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

发现用于皮肤鳞状细胞癌的表皮/真皮靶向制剂

• 批准号: 10259286
• 负责人: John Joseph Koleng
• 金额: $ 25.19万
• 依托单位: VIA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259286
• 关键词: Adverse effects; American; Animal Model; Biological Availability; Blood Circulation; Cells; Cream; Cutaneous Melanoma; Data; Deposition; Dermal; Dermis; Diffusion; Disease; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Targeting; Emulsions; Epidermis; Excision; Formulation; Gel; Goals; Guidelines; Human; Hypersensitivity skin testing; Incidence; Intravenous; Lead; Lesion; Libraries; Lotion; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Methods; Mission; Modality; Mus; Natural Products; Ointments; Operative Surgical Procedures; Oral; Organ; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Prevention; Process; Property; Protocols documentation; Public Health; Research; Research Support; Resveratrol; Site; Skin; Skin Cancer; Stratum corneum; Tannic Acid; Testing; Time; Topical agent; Topical application; Toxicity Tests; Treatment Efficacy; UV carcinogenesis; UV induced; United States National Institutes of Health; Zoledronic Acid; absorption; base; cancer prevention; compliance behavior; dermatome; drug repurposing; efficacy testing; high throughput screening; improved; in vitro testing; in vivo; mortality; novel therapeutics; premalignant; prevent; receptor; response; screening; selective prevention; side effect; skin barrier; skin disorder; skin irritation; skin squamous cell carcinoma; tumor progression; ultraviolet irradiation

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.

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会在有生之年患上皮肤癌。 尽管手术切除是典型的适应症和有效的手术，手术并不总是合适的或 有可能。治疗和/或预防使用药剂的努力受到以下因素的限制 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，几乎没有可用的局部用药。现有药物和天然药物的组合 有潜力用于治疗皮肤癌的化合物，包括CSCC，具有1%的生物利用度 口服时，这意味着它们在到达作用部位时无效，因此 产生不充分的药理反应，而静脉给药会导致 具有侵略性的副作用。虽然皮肤是一个可以接触到的器官，但皮肤的局部治疗 癌症和癌前病变受到药物渗透不足的限制 角质层或药物渗入过多的体循环而脱离靶点。我们在寻找 为了利用高通量筛选方法克服这些相反的药物输送障碍，我们 已经开发出包括配方库在内的配方库，允许发现具有活性的表皮/真皮 靶向给药系统。利用重建的人皮肤的皮肤刺激性潜力和疗效 还将进行基于紫外线诱导的SKH-1小鼠光致癌的测试。整体而言 这项建议的目标是开发预防、治疗和避免 能够在皮肤内传递药物并在皮肤中维持的CSCC的进展 在一段时间内通过避免或最大限度地减少全身吸收和偏离目标的影响 增强治疗效果。基于强有力的初步数据，我们假设 具有减少和防止肿瘤进展特性的药物能够在 局部配方，将药物输送到皮肤内，同时最大限度地减少全身吸收和 不良影响。这种治疗方式对患者来说更加方便，可以使患者病情好转 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效果。