PROJECT 1: PROJECT SUMMARY Cancers that derive from skin cells comprise the most commonly diagnosed malignancies in the US, including ~76,000 cases of cutaneous malignant melanoma responsible for over $100M in healthcare costs and ~10,000 deaths annually. Ultraviolet radiation (UVR) exposure is the major environmental risk factor for melanoma development; thus, limiting UVR exposure and its damaging effects is a logical strategy for melanoma prevention. We hypothesize that early and fundamental processes of melanomagenesis can be inhibited via complementary approaches that reduce both direct and indirect UVR-induced melanocyte genotoxicity. While previous topical formulations have attempted to address direct damage pathways (using sunscreens) and indirect damage pathways (using antioxidants), recent breakthroughs from our research programs provide us with unique opportunities for further technological innovation in preventing malignant melanoma. We have developed a novel sunscreen delivery platform for the prevention of UVR-damage that uses bioadhesive nanoparticles (BNPs). UVR-absorbing compounds are stably encapsulated within particles that have a biodegradable polymer core and a surface coating that allows them to adhere covalently to the stratum corneum, increasing sunscreen agent efficiency and durability while mitigating safety concerns attributable to penetration of agents into the epidermis, e.g. contact allergy, increased generation of ROS, and hormone receptor binding. We have also identified a novel pathway of indirect damage that continues long after UVR- exposure, via triplet-state electrons in melanin fragments that also drive formation of cyclobutane pyrimidine dimers (CPDs). This process of chemiexcitation occurs over the course of hours, suggesting several opportunities to prevent or dissipate the high energy excited states involved, by using agents that have not yet been examined for this novel activity. Accordingly, we have demonstrated the potential of triplet-state quenchers (TSQs) and triplet-state preventers (TSPs) to avert formation of these delayed CPDs. The overall goal of this proposal is to systematically optimize these approaches for melanoma prevention. To accomplish this, we will develop both a novel broad-spectrum BNP-sunscreen and a novel TSQ/TSP topical formulation that, in combination, we hypothesize will provide optimized prevention of the direct and indirect UVR-induced melanocyte genotoxicity that fundamentally drives melanomagenesis.