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Eva Tuominen, George Mihov, Mengmeng Zong, Sanjay Sarkhel, Aylvin Dias, Arto Urtti; In vitro cytotoxicity screening and pharmacokinetic modeling: a tool in the development of ocular drug delivery systems. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5065.
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© ARVO (1962-2015); The Authors (2016-present)
The aim was to combine in vitro cytotoxicity screening assays and ocular pharmacokinetic modeling in order to aid the development of safe ocular drug delivery systems. Polyesteramide (PEA) is a potential polymer platform for controlled release systems of ocular drugs. Cytotoxicity of hydrolytic degradation products of biodegradable polyesteramide were tested using this combination method.
A cell based cytotoxicity screening platform has been designed for testing of polymers, associated particles and degradation products of polymers. Human retinal pigment epithelial cell line (ARPE-19) was used as the test cell line. A broad concentration range of the materials was used in the tests. Degradation products of PEA were tested with MTT assay and, polyethylene imine (PEI) and poly-L-lysine (PLL) were used as controls. ARPE-19 cells on a 96-well plate were incubated for 5 hours with different concentrations of the polymers (0.0001 - 5 mg/ml). Kinetic ocular modelling was carried out using Stella software (ISEE systems 9.0). Kinetic simulation model was built to predict the intravitreal concentrations of the PEA degradation products and control polymers. In the model, the intravitreal polymer dose was set at 10 mg, the dissolution took place in sink conditions, and the degradation rate of free PEA was varied in the simulations.
The PEA degradation products did not show any signs of toxicity in the MTT assay at test concentrations (0.0001 - 5 mg/ml), but the control polymers showed toxicity (PEI: IC 50 = 6.3 ± 1.0 µg/ml; PLL: IC50 = 48.7 ± 11.0 µg/ml). For PEA borne materials the pharmacokinetic model predicted a maximum total concentration range of 0.2 - 4 mg/ml, for PEI 1.4 - 6 mg/ml and PLL 1.2 - 6 mg/ml.
Combination of kinetic modeling and cellular toxicity testing indicates ocular toxicity of PLL and PEI. PEA and its degradation are predicted to be safe after intravitreal administration. Cytotoxicity screening and pharmacokinetic simulations are a promising tool in the development of ocular drug delivery systems.
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