The therapeutic effectiveness of 5-fluorouracil (5-FU) in the treatment of proliferative diseases such as basal cell carcinoma (BCC), actinic keratoses (AK) and psoriasis could be greatly improved by enhancing its dermal delivery. A prodrug approach utilizing a sequential combination of a labile, water solubilizing promoiety and a stable, lipid solubilizing promoiety is proposed to accomplish this objective. The hypothesis is that the combination prodrug, with the additional labile, water solubilizing promoiety attached, will partition from the vehicle into the skin more effectively than the prodrug with only the lipid solubilizing promoiety. In the skin the water solubilizing promoiety will be rapidly hydrolyzed to give the lipid soluble prodrug which will hydrolyze and partition through the skin relatively slowly to give more specific dermal delivery of 5-FU. In this proposal the labile, water solubilizing promoiety will be the 1-acetyl group and the stable, lipid solubilizing promoiety will be a 3-alkylcarbonyloxymethyl promoiety. A series of linear alkyl chain 3-alkylcarbonyloxymethyl derivatives (single promoiety) and combinations of the 3-alkylcarbonyloxymethyl derivatives with the 1-acetyl group will be synthesized, characterized (solubilities and stabilities), and the abilities of the single promoiety and combination prodrugs to deliver 5-FU and intact single promoiety prodrug into and through hairless mouse skin will be determined in diffusion cell experiments. The results from the diffusion cell experiments will be analyzed to determine if the combination prodrugs are more effective than the 3-alkylcarbonyloxymethyl prodrugs at enhancing the ratio of dermal (delivery into the skin) to transdermal delivery (delivery through the skin) of 5-FU. A prodrug approach that exhibits a better ratio of dermal to transdermal delivery than 5-FU while delivering more 5-FU dermally should be more effective than 5-FU in treating BCC, AK and psoriasis while reducing the risk of systemic side effects.
