Determinants of transdermal drug delivery to the normal and the radiated breast

正常乳房和放射乳房经皮药物输送的决定因素

• 批准号: 10559716
• 负责人: SEEMA Ahsan KHAN
• 金额: $ 59.34万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559716
• 关键词: 4-Hydroxy-Tamoxifen; ABCB1 gene; ABCG2 gene; Address; Adverse effects; Affect; Agreement; Area; Aromatase Inhibitors; Biological Assay; Blood; Blood Vessels; Breast; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer survivor; Breast-Conserving Surgery; Carrier Proteins; Characteristics; Clinical Trials; Conduct Clinical Trials; Contralateral; Contralateral Breast; Core Biopsy; Data; Dermal; Development; Drug Delivery Systems; Drug Evaluation; Enrollment; Enzymes; Evaluation; Event; Exclusion; Excretory function; Future; Gel; Gene Expression; High Risk Woman; Histology; Hormones; Immunohistochemistry; Individual; Ipsilateral; Knowledge; Malignant Neoplasms; Mammary Gland Parenchyma; Measures; Metabolic; Methods; Microscopy; Musculoskeletal; New Agents; Noninfiltrating Intraductal Carcinoma; Obesity; Oral; Organ; Patient Selection; Patients; Penetration; Performance; Pharmaceutical Preparations; Population; Postoperative Period; Prevention; Radiation; Radiation therapy; Risk; Risk Reduction; Selective Estrogen Receptor Modulators; Side; Skin; Stratum corneum; Structure; Testing; Thick; Tissues; Toxic effect; Transdermal substance administration; Uterus; Visualization; Woman; Work; Xenobiotics; breast malignancies; cancer prevention; density; high risk; hormone receptor-negative; hormone therapy; individual variation; insight; inter-individual variation; liver metabolism; lymphatic vessel; malignant breast neoplasm; non-invasive imaging; novel; pill; pre-clinical; predictive modeling; protein expression; reflectance confocal microscopy; side effect; success; tool

Duct carcinoma in situ (DCIS) of the breast comprises about 20% of new breast malignancies in screened populations. Treatment consists of breast conserving surgery (BCS) in about 75% of women, usually followed by (RT), which halves the risk of new cancer events on the same side. Oral endocrine therapy (OET) further reduces the risk to the same breast by 1/3rd , and cuts the risk to the other breast by one-half. However, OET is declined by more than half of DCIS patients, given its thromboembolic and uterine risks (selective estrogen receptor modulators), and musculoskeletal effects (aromatase inhibitors). Drug delivery methods that avoid the adverse effects of these agents will represent a significant advance. Transdermal delivery is a well-recognized and effective alternative. Advantages include low systemic exposure, longer retention in the local tissue, and avoidance of first-pass hepatic metabolism. Encouraging preliminary data on local transdermal therapy (LTT) with 4-hydroxytamoxifen (4-OHT) applied to the breast skin have led us to conduct clinical trials aimed at establishing the equivalence of transdermal and oral treatment of the breast. If successful, this will be a novel and potentially transformative development for the DCIS population, and for women at high risk for breast cancer. However, there are significant knowledge gaps regarding the causes of individual variations in dermal permeation. And current studies exclude women who have undergone breast RT because this may alter dermal permeation and/or distribution through the breast. Since DCIS patients who receive RT breast derive additional protection for both breasts through the use of OET, an evaluation of drug permeation through radiated skin is important. The Aims of our study are 1) to identify the skin features that drive inter-individual variation in dermal drug permeation between individuals, and 2) to assess the feasibility of transdermal drug delivery to the radiated breast. We will do this by enrolling breast cancer survivors who have one radiated and one intact, non- radiated breast, and are willing to apply 4-OHT gel to both breasts for a period of 3-5 weeks. We will then obtain skin punch and core needle biopsies of both breasts, measure drug concentration in the breast tissue cores, and assess individual characteristics (breast size, adiposity) and skin features (thickness of skin layers, gene and protein expression) that may explain the inter-individual variation in drug concentration. In Aim 1, these features will be used to develop a predictive model that identifies the important determinants of dermal drug delivery in the unradiated breast. In Aim 2, skin features will be compared between the radiated and unradiated breast, to determine differences introduced by radiation that are important for dermal permeation. Drug concentrations will be compared between the radiated and unradiated breast. At the end, we will answer two questions regarding which little information exists currently: 1) which women are good candidates for transdermal therapy? 2) Will transdermal delivery work for the radiated breast?

乳腺导管原位癌 (DCIS) 约占筛查中新发乳腺恶性肿瘤的 20% 人口。约 75% 的女性接受保乳手术 (BCS) 治疗，通常随后进行 通过（RT），这将同一侧发生新癌症事件的风险减半。进一步口服内分泌治疗（OET） 同一乳房的风险降低 1/3，另一侧乳房的风险降低一半。然而，OET 是 鉴于其血栓栓塞和子宫风险（选择性雌激素 受体调节剂）和肌肉骨骼效应（芳香酶抑制剂）。避免药物输送的方法 这些药物的副作用将代表重大进步。透皮给药是公认的 和有效的替代方案。优点包括全身暴露量低、在局部组织中保留时间较长，以及 避免首过肝脏代谢。 使用 4-羟基他莫昔芬 (4-OHT) 进行局部透皮治疗 (LTT) 的初步数据令人鼓舞 乳房皮肤的作用促使我们进行临床试验，旨在建立透皮和 口服乳房治疗。如果成功，这将是一项新颖且具有潜在变革性的发展 DCIS 人群以及乳腺癌高危女性。但其中蕴含着重要的知识 关于真皮渗透性个体差异的原因存在分歧。目前的研究排除了女性 接受过乳房放疗的人，因为这可能会改变皮肤的渗透性和/或分布 胸部。由于接受乳房放疗的 DCIS 患者通过使用 对于 OET，评估药物通过辐射皮肤的渗透性非常重要。 我们研究的目的是 1) 确定导致真皮个体间差异的皮肤特征 药物在个体之间的渗透，以及 2) 评估透皮药物递送至个体的可行性 辐射乳房。我们将通过招募乳腺癌幸存者来做到这一点，其中一名乳腺癌幸存者接受了放射治疗，另一名患者接受了完整的非治疗。 接受过放射治疗的乳房，并愿意在双侧乳房上涂抹 4-OHT 凝胶，为期 3-5 周。我们随后将 获得双侧乳房的皮肤穿孔和空心针活检，测量乳房组织中的药物浓度 核心，并评估个人特征（乳房大小、肥胖）和皮肤特征（皮肤层厚度、 基因和蛋白质表达）可以解释药物浓度的个体间差异。在目标 1 中， 这些特征将用于开发一个预测模型，识别真皮的重要决定因素。 在未辐射的乳房中进行药物输送。在目标 2 中，将比较辐射和辐射之间的皮肤特征 未经辐射的乳房，以确定辐射引起的差异对于真皮渗透很重要。 将比较经辐射和未经辐射的乳房之间的药物浓度。最后我们来解答 目前关于两个问题的信息很少：1）哪些女性是良好的候选人 透皮疗法？ 2) 透皮给药对接受放射治疗的乳房有效吗？