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Yueran Yan, Haijiang Lin, Hidetaka Matsumoto, Peggy Bouzika, Joan Miller, Demetrios Vavvas; Comparison of the toxicity of different drug delivery nanoparticles in RPE and photoreceptor cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1940.
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© ARVO (1962-2015); The Authors (2016-present)
Multiple nanoparticles made of synthetic materials have been widely used as drug delivery systems. However, their toxicity to the retina is still not clear. In this study, three different kinds of nanoparticles made of poly lactic-co-glycolic acid (PLGA), polycaprolactone (PCL) and PEGylated polymer (PEG-P) were studied and their toxic effects in RPE cells and photoreceptors were determined in vitro and in vivo.
PLGA, PCL, and PEG-P nanoparticles were prepared by an oil-in-water (O/W) emulsion/solvent evaporation method. ARPE19 cells were treated with different concentrations of each of the three nanoparticles. The toxicity observed in each case was determined at different time points by MTT (Sigma Aldrich), LDH (Promega), ATP (Promega) and TUNEL (Millipore) assays. For the in vivo study, PEG-P nanoparticles were injected into C57BL/6 mouse eyes intravitreally and sub-retinally. Eyes were enucleated at day 3 or 7. TUNEL staining was used to evaluate photoreceptor cell death. Photoreceptor cell loss was evaluated by measuring the thickness of outer nuclear layer (ONL). Microglias in ONL were quantified in retinal whole mount immunolabeled with Iba-1 antibody. RPE degeneration was also assessed in RPE whole mount immunolabeled with ZO-1 antibody.
Our experiments showed that there was almost no toxicity of PEG-P nanoparticles in ARPE19 cells. Most importantly, no toxicity was observed when exposing the cells to a high PEG-P concentration (200ug/ml) for up to 1 week. PLGA nanoparticles showed greater toxicity than their counterparts. At 24 hours, PLGA caused more than 20% cell death at a concentration of 25ug/ml and 50% cell death at 200ug/ml. These results were confirmed with different cell death assays. The toxic effect of these nanoparticles in the RPE cells and the photoreceptors was also determined in vivo.
PLGA, PCL, and PEG-P nanoparticles show different toxicity profiles. PEG-P has the least toxicity in the RPE cells and photoreceptors.
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