Abstract
Purpose: :
Cidofovir (CDF) has shown potential antiviral activity and currently indicated for the treatment of AIDS-related cytomegalovirus (CMV) retinitis. The major drawback with CDF is its low bioavailability (attributable to low lipid solubility) and hence poor passive transport into virus infected tissue such as retina which leads to limited therapeutic efficacy. Therefore, with a strategy to simultaneously enhancing lipid mediated and transporter targeted cellular uptake of CDF, we have evaluated novel transporter targeted lipid prodrugs of CDF for the treatment of CMV retinitis.
Methods: :
We have successfully synthesized sodium dependent multivitamin transporter (SMVT/Biotin) targeted lipid prodrugs with lipid moiety of carbon chain length C6 or C12 as a linker between biotin (B) and CDF (B-C6-CDF and B-C12-CDF). All synthesized prodrugs were characterized and evaluated for their physicochemical properties and cytotoxicity. We have also performed in vitro uptake and transport of [3H]Biotin in presence of these prodrugs on a model cell line MDCK-MDR1 and human retinal cell line ARPE-19. To elucidate the affinity interaction of these prodrugs with SMVT transporter, uptake of [3H]Biotin in presence of different concentrations of prodrugs has been performed and IC50 value of individual prodrugs has been calculated.
Results: :
Inhibition of [3H]Biotin uptake in presence of all prodrugs shows strong interaction with SMVT transporter. B-C12-CDF (0.90±0.07µM, IC50) shows higher affinity towards SMVT transporter than B-C6-CDF (11.25±1.48 µM, IC50) and B-CDF (31.42± 3.05µM, IC50) suggesting that increasing in lipid chain length will improve cellular uptake via SMVT transporter. Cellular uptake of B-C12-CDF (18 fold), B-C6-CDF (5 fold) and B-CDF (3.5 fold) prodrugs was found to be higher relative to CDF, shows our novel conjugates have higher cellular accumulation in retina.
Conclusions: :
Above studies demonstrated that transporter targeted lipid prodrugs of CDF pose superior affinity for SMVT transporter and hence will have higher bioavailability into human retinal cells owing to higher expression of SMVT on the human retina. This strategy will augment antiviral and therapeutic efficacy of CDF into retina due to synergistic effect of lipid and transporter targeting moiety. Finally, these novel prodrugs appear to be potential clinical candidates for the treatment of CMV retinitis.
Keywords: cytomegalovirus • retinitis • AIDS/HIV