Pro-NP prevention of UV-induced skin cancer

摘要 非黑色素瘤皮肤癌是美国最常见的癌症，在他们的生活中，每5个美国人中就有1个发生。 辈子皮肤癌的发病率也在上升，这是由于暴露在阳光和其他来源的增加 紫外线（UV）照射，约90%的皮肤癌的主要原因。过度紫外线辐射 暴露于皮肤导致氧化应激，其可压倒皮肤的天然抗氧化剂防御。 这导致活性氧物质（ROS）的显著且快速的产生。ROS会导致DNA 导致突变和癌症。目前使用的防晒剂和抗氧化剂不足以 防止或保护免受紫外线照射。防晒霜在阻挡长波UVA方面特别差 产生大量活性氧，必须经常重复使用，而抗氧化剂通常用于保护 皮肤稳定性差，不能穿透皮肤到达基底表皮角质细胞， 致癌转化因此，我们推断，有效和持续的抗氧化剂输送， 特别是超氧化物歧化酶（SOD）和过氧化氢酶（CAT），对皮肤可以防止氧化应激- 诱发致癌反应，从而导致皮肤癌。为了研究这个假设，我们将利用一个新的 试剂Pro-NP™，其由含有抗氧化酶的可生物降解的纳米颗粒壳组成 Pro-NP™采用FDA批准的生物可降解和生物相容性聚合物配制， 保护包封的酶免于降解，并允许它们以活性形式持续释放， 段时间我们在人表皮组织等同物中的初步数据显示，Pro-NP™渗透至 表皮的最深层，防止紫外线引起的ROS和DNA损伤的增加。我们 假设Pro-NP™局部应用将安全地将SOD和CAT递送至 防止皮肤响应紫外线照射产生ROS，从而减少皮肤DNA损伤 癌症发展将使用无毛SKH 1小鼠的UV暴露来检验该假设，以1）评价 Pro-NP™将抗氧化酶输送到皮肤中以预防紫外线的有效性。 诱导的ROS，活性氮物种，和DNA损伤和2）评估的安全性和有效性的Pro- NP™用于预防UV诱导的皮肤癌。我们期待着成功的原则证明证据， 局部Pro-NP™治疗安全预防长期紫外线照射皮肤中皮肤癌的能力。

ABSTRACT Nonmelanoma skin cancer is the most common cancer in the USA, occurring in 1 of 5 Americans during their lifetime. The incidence of skin cancer is rising as well, due to increased exposure to sunlight and other sources of ultraviolet (UV) irradiation, the primary cause of approximately 90% of skin cancers. Excessive UV radiation exposure to the skin results in oxidative stress that can overwhelm the natural antioxidant defenses of the skin. This leads to significant and rapid generation of reactive oxygen species (ROS). ROS can cause DNA damage and lead to mutations and cancer. Currently used sunscreens and antioxidants are not adequate to prevent or protect against UV exposure. Sunscreens are particularly poor at blocking the long wavelength UVA that produces much of the ROS and must be frequently reapplied, while antioxidants typically used to protect skin have poor stability and do not penetrate the skin to reach the basal epidermal keratinocytes at risk for oncogenic transformation. Therefore, we reasoned that effective and sustained delivery of antioxidants, particularly superoxide dismutase (SOD) and catalase (CAT), to the skin could prevent oxidative stress- induced oncogenic responses and hence skin cancer. To investigate this hypothesis, we will utilize a novel agent, Pro-NP™, which consists of a biodegradable nanoparticle shell containing the antioxidant enzymes SOD and CAT. Pro-NP™ is formulated using an FDA approved biodegradable and biocompatible polymer that protects the encapsulated enzymes from degradation and allows their release in active form over a sustained period of time. Our preliminary data in human epidermal tissue equivalents show that Pro-NP™ penetrates to the deepest layers of the epidermis and prevents UV-induced increases in ROS and DNA damage. We hypothesize that topical application of Pro-NP™ will safely deliver SOD and CAT to the basal keratinocytes of the skin to prevent ROS generation in response to UV irradiation, and thus reduce DNA damage and skin cancer development. This hypothesis will be tested using UV exposure of Hairless SKH1 mice to 1) evaluate the effectiveness of Pro-NP™ for delivering antioxidant enzymes into the skin for prevention of UV- induced ROS, reactive nitrogen species, and DNA damage and 2) assess the safety and efficacy of Pro- NP™ for prevention of UV-induced skin cancer. We anticipate successful proof-of-principle evidence of the ability of topical Pro-NP™ treatment to safely prevent skin cancer in chronically UV irradiated skin.