Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV.
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-glycine-aspartic acid (RGD) peptide or dual-functionalized poly-(lactide-co-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, surface-functionalized nanoparticles allow targeted gene delivery to the neovascular eye on intravenous administration and inhibit the progression of laser-induced CNV in a rodent model.
Singh
S R
SR
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
Grossniklaus
H E
HE
Kang
S J
SJ
Edelhauser
H F
HF
Ambati
B K
BK
Kompella
U B
UB
D000818:Animals; D002627:Chemistry, Physical; D020256:Choroidal Neovascularization / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007275:Injections, Intravenous; D007834:Lasers; D008297:Male; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D014018:Tissue Distribution; D014168:Transferrin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D009842:Oligopeptides; D014168:Transferrin; D042461:Vascular Endothelial Growth Factor A; C047981:arginyl-glycyl-aspartic acid; D040262:Receptors, Vascular Endothelial Growth Factor