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: 10334490
• 负责人: SEEMA Ahsan KHAN
• 金额: $ 35.45万
• 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/10334490
• 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?

乳腺导管原位癌（DCIS）约占筛查的新发乳腺恶性肿瘤的20%。 人口。治疗包括乳房保留手术（BCS）在约75%的妇女，通常随后 通过（RT），这将使同一侧的新癌症事件风险减半。口服内分泌治疗（OET） 同一个乳房的风险降低了三分之一，另一个乳房的风险降低了一半。然而，OET是 考虑到其血栓栓塞和子宫风险（选择性雌激素）， 受体调节剂）和肌肉骨骼作用（芳香酶抑制剂）。药物输送方法，避免了 这些试剂的副作用将代表一个显著的进步。经皮给药是一种公认的 有效的替代品。优点包括全身暴露低，在局部组织中保留时间长， 避免首过肝代谢。 关于应用4-羟基他莫昔芬（4-OHT）的局部透皮治疗（LTT）的令人鼓舞的初步数据 导致我们进行临床试验，旨在建立经皮和经皮给药的等效性。 乳房的口服治疗。如果成功，这将是一个新的和潜在的变革性发展， DCIS人群和乳腺癌高危女性。然而，有重要的知识 关于皮肤渗透的个体差异的原因的差距。目前的研究排除了女性 因为这可能会改变皮肤渗透和/或分布， 乳房由于接受RT乳房的DCIS患者通过使用 在OET中，评价药物通过辐射皮肤的渗透是重要的。 我们研究的目的是：1）确定皮肤特征，这些特征驱动真皮中的个体间差异。 个体之间的药物渗透，以及2）评估经皮药物递送至 辐射乳房我们将通过招募乳腺癌幸存者来做到这一点，这些幸存者一个接受了放射治疗，一个完好无损， 辐射乳房，并愿意将4-OHT凝胶应用于两个乳房3-5周的时间。然后我们将 获得两个乳房的皮肤穿孔和芯针活检，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（皮肤层的厚度， 基因和蛋白质表达），这可能解释药物浓度的个体间差异。在目标1中， 这些特征将被用于开发一个预测模型，该模型识别皮肤的重要决定因素， 在未辐射的乳房中的药物输送。在目标2中，皮肤特征将在辐射和 未经辐射的乳房，以确定辐射引入的差异，这对皮肤渗透很重要。 将比较辐射和未辐射乳房之间的药物浓度。最后，我们将回答 关于这两个问题，目前几乎没有什么资料：1）哪些妇女是好的候选人， 透皮治疗2)经皮给药对放射性乳腺有效吗？