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Xiaohui Zhang, Ling Luo, Hironori Uehara, Tadashi Miya, Christina Mamalis, Alex Jones, Bonnie Archer, Balamurali K. Ambati; RGD-targeted Nanoparticles Expressing Flt23k Inhibit CNV In a Murine CNV Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):445.
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© ARVO (1962-2015); The Authors (2016-present)
Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration (AMD) patients in the developed world. Currently, the most effective therapies are monthly intravitreal injections of anti-VEGF agents such as bevacizumab or ranibizumab. However there are significant risks associated with repeated intravitreal injections. The purpose of this study was to determine whether a single intravenous administration of RGD-coated nanoparticles delivering plasmids expressing Flt23k intraceptors could suppress CNV in a murine model.
We prepared nile-red labeled nanoparticles which were blank, loaded with pCMV.Flt23k, or loaded with pCMV.Flt23k conjugated with RGD oligopeptides (which home to alpha-v-beta-3 integrin). All three nanoparticles were dissolved in MES buffer. The total volume delivered was 4 μl (plasmid concentration is 0.1μg/μl) in each mouse, and similar volumes of MES buffer served as blank control. Mice CNV was induced by 532 nm laser or subretinal injecton of adeno-associated virus mediated small hairpin ribonucleic acid (shRNA) sFlt-1. Tail vein injection was performed 2 weeks after induction of CNV. CNV regression was evaluated 2 weeks after tail vein injection in histological sections and CNV volume quantified using newly developed software, Seg3D in vivo image. RGD.Flt23k.NR.NP was detected by immunostaining in CNV.
α5 expression in CNV area was confirmed by immunostaining. H&E stained sections show the CNV size was dramatically decreased in RGD.Flt23k.NR.NP injected mice (treatment group) compare to the other three control groups (Flt23k.NR.NPs, blank NR.NPs or MES buffer). The treatment group mice CNV volume was decreased by 23%, which showed significantly more reduction than observed with unlabeled nanoparticles, blank nanoparticles, or MES control (all p’s <0.05), As a positive control, CNV lesions treated with anti-mouse VEGF antibody intravitreal injections were decreased by 11% (p=0.1).
This study exploits a new method to treat CNV by providing a novel therapeutic, a safer route of delivery, and also a nonviral delivery system for extended gene delivery.
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