Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially all-trans-retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of all-trans-retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4(-/-)Rdh8(-/-) (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration.

Biocompatible dendrimers with well-defined nanosizes are increasingly being used as carriers for drug delivery. 5-Aminosalicylic acid (5-ASA) is an FDA-approved therapeutic agent recently found effective in treating retinal degeneration of animal models. Here, a water-soluble dendrimer conjugate of 5-ASA (AGFB-ASA) was designed to treat such retinal degeneration. The drug was conjugated to a generation 2 (G2) lysine dendrimer with a silsesquioxane core (nanoglobule) by using a hydrolyzable Schiff base spacer. Incubation of nanoglobular G2 dendrimer conjugates containing a 4-formylbenzoate (FB) Schiff base spacer in pH 7.4 phosphate buffers at 37 °C gradually released 5-ASA. Drug release from the dendrimer conjugate was significantly slower than from the low molecular weight free Schiff base of 5-ASA (FB-ASA). 5-ASA release from the dendrimer conjugate was dependent on steric hindrance around the spacer. After intraperitoneal injection, the nanoglobular 5-ASA conjugate provided more effective 7-day protection against light-induced retinal degeneration at a reduced dose than free 5-ASA in Abca4(-/-)Rdh8(-/-) mice. The dendrimer 5-ASA conjugate with a degradable spacer could be a good candidate for controlled delivery of 5-ASA to the eye for treatment of retinal degeneration.