Pro-NP prevention of UV-induced skin cancer

Pro-NP 预防紫外线诱发的皮肤癌

• 批准号: 9757768
• 负责人: LAURA A HANSEN
• 金额: $ 17.7万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757768
• 关键词: American; Antioxidants; Carcinogens; Chronic; Clinical; Clinical Trials; Cutaneous; DNA Damage; Data; Development; Effectiveness; Encapsulated; Enzymes; Epidermis; Exhibits; Exposure to; FDA approved; Future; Gene Mutation; Generations; Goals; HGF gene; Human; Incidence; Inflammation; Lead; Lipid Peroxidation; Malignant Neoplasms; Melanins; Mus; Mutation; Oncogenic; Organ; Oxidative Stress; Plasticizers; Prevalence; Prevention; Production; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Resistance; Risk; Role; Safety; Signal Pathway; Site; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Source; Sun Exposure; Sunlight; Sunscreening Agents; Superoxide Dismutase; TP53 gene; Testing; Therapeutic; Time; Tissues; Topical application; Transgenic Mice; Transgenic Organisms; Tumor Burden; UV Radiation Exposure; UV induced; UV protection; Ultraviolet Rays; antioxidant enzyme; base; biocompatible polymer; biodegradable polymer; cancer type; carcinogenicity; catalase; cell injury; design; experimental study; in vivo; keratinocyte; melanocyte; mouse model; nanoparticle; novel; oxidative damage; prevent; response; skin cancer prevention; systemic toxicity; titanium dioxide; tumor; ultraviolet; ultraviolet irradiation

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.

摘要 非黑色素瘤皮肤癌是美国最常见的癌症，五分之一的美国人在 一辈子。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。 大约90%的皮肤癌的主要原因是紫外线(UV)照射。过量的紫外线辐射 暴露在皮肤中会导致氧化应激，从而压倒皮肤的天然抗氧化防御能力。 这导致了大量和快速的活性氧物种(ROS)的产生。ROS可导致DNA 损害并导致突变和癌症。目前使用的防晒霜和抗氧化剂不足以 防止或保护免受紫外线照射。防晒霜在阻挡长波紫外线方面尤其糟糕。 这会产生大量的ROS，必须经常重复使用，而抗氧化剂通常用于保护 皮肤的稳定性较差，不能穿透皮肤到达基底表皮角质形成细胞，有患上 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)对皮肤的作用可以防止氧化应激- 诱发致癌反应，从而引发皮肤癌。为了研究这一假设，我们将利用一本小说 试剂，Pro-NP™，由含有抗氧化酶的可生物降解的纳米颗粒外壳组成 草皮和猫。Pro-NP™是使用FDA批准的可生物降解和生物兼容的聚合物配制的 保护包裹的酶不被降解，并允许它们以活性形式在持续的 一段时间。我们在人体表皮组织中的初步数据显示，前-NP™可以穿透到 保护表皮最深层，防止紫外线引起的ROS增加和DNA损伤。我们 假设局部应用Pro-NP™可以安全地将超氧化物歧化酶和过氧化氢酶传递到基础角质形成细胞。 防止皮肤在紫外线照射下产生ROS，从而减少DNA损伤和皮肤 癌症的发展。这一假设将通过无毛SKH1小鼠的紫外线暴露来检验，以1)评估 Pro-NP™向皮肤输送抗氧化酶预防紫外线损伤的效果 诱导的ROS、活性氮物种和DNA损伤；2)评估Pro-ROS的安全性和有效性。 NP™用于预防紫外线诱发的皮肤癌。我们期待成功的原则证明证据 局部亲NP™治疗能够安全地预防慢性紫外线照射皮肤中的皮肤癌。