Developing topical prodrugs for skin cancer prevention

The skin plays multiple roles in protection from environmental insults yet skin damage, particularly that derived from sunlight, constitutes a major public health problem. End stage skin damage in the form of non-melanoma skin cancers (NMSC) are the most frequent malignancies in the United States with more than 1,000,000 cases diagnosed annually (Karagas et al. 1999). Melanoma skin cancer is the most rapidly increasing cancer. Actinic keratosis (AK), skin lesions that can progress to NMSC are far more prevalent than skin cancers. The occurrence of DNA damage and cellular responses to DNA damage are major determinants of skin damage including skin cancer (Ames 2001; Ullrich 2002). A compelling body of evidence now indicates that there are multiple targets for reducing skin damage and that several key micronutrients are candidates for skin damage prevention. However, a major challenge for the development of prevention strategies for skin damage is the difficulty of delivering micronutrients to skin. Delivery to skin via the blood circulation of nutrients taken orally is inherently inefficient since this delivery is distal to other organs, particularly the liver, which removes many agents by first pass metabolism. In addition the major cell targets for prevention of skin cancer are located in the epidermis, which is non-vascular. Described here are strategies to limit skin damage and thus skin cancer by targeting multiple mechanisms that include preventing DNA damage, enhancing DNA repair, preventing immune suppression, and preventing migration of transformed cells from epidermis to dermis. Further, an approach for delivery of key protective agents to skin cells using prodrugs specifically tailored for topical delivery is described. Finally, this approach is illustrated using niacin as a model micronutrient demonstrating that topical delivery of this polar compound to skin cells via prodrugs is feasible and that targeted delivery provides prevention benefit for skin.