Development and testing of a silibin-containing sunscreen

描述（由申请人提供）：我们建议开发一种化妆品防晒配方Sunsil，其中含有已被证明具有抗癌作用的水飞蓟宾。随着人类的休闲时间越来越多，生活方式和衣着的选择也在改变，皮肤癌的全球发病率正在上升。我们在细胞培养和小鼠模型中积累的数据表明，水飞蓟宾是一种有效的抗肿瘤药物，具有非常有利的治疗指数；水飞蓟宾可能通过其对信号转导和细胞周期调节的复杂多效性作用来逆转或减缓皮肤癌的发展。这种药物作为一种新型防晒霜的商业化将取决于进一步的配方努力、临床前数据的生成，以及最终在高风险患者（如移植人群）中进行大规模的国际试验。我们相信Sunsil在器官移植领域的机会是显而易见的，但考虑到更普通的人群对有效的防晒霜产品的兴趣，我们相信Sunsil在更广泛的受众中占据市场份额的潜力很大。保守地说，由于Sunsil的独特性，它满足了特定的未满足的需求，我们相信Sunsil可以在完整产品发布后的5年内占据全球防晒霜市场的5%，或大约2000万美元的销售额。虽然水飞蓟宾是一种从水飞蓟提取物中提取的“天然”产品，但我们使用的配方是纯的，其生物学和作用机制在基础科学水平上是很好的理解。我们在UCDHSC进行了我们所知道的唯一的一期试验，检查水飞蓟宾-植物sometm在前列腺癌患者中的安全性和剂量，我们即将开始两项不同的二期研究，详见下面的初步研究部分。我们在血液和尿液中关于游离水飞蓟宾和结合水飞蓟宾水平的详细人体药代动力学数据，其中一些在这里提出，以及我们对水飞蓟宾作用机制的广泛研究，使我们能够进行这里描述的研究。本提案的具体目的是：(1)制备含或不含紫外线阻滞剂的环糊精基Sunsil候选制剂；(2)在SKH1无毛小鼠中测试候选Sunsil制剂对急性、单次UVB辐射诱导的DNA损伤和p53状态、增殖和凋亡改变的生物学效应；(3)使用目标2中确定的最佳Sunsil配方在SKH1无毛小鼠中进行肿瘤发生研究。

DESCRIPTION (provided by applicant): We propose to develop a cosmetic sunscreen formulation Sunsil, containing silibin which has been demonstrated to have anti-cancer effects. There is a global increase in skin cancer as humans have more and more leisure time and alter both their lifestyles and clothing choices. We have accumulated data in cell culture and in mouse models that reveal silibin to be a potent anti-neoplastic agent with a very favorable therapeutic index; it is likely that silibin can reverse or slow the development of skin cancer via its complex pleitropic effects on signal transduction and cell cycle regulation. Commercialization of this agent as a novel sunscreen lotion will depend on further formulation efforts, preclinical data generation, and ultimately a large international trial in high-risk patients such as the transplant population. We believe the opportunity for Sunsil is obvious among the organ transplant community, but given the more general population's interest in effective sunscreen products, we believe Sunsil has significant potential of capturing market share among a much broader audience. Conservatively, because of the uniqueness of Sunsil in that it fulfills a specific unmet need, we believe Sunsil can capture 5% of the worldwide sunscreen market, or approximately 20 million dollars in sales, within the 5-year window following full product launch. While silibin is a "natural" product derived from milk thistle extract, the formulation we work with is pure, and its biology and mechanism of action is well understood at the basic science level. We at UCDHSC have the only Phase I trial we are aware of examining safety and dosage of Silybin-PhytosomeTM in prostate cancer patients, and we are about to commence two different Phase II studies as detailed below in preliminary studies section. Our detailed human pharmacokinetic data on free and conjugated silibin levels in blood and urine, some of which is presented herein, and our extensive studies on silibin's mechanisms of action, uniquely situates us to perform the studies described here. The specific aims of this proposal are to: (1) Prepare candidate Sunsil formulations in cyclodextrin base with and without UV blockers; (2) Test candidate Sunsil formulations in SKH1 hairless mice for biological effects against acute, single UVB radiation-induced DNA damage and alterations in p53 status, proliferation and apoptosis; and (3) Perform tumorigenesis studies in SKH1 hairless mice using the best Sunsil formulation as identified in aim 2.