Project 1- Bioadhesive Sunscreens and Triplet-State Quenchers for Melanoma Prevention

项目1：项目概要 皮肤细胞来源的癌症是美国最常见的恶性肿瘤，包括 约76，000例皮肤恶性黑色素瘤导致超过1亿美元的医疗保健费用，约10，000例 每年死亡。紫外线辐射（UVR）暴露是黑色素瘤的主要环境危险因素 因此，限制UVR暴露及其破坏作用是黑色素瘤的合理策略。 预防我们假设，黑色素瘤的早期和基本过程可以通过以下方式抑制： 补充的方法，减少直接和间接的紫外线诱导的黑素细胞遗传毒性。而 先前的局部制剂试图解决直接损伤途径（使用防晒剂）， 间接损害途径（使用抗氧化剂），我们的研究计划最近的突破为我们提供了 在预防恶性黑色素瘤方面有进一步技术创新的独特机会。我们有 开发了一种新的防晒霜输送平台，用于预防紫外线损伤， 纳米颗粒（BNPs）。紫外线吸收化合物被稳定地包封在颗粒内， 可生物降解的聚合物芯和允许它们共价粘附到地层的表面涂层 角质层，增加防晒剂的效率和耐久性，同时减轻归因于 药剂渗透到表皮中，例如接触性变态反应、ROS和激素生成增加 受体结合我们还发现了一种新的间接损伤途径，这种损伤在紫外线照射后很长时间内仍在继续。 暴露，通过黑色素碎片中的三重态电子，也驱动环丁烷嘧啶的形成 二聚体（CPD）。这种化学激发的过程发生在数小时的过程中，这表明几个 机会，以防止或消散高能量激发态所涉及的，通过使用代理，尚未 对这种新的活动进行了检查。因此，我们已经证明了三重态的潜力 猝灭剂（TSQ）和三重态预防剂（TSP）以避免这些延迟CPD的形成。整体 该提案的目标是系统地优化这些用于黑色素瘤预防的方法。完成 为此，我们将开发一种新的广谱BNP防晒剂和一种新的TSQ/TSP局部制剂 结合起来，我们假设将提供优化的预防直接和间接的紫外线诱导的 黑素细胞的遗传毒性，从根本上驱动黑色素瘤的发生。

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.