Abstract
Non-melanoma skin cancer is the most common cancer in the U.S. Ultraviolet radiation (UV), which causes over 90% of skin cancers, is inherently carcinogenic because it generates reactive oxygen species (ROS), DNA damage, mutations and inflammation which enhance the oncogenic transformation of skin cells. Currently available sunscreens are inadequate at preventing UV-induced skin cancer development because they are poor at blocking long wavelength UVA and typically unstable in vivo, must be frequently reapplied and can actually increase ROS. Therefore, we reasoned that effective and sustained delivery of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) to the skin could suppress UV-induced DNA damage and hence, skin cancer. Pro-NPTM, which consists of SOD and CAT encapsulated in poly lactic-co-glycolic acid nanoparticles, was developed to allow for stable and sustained delivery of these ROS scavenging enzymes. We hypothesized that daily topical application of Pro-NP would safely deliver SOD and CAT to the viable layers of the epidermis, decrease UV-induced DNA damage, and suppress skin cancer development. To test this hypothesis, short-term dose setting experiments and long-term skin carcinogenesis experiments were conducted in hairless mice, enabling the assessment of the anti-carcinogenic effects of Pro-NP in vivo. Pro-NP decreased UV-induced CPD formation and DNA damage response pathway activation in male and female mice in a dose response manner after both short-term (2 weeks) and long-term (22 weeks) treatment. Surprisingly, Pro-NP only protected female mice from UV-induced tumorigenesis, as observed by a two-week delay in tumor development, an approximate 32% decrease in tumor multiplicity at week 25, and a four week in delay in SCC onset when compared to vehicle-treated and UV exposed females, but had no effect on skin carcinogenesis in male mice. Correlating with the sex-linked differences in suppression of skin tumorigenesis, Pro-NP reduced UV-induced proliferation and dermal cellularity to a greater extent in female mice compared to male mice. Taken together, these results demonstrate that even though Pro-NP protects both sexes from DNA damage following UV exposure, a suppressive effect on UV-induced skin carcinogenesis was noted solely in female mice.