Purpose: The overall aim of this research work was to evaluate a series of dipeptide monoester prodrugs of an antiviral agent, ganciclovir (GCV), for oligopeptide transporter-targeted transscleral drug delivery to rabbit retina.
Methods: The permeability and enzymatic hydrolysis of dipeptide monoester GCV prodrugs were evaluated using freshly excized rabbit retinal pigment epithelium (RPE)-choroidsclera (RCS) and sclera tissue preparations. Affinity and transport mechanism of these prodrugs and their translocation across RCS were investigated through competitive inhibition studies of [3H]glycylsarcosine with the prodrugs.
Results: The transport of glycylsarcosine was found to be saturable (K
m
= 1.21 ± 0.41 mM, V
max
= 15.89 ± 1.54 pmoles/min/cm2), pH, temperature, and energy dependant. Dipeptides, angiotensin converting enzyme inhibitors, and a β-lactum antibiotic strongly inhibited the transport of glycylsarcosine indicating the functional presence of oligopeptide transport (OPT) system on the RPE. Dipeptide prodrugs (valine-valine-GCV, glycine-valine-GCV, and tyrosine-valine-GCV), and valine-GCV demonstrate a high enzymatic stability and affinity toward the retinal OPT system. The transport of the prodrugs was significantly inhibited (∼50%) in the presence of glycylsarcosine. The rank order of scleral permeability was Gly-Val-GCV≈GCV>Val-GCV>Tyr-Val-GCV≈Val-Val-GCV. The RCS permeability values of Val-GCV (3.29 ± 0.09 × 10−6cm/s), Val-Val-GCV (4.14 ± 0.33 × 10−6cm/s), Gly-Val-GCV (3.40 ± 0.47 × 10−6cm/s) and Tyr-Val-GCV (3.08 ± 0.29 × 10−6cm/s) were two-fold higher than that of GCV (1.61 ± 0.06 × 10−6cm/s).
Conclusions: The dipeptide monoester GCV prodrugs, owning to higher lipophilicity and OPT-mediated translocation across RPE, appear to be promising candidates in the treatment of ocular cytomegalovirus infections following an episcleral administration.
