly acting VEGF inhibitory modality. The results of the study show that nanoparticles allow targeted delivery to the neovascular eye but not the control eye on intravenous administration.Functionalizing the nanoparticle surface with transferrin, a linear RGD peptide or both increased the retinal delivery of nanoparticles and subsequently the intraceptor gene expression in retinal vascular endothelial cells, photoreceptor outer segments and retinal pigment epithelial cells when compared to nonfunctionalized nanoparticles. Most significantly, the CNV areas were significantly smaller in rats treated with functionalized nanoparticles as compared to the ones treated with vehicle or nonfunctionalized nanoparticles. Thus, surfacefunctionalized nanoparticles allow targeted gene delivery to the neovascular eye on intravenous administration and inhibit the progression of laser-induced CNV in a rodent model.

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

“…37,38 Biodegradation and ocular tissue reaction to microspheres or NPs of poly (D, L-lactide) or PLGA have been studied earlier in vitro 39,40 and in vivo. [41][42][43][44] In this study, we showed the inhibitory efficiency of shRNA-expressing plasmid DNA (pDNA) targeting HIF1a (pshHIF-1a) on laser-induced CNV in rats, and further evaluated the therapeutic potential of PLGA NPs as a non-viral vector for pshHIF-1a gene transfection to the posterior segment of eyes.…”

Novel RGD-lipid conjugate-modified liposomes for enhancing siRNA delivery in human retinal pigment epithelial cells

“…29 However, previous studies have usually prepared the nanoparticles first, and then added a targeting molecule for conjugation on the surface of the nanoparticle. 17,29,30 This method is limited by the difficulty in controlling the number of targeting moieties conjugated to the constructed nanoparticles. In this report, synthesis of the ligand-conjugated lipid, DSPE-PEG-RGD, was performed by Michael addition reactions between activated maleimide and thiol groups prior to preparation of the liposomes ( Figure 1A).…”

Target Nanoparticles: An Appealing Drug Delivery Platform

“…Most research has focused on the specific targeting of cells expressing disease-associated biomarkers, as in the case of cancer. Various moieties have been examined as targeting agents, including vitamins, [24] carbohydrates, [25] aptamers, [26] peptides (e.g., Arg-Gly-Asp, allatostatin, transactivating transcriptional activator) [27][28][29] and proteins (e.g., lectins, and transferrin) [30][31] However, active agents, such as ligands for the receptors and antibodies to the surface proteins have been used extensively to target specific cells, the majority of research to date has focused on antibodies.…”