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（CSCC）和皮肤癌的发病率和死亡率 继续增加。预计，五分之一的美国人一生中将患上皮肤癌。 尽管通常表示手术切除术有效，但手术并不总是适当的 可能的。治疗和/或防止使用药理学剂的努力受到交付不佳的限制 作用部位（皮肤表皮和真皮）和大多数药理学疗法涉及 全身管理，几乎没有局部代理。现有药物和自然组合 具有针对皮肤癌的潜力的化合物，包括CSCC，具有<1％的生物利用度 口服管理时，这意味着他们无法有效地到达行动地点，因此 产生不充分的药理反应，而当静脉注射时可以导致 积极的不良副作用。尽管皮肤是可及的器官，但对皮肤的局部治疗 癌症和癌前病变受到限制。 角质层或过多的药物渗透到全身循环和靶向范围内。我们寻找 为了克服这些使用高通量筛查方法的药物输送障碍，我们 已经开发了包括允许发现可行表皮/真皮的配方库 有针对性的药物输送系统。使用重建的人皮和功效的皮肤刺激潜力 还将在SKH-1小鼠中基于紫外线诱导的光钙局发生的测试。总体 该建议的目标是开发用于预防，治疗和避免的药物制剂 CSCC的进展能够将药物输送到皮肤中并保持在皮肤中 一段时间以来，避免或最小化系统性吸收和脱离靶向效果，而 增强治疗功效。基于强大的初步数据，我们假设交付 能够在A中开发出降低和预防肿瘤进展特性的药物 局部配方可将药物输送在皮肤内，同时最大程度地减少全身吸收和 不利影响。这种类型的疗法对患者更方便，可以导致更好的患者 通过在作用部位增加药物的生物利用度，合规性和治疗功效。