Discovery of epidermal/dermal targeting formulations for cutaneous squamous cell carcinoma

皮肤鳞状细胞癌和皮肤癌的发病率和死亡率 继续增加。预计五分之一的美国人在一生中会患上皮肤癌。 虽然手术切除通常是指征和有效的，但手术并不总是合适的， 可能使用药理学试剂治疗和/或预防的努力受限于向患者的不良递送。 作用部位（皮肤表皮和真皮）和大多数药物治疗涉及 全身给药，可用的局部药物很少。现有药物和天然药物的组合 有潜力用于治疗皮肤癌（包括cSCC）的化合物的生物利用度<1% 当口服给药时，这意味着它们在到达作用部位时无效， 产生不充分的药理学反应，而当静脉内给药时可导致 严重的副作用虽然皮肤是一个可触及的器官， 癌症和癌前病变受到药物通过 角质层或过多的药物渗透进入体循环和脱靶。我们寻求 为了克服利用高通量筛选方法的药物递送的这些相反障碍， 已经开发了包括制剂库，其允许发现有活力的表皮/真皮 靶向药物输送系统。利用重建的人类皮肤的皮肤刺激潜力和功效 还将在SKH-1小鼠中进行基于UV诱导的光致癌作用的测试。整体 该提案的目标是开发用于预防、治疗和避免 能够将药物递送到皮肤内并维持在皮肤中的cSCC的进展 通过避免或最小化全身吸收和脱靶效应持续一段时间， 增强治疗功效。基于强有力的初步数据，我们假设， 具有减少和预防肿瘤进展特性的药物能够以一种 局部制剂，其将药物递送到皮肤内，同时使全身吸收最小化， 不良影响这种类型的治疗对患者来说更方便，可以使患者更好地接受治疗。 通过增加药物在作用部位的生物利用度来提高依从性和治疗功效。

The incidence and mortality rates of cutaneous squamous cell carcinoma (cSCC) and skin cancer continues to increase. It is expected that 1 in 5 Americans will develop skin cancer in their lifetime. Although surgical excision is typically indicated and effective, surgery is not always appropriate or possible. Efforts to treat and/or prevent using pharmacological agents are limited by poor delivery to the site of action (the skin epidermis and dermis) and majority of the pharmacological therapy involves systemic administration with few topical agents available. Existing drugs and combinations of natural compounds with potential to be used against skin cancer, including cSCC, have <1% bioavailability when administered orally, which means that they are ineffective in reaching the site of action and thus produce an inadequate pharmacological response, while when administered intravenously can lead to aggressive adverse side-effects. Although the skin is an accessible organ, topical treatment of skin cancers and precancerous lesions has been limited by either insufficient drug permeation through the stratum corneum or too much drug permeation into the systemic circulation and off-targeting. We seek to overcome these opposing barriers to drug delivery utilizing a high-throughput screening method we have developed including formulation libraries which allow the discovery of viable epidermal/dermal targeted drug delivery systems. Skin irritation potential utilizing reconstructed human skin and efficacy testing based on UV-induced photocarcinogenesis in SKH-1 mice will also be performed. The overall goal of this proposal is to develop drug formulations for the prevention, treatment, and the avoidance of progression of cSCC that would be able to deliver the drug inside the skin and be maintained in the skin for a period of time by avoiding or minimizing systemic absorption and off-target effects while potentiating therapeutic efficacy. Based on strong preliminary data, we hypothesize that the delivery of drugs with reduction and prevention of tumor progression properties are able to be developed in a topical formulation that delivers the drug inside the skin while minimizing systemic absorption and adverse effects. This type of therapy is more convenient to the patient and can lead to better patient compliance and therapeutic efficacy by increasing the drug's bioavailability at the site of action.