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L. Cheng, N. Valiaeva, A.M. Tammewar, K. Hostetler, I. Falkenstein, J. Beadle, W.R. Freeman; Synthesis and Investigation of Hexadecyloxypropyl 5–Fluoro–2–Deoxyuridine Cyclic 3,5–Monophosphate for Antiproliferation in Vitreoretinal Diseases . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5121.
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© ARVO (1962-2015); The Authors (2016-present)
A long–lasting, slow release crystalline drug delivery system was initially reported using antiviral compounds as a prototype (IOVS 2004 Nov;45(11):4138–44). Our current study investigates the application of this novel intraocular drug delivery system to antiproliferating compounds.
Hexadecyloxypropyl 5–fluoro–2–deoxyuridine cyclic 3,5–monophosphate (HDP–cP–5F2dUrd) and hexadecyloxypropyl 5–fluoro–2–deoxyuridine 5–monophosphate (HDP–P–5F2dUrd) were synthesized from 5–fluoro–2–deoxyuridine and both compounds were tested at escalating doses (35µg/eye, 70µg/eye, and 210µg/eye) in rabbit eyes. Only one eye of each animal was injected with test compound and the fellow eye was injected with 5% dextrose as control. After injection, the eyes were monitored with slit lamp, Tonopen, indirect ophthalmoscopy, and electroretinography (ERG). Animals were sacrificed at 8 weeks and the globes were processed for histology.
All eyes with HDP–cP–5F2dUrd, including the highest dose of 210µg/eye, showed no toxicity and a drug depot of crystalline aggregate in the vitreous or on the retina. IOP was OD vs. OS =16.2 ± 4 vs. 16.2 ± 1.5mmHg, p=1.0. The value from a wave trough to b wave peak of the ERGs was OD vs. OS = 101±26 vs. 94±11µV, p = 0.5. The eyes injected with HDP–P–5F2dUrd at doses of 35µg/eye and 70µg/eye showed no toxicity and drug depot manifested as a localized haze in vitreous with clear view of retina. The dose of 210µg/eye HDP–P–5F2dUrd was toxic, causing localized retinal damage and late retinal detachment. The highest non–toxic dose was 70µg/eye. The vitreous drug depots from both compounds at all doses were still visible at the 8th week following single intravitreal injection. In vitro the IC50 in MRC–5 cells for HDP–cP–5F2dUrd and HDP–P–5F2dUrd were 6.4µM and 4.2µM respectively, while for 5–fluoro–2–deoxyuridine was greater than 100µM.
Intravitreal injectable lipid prodrugs of 5–fluoro–2–deoxyuridine, HDP–cP–5F2dUrd and HDP–P–5F2dUrd, could be long–lasting, slow release antiproliferative compounds to treat proliferative retinopathies. Further pharmacokinetic and treatment studies are warranted.
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