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Songqi Gao, Tadao Maeda, Kiichiro Okano, Krzysztof Palczewski; A Drug Delivery System for Sustained Release of 9-cis-Retinoids. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3418.
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Design and develop a drug delivery system containing a combination of poly(d,l-lactide-co-glycolide) (PLGA) microparticles and alginate hydrogel for sustained release of 9-cis-retinoids for the treatment of retinal diseases, such as Leber congenital amaurosis (LCA) that lack a normal supply of 11-cis retinal.
Biodegradable PLGA microparticles loaded with 9-cis-retinoids were prepared using an emulsion and solvent evaporation method, and then embedded into biocompatible alginate hydrogels by ionic cross-linking. The morphology and size of PLGA microspheres were characterized by scanning electron microscopy (SEM) and the loading efficiency and capacity of these microparticles were determined by UV spectroscopy. To study in vivo drug release, the microparticle/ hydrogel combination loaded with drug was subcutaneously injected to Lrat-/- mice. Oral administration of 9-cis-retinoids was used for comparison and drug concentrations in plasma were determined by HPLC. Electroretinography (ERG), retinoid concentrations, and histologic analysis were used to evaluate retinoid effects on visual function and morphology.
Experimental results demonstrated that the size of the microparticles were less than 10 µm. The loading efficiency and capacity of the microparticles was about 99% and 28%, respectively. In vivo study demonstrated a constant drug release from the microparticle/hydrogel combination that lasted four weeks after subcutaneous injection. In comparison, drug concentrations in the plasma of the control group were high and toxic a few hours after oral administration of the same dose, and then dropped sharply one day after injection. Significantly increased ERG response and considerably improved RPE-ROS interface were observed after subcutaneous injection of the delivery system loaded with drug.
Sustained release of 9-cis-retinoids was achieved by using an injectable microparticle/hydrogel drug delivery system. Subcutaneous injection of this combination proved more efficacious with lower toxicity than oral administration of the same drug dose in Lrat-/- mice. Sustained delivery of 9-cis-retinal to photoreceptors by this drug delivery system offers the potential to restore vision in humans with certain forms of hereditary blindness.
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