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L. Cheng, J. Kim, N. Valiaeva, K. Y. Hostetler, K. Hartmann, J. R. Beadle, I. Kozak, W. R. Freeman; Ocular Toxicology of a Novel Lipid Prodrug of Cytarabine Cyclic Monophosphate (HDP-cP-Ara C). Invest. Ophthalmol. Vis. Sci. 2010;51(13):5322.
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To develop a crystalline lipid prodrug of cytarabine to treat vitreoretinal proliferation by intravitreal administration. Hexadecyloxypropyl cytarabine 5'-monophosphate was synthesized previously and found to be too soluble to provide slow release from a depot after intravitreal injection. However, the corresponding 3', 5'-cyclic monophosphate analog was synthesized and, due to its limited solubility, appeared suitable for evaluation as a long lasting intravitreal treatment.
HDP-cP-Ara C was synthesized and its solubility, cytotoxicity, and ocular toxicity were evaluated. Solubility was determined by measuring HDP-cP-Ara C in the supernatant of a saturated HDP-cP-Ara C solution using a liquid chromatography/mass spectrometry method. Cytotoxicity was determined by XTT assay using human foreskin fibroblast (HFF) cells. Ocular toxicity was examined by intravitreal injection of four doses (25µg/eye, 80µg/eye, 250µg/eye, and 800µg/eye) and the toxicity was monitored using slit-lamp, tonometry, indirect ophthalmolscopy, ERG, and histology. Only one eye of each rabbit was used for drug injection and the fellow eye was used as control, injecting an equivalent volume of 5% dextrose. Each dose was tested in four rabbit eyes.
The solubility of HDP-cP-Ara C was 0.32 mM. The CC50 for HFF was 19 ± 3.6 (n=3) µM. All eyes demonstrated clear vitreous with vitreous drug depot still visible in all eyes 8 weeks after intravitreal injection. The least square means of ERG b-wave amplitude from different groups (800µg: 93.2µV, 250µg: 81.8 µV, 80µg: 83µV, 25µg: 99.6µV, control eyes: 82.4µV) was not significant (GEE, p=0.27). The least square means of intraocular pressure from different groups (800µg: 17.7mmHg, 250µg: 19.3mmHg, 80µg: 18.5mmHg, 25µg: 19.5mmHg, control eyes: 19mmHg) was also not significant (GEE, p=0.57). Clinical exam revealed normal fundus in all eyes except for one eye that received 800µg dose where the drug depot was seen touching the medullary ray, causing local hyperemia. Histology was not remarkable except for two eyes with 250µg dose, showing mild vitritis. Eyes that received 800µg doses are still being followed up.
HDP-cP-Ara C is a low solubility crystalline compound which may be useful as an intravitreal long-lasting slow release therapeutic to treat intraocular proliferation. Further ocular pharmacokinetics and in vivo efficacy studies are underway.
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