The incidence and mortality rates of cutaneous squamous cell carcinoma (cSCC) and skin cancer continues to increase. It is expected that 1 in 5 Americans will develop skin cancer in their lifetime. Although surgical excision is typically indicated and effective, surgery is not always appropriate or possible. Efforts to treat and/or prevent using pharmacological agents are limited by poor delivery to the site of action (the skin epidermis and dermis) and majority of the pharmacological therapy involves systemic administration with few topical agents available. Existing drugs and combinations of natural compounds with potential to be used against skin cancer, including cSCC, have <1% bioavailability when administered orally, which means that they are ineffective in reaching the site of action and thus produce an inadequate pharmacological response, while when administered intravenously can lead to aggressive adverse side-effects. Although the skin is an accessible organ, topical treatment of skin cancers and precancerous lesions has been limited by either insufficient drug permeation through the stratum corneum or too much drug permeation into the systemic circulation and off-targeting. We seek to overcome these opposing barriers to drug delivery utilizing a high-throughput screening method we have developed including formulation libraries which allow the discovery of viable epidermal/dermal targeted drug delivery systems. Skin irritation potential utilizing reconstructed human skin and efficacy testing based on UV-induced photocarcinogenesis in SKH-1 mice will also be performed. The overall goal of this proposal is to develop drug formulations for the prevention, treatment, and the avoidance of progression of cSCC that would be able to deliver the drug inside the skin and be maintained in the skin for a period of time by avoiding or minimizing systemic absorption and off-target effects while potentiating therapeutic efficacy. Based on strong preliminary data, we hypothesize that the delivery of drugs with reduction and prevention of tumor progression properties are able to be developed in a topical formulation that delivers the drug inside the skin while minimizing systemic absorption and adverse effects. This type of therapy is more convenient to the patient and can lead to better patient compliance and therapeutic efficacy by increasing the drug's bioavailability at the site of action.