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?

乳腺导管原位癌(DCIS)约占筛查的乳腺新发恶性肿瘤的20% 人口。治疗包括大约75%的女性的保乳手术(BCS)，通常是之后 通过(RT)，将同一侧新癌症事件的风险减半。口服内分泌治疗(OET)进一步 将同一只乳房的风险降低1/3，将另一只乳房的风险降低一半。然而，OET是 超过一半的DCIS患者下降，考虑到其血栓栓子和子宫风险(选择性雌激素 受体调节剂)和肌肉骨骼效应(芳香酶抑制剂)。避免药物传递的方法 这些药物的不良影响将是一个重大的进步。经皮给药是公认的 和有效的替代方案。优点包括全身暴露低，在局部组织中滞留时间更长，以及 避免肝脏代谢首过。 应用4-羟基三苯氧胺(4-OHT)的局部透皮疗法(LTT)的初步数据令人鼓舞 导致我们进行了临床试验，旨在建立经皮和乳房皮肤的等效性 乳房的口服治疗。如果成功，这将是一个新颖的、潜在的变革性发展 DCIS人群，以及乳腺癌高危人群。然而，有很多重要的知识 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 接受过乳房RT的人，因为这可能会改变皮肤的渗透和/或通过 胸部。因为接受RT乳房治疗的DCIS患者通过使用 对于OET，评估药物对辐射皮肤的渗透性是很重要的。 我们研究的目的是：1)找出导致皮肤的个体差异的皮肤特征 药物在人与人之间的渗透，以及2)评估经皮给药的可行性 辐射过的乳房。我们将通过招募乳腺癌幸存者来做到这一点，这些幸存者中有一个是辐射的，另一个是完好无损的， 美容乳房，并愿意在两个乳房涂抹4-羟色胺凝胶，为期3-5周。到时候我们会的 获取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 并评估个体特征(乳房大小、肥胖)和皮肤特征(皮肤层厚度， 基因和蛋白质表达)，这可以解释药物浓度的个体间差异。在目标1中， 这些特征将被用来开发一个预测模型，以确定真皮的重要决定因素 药物在未受辐射的乳房中的输送。在目标2中，将比较辐射和辐射后的皮肤特征 未受辐射的乳房，以确定辐射引起的对皮肤渗透很重要的差异。 药物浓度将在辐射和未辐射的乳房之间进行比较。最后，我们会回答 关于目前几乎没有什么信息的两个问题：1)哪些女性是好的候选人 透皮疗法？2)透皮给药对受辐射的乳房有效吗？