Synthesis and Characterization of Ganciclovir Long Chain Lipid Prodrugs

Ganciclovir (GCV) is indicated for the treatment of human cytomegalo virus (HCMV) retinitis in immunocompromised patients. Sub-optimal physicochemical properties prevent GCV from reaching therapeutic concentrations in back of the eye (retina) tissue after oral and intravenous administration. Chronic high dose administration results in systemic toxicity. Local intravitreal injections suffer from poor ocular bioavailability and require repeated administration which can cause retinal detachment, retinal/vitreal hemorrhage and endophthalmitis. In the current study, we synthesized long chain acyl ester derivatives of GCV to improve lipophilicity and bioavailability. Ester conjugates (C₅, C₁₀ and C₁₃ mono- and di-(O-acyl)) of GCV were synthesized in one step reaction following conventional esterification reaction. Purity of the novel prodrugs was determined with reversed phase high performance liquid chromatography. Conjugation of long lipid chain to GCV was confirmed with proton (¹H) and carbon (¹³C) nuclear magnetic resonance and mass spectroscopy. Also, melting point and lipophilicity for the prodrugs and GCV were determined. MTS assay was used to assess in vitro toxicity of GCV and its long chain lipid prodrugs on human retinal pigment epithelial cell line (ARPE-19) cells. Results indicated that long chain lipid GCV prodrugs are nontoxic, safe and well-tolerated by ARPE-19 cells. These results suggest that novel long chain lipid GCV prodrugs may be further evaluated for ocular delivery and treatment of HCMV retinitis.