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: 10093981
• 负责人: SEEMA Ahsan KHAN
• 金额: $ 36.17万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093981
• 关键词: 4-Hydroxy-Tamoxifen; ABCB1 gene; ABCG2 gene; Address; Adverse effects; Affect; 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; Event; Excretory function; Future; Gel; Gene Expression; High Risk Woman; Histology; Immunohistochemistry; Individual; Ipsilateral; Knowledge; Malignant Neoplasms; Mammary Gland Parenchyma; Measures; Metabolic; Methods; Musculoskeletal; New Agents; Noninfiltrating Intraductal Carcinoma; Obesity; Oral; Organ; Patient Selection; Patients; Penetration; Performance; Pharmaceutical Preparations; Population; Postoperative Period; Prevention; Radiation; Radiation therapy; Risk; Selective Estrogen Receptor Modulators; Side; Skin; Stratum corneum; Structure; Testing; Therapy Evaluation; Thick; Tissues; Toxic effect; Transdermal substance administration; Uterus; Woman; Work; Xenobiotics; base; 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?

乳房的原位癌（DCI）占筛查中新乳腺恶性肿瘤的20％ 人群。治疗包括约75％的女性的乳房保存手术（BC），通常遵循 （RT）将新癌症事件的风险减半。口服内分泌疗法（OET） 将同一乳房的风险降低了1/3，并将对另一个乳房的风险降低了一半。但是，oet是 鉴于其血栓栓塞和子宫风险，超过一半的DCIS患者下降（选择性雌激素 受体调节剂）和肌肉骨骼作用（芳香酶抑制剂）。避免的药物输送方法 这些药物的不利影响将代表一个重大进展。透皮交付是一种公认​​的 和有效的替代方案。优势包括较低的全身性暴露，在局部组织中较长的保留率以及 避免肝肝新陈代谢。 使用4-羟基莫昔芬（4-OHT）的局部透皮疗法（LTT）进行鼓励的初步数据 乳房皮肤使我们进行了旨在建立透皮和等效性的临床试验 口服乳房。如果成功的话，这将是一种新颖而潜在的变革性发展 DCIS人口，以及患乳腺癌高风险的女性。但是，有重要的知识 关于真皮渗透中各个变化的原因的差距。目前的研究排除了女性 他们经历了乳房RT，因为这可能会改变真皮的渗透和/或分布 胸部。由于接受RT乳房的DCIS患者通过使用为两种乳房提供了额外的保护 在OET中，通过辐射皮肤对药物渗透的评估很重要。 我们研究的目的是1）确定皮肤特征的皮肤间个体变化 个体之间的药物渗透，2）评估透皮药物递送到该的可行性 辐射乳房。我们将通过招募一个辐射且一个完整的，非 - 的乳腺癌幸存者来做到这一点 放射的乳房，愿意在3-5周的两个乳房上涂4欧特凝胶。然后我们会 获得两种乳房的皮肤打孔和核心针活检，测量乳房组织中的药物浓度 核心，并评估个体特征（乳房大小，肥胖）和皮肤特征（皮肤层的厚度， 基因和蛋白质表达），可以解释药物浓度的个体间变化。在AIM 1中， 这些功能将用于开发一个预测模型，该模型识别真皮的重要决定因素 在未耐乳房中输送药物。在AIM 2中，将比较辐射和 未耐托的乳房，以确定辐射引入的差异，这对于真皮渗透很重要。 将在辐射乳房和未耐导的乳房之间比较药物浓度。最后，我们会回答 有关目前有哪些信息的两个问题：1）哪些女性是良好的候选人 透皮疗法？ 2）透皮递送会用于辐射乳房吗？