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Anthony Puntel, Akiko Maeda, Marcin Golczak, Tadao Maeda, Songqi Gao, Krzysztof Palczewski, Zheng-Rong Lu; Prophylactic Treatment of Optimized Retinylamine Loaded PLA Particles in a Macular Degeneration Mouse Model. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6000.
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Vitreoretinopathic diseases, specifically age-related macular degeneration (AMD), present particularly challenging therapy options and aim solely to palliate the symptoms of advanced staged disease. Proof-of-concept therapies have begun with the development of RPE65 antagonists, and the administration of retinylamine has been extensively examined for its therapeutic efficacy in model mice with the phenotype of retinal degeneration. However, a method for controlled and sustained release remains elusive for the delivery of retinopathy therapeutics, and thus is essential to be addressed.
Poly (lactic acid) particles were formulated using a single emulsion/solvent evaporation method at [20mg/mL] polymer concentration and a 6.9% drug loading capacity. Particles were then subcutaneously injected with the minimal effective dose, 10mg/kg, into dark adapted Abca4-/- Rdh8-/- double knockout mice (n=6) at predetermined time points prior to photobleach. Photobleach was carried out by intense yellow light at 10,000 lux for 30 minutes. Mice were then returned to the dark room for one week. Mice were analyzed utilizing Optical Coherence Tomography (OCT), Immunohistochemistry (IHC) and Electroretinography (ERG) to investigate the state of the retina, specifically the state of the photoreceptor cells. Normal phase HPLC analysis of 11-cis-retinal was carried out at λ=325nm at a 90:10 hexane:ethyl acetate ratio. and flow rate of 1.4mL/min to establish overall rhodopsin levels.
Analysis revealed that sustained release of retinylamine prolonged protective effects to the retina as long as 7 days. Control quantities of both electrical signal (a-wave) and outer nuclear layer (ONL) thickness were conserved, whereas treatment of free drug showed similar levels for only 1 day and pronounced retinal degeneration at 6 days. These results were corroborated via HPLC analysis of 11-cis-retinal levels within retinas.
The optimized PLA particle platform presented here significantly prolonged the protective effects of the ocular therapeutic, retinylamine, at a minimal effective dosage. Controlled and sustained release platforms of therapeutics is optimal to any drug regimen and allows for complete patient compliance and maximal therapeutic efficacy throughout the duration of treatment while minimizing dosing occurrence.
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