Abstract
A long-lasting, slow-release, crystalline antiviral drug delivery system was initially reported using ganciclovir and cyclic cidofovir as the prototype compounds. The present study was undertaken to investigate the feasibility of applying this system to antiproliferative small molecules. The crystalline lipid prodrugs of hexadecyloxypropyl-arabinofuranosylguanine 5'-monophosphate (HDP-P-AraG), hexadecyloxypropyl 5-fluoro-2'-deoxyuridine cyclic 3',5'-monophosphate (HDP-cP-5-F-2dUrd), and hexadecyloxypropyl 5-fluoro-2'-deoxyuridine 5'-monophosphate (HDP-P-5-F-2dUrd) were synthesized from their parent compounds arabinofuranosylguanine (AraG) and 5-fluoro-2'-deoxyuridine (5-F-2dUrd). All three compounds were tested at escalating doses in rabbit eyes. Only one eye of each animal was injected with test compound, and the fellow eye was injected with 5% dextrose as the control. The injected eyes were monitored by slit lamp, a handheld tonometer, indirect ophthalmoscopy, electroretinography (ERG), and histology. The selected doses were used for efficacy study with the rat CNV model or the rabbit PVR model. The highest nontoxic dose for HDP-P-AraG was 75 microg/eye, and was 70 and 210 microg/eye for HDP-P-5-F-2dUrd and HDP-cP-5-F-2dUrd, respectively. All compounds demonstrated a localized depot of crystalline aggregate in the vitreous with a clear view of vitreous and retina elsewhere. The drug depot of HDP-P-AraG was visible for 4 to 5 weeks; HDP-P-5-F-2dUrd, 8 to 10 weeks; and HDP-cP-5-F-2dUrd longer than 14 weeks. The treatment study showed HDP-P-AraG led to 33% reduction in CNV in the rat (P = 0.015), and HDP-cP-5-F-2dUrd provided 100% prevention of trauma-induced PVR in the rabbit (P = 0.046). The pretreatment study demonstrated a significant protection against intraocular proliferation compared with the 5-FU in a parallel study (P = 0.014). The intravitreous injectable lipid prodrugs of AraG and 5-fluoro-2'-deoxyuridine could be long-lasting, slow-release, antiproliferative compounds to treat unwanted intraocular proliferation.
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