Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Michael Girardi

Abstract

Melanoma is one of the most common cancer with more than 100,000 cases of cutaneous malignant melanoma diagnosed in the US in 2020, resulting in nearly 7000 deaths. Although many risk factors are associated with melanoma, a well-established and most preventable risk factor is ultraviolet radiation (UVR) exposure. Two class of UVR blockers are currently available: the physical sunscreens that are aesthetically unappealing and the organic sunscreens that readily penetrate into the skin. Nanoparticle encapsulation of sunscreen actives can improve appearance, performance, and safety of sunscreens. The aim of this study is to develop biodegradable bioadhesive nanoparticle (BNP)-based strategies to prevent UVR induced melanoma genotoxicity using a mouse model. First, the effect of chronic UVR on mouse skin was studied by immunofluorescence staining of mouse dorsal epidermis after exposing them to UVB alone or UVB+UVA for 10-12 weeks. Experiments showed that chronic UVR did not significantly alter the number or cross-sectional size of melanocytes. The experiments also showed that mice were more likely to develop P53 mutant clonal islands when they were exposed to UVB alone compared to UVB+UVA when the dose of UVB were the same, and that mice with melanocytes in the epidermis (K14SCF) generated lower density of P53 islands compared to the mice without melanocytes in epidermis (WT). Second, the effect of different topical applications on direct genotoxicity was compared by measuring the amount of cyclobutene pyrimidine dimer (CPD) from mouse dorsal skin post UVR exposure. Experiments showed that avobenzone and octocrylene in free form or encapsulated in BNP significantly reduced the amount of CPD immediately post UVR compared to no sunscreen. Last, UVR-induced indirect genotoxicity were studied by comparing CPD from mouse skin immediately and at certain time points post UVR exposure, termed “dark CPD”. No dark CPD was detected using the current models. Future studies for the effect of chronic UVR exposure on melanocytes should include DNA sequencing for mutations. Direct genotoxicity studies should include investigation of additional properties of BNP encapsulated sunscreen such as photostability, water resistance, and systemic absorption, which are potential advantages over currently available sunscreens. For dark CPD studies, future studies should include alternative CPD detection methods and mouse models including DNA repair deficiency.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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