Synthesis and Investigation of Hexadecyloxypropyl 5–Fluoro–2–Deoxyuridine Cyclic 3,5–Monophosphate for Antiproliferation in Vitreoretinal Diseases

Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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 8^th 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.

Conclusions: : 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.

Keywords: retina • proliferative vitreoretinopathy • drug toxicity/drug effects