Steroid-Based Contrast Agents for Magnetic Resonance Imaging of Endocrine Disease

用于内分泌疾病磁共振成像的类固醇造影剂

• 批准号: 8545175
• 负责人: Thomas J Meade
• 金额: $ 32.44万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545175
• 关键词: Aging; Animal Model; Animals; Applications Grants; Benign; Binding; Biological; Biological Assay; Breast Diseases; Cell Nucleus; Cell membrane; Cells; Charge; Chemicals; Chemistry; Conjugated Estrogens; Contrast Media; Development; Developmental Biology; Diagnosis; Disease; Disease Progression; Endocrine System Diseases; Estrogen Receptors; Estrogen receptor positive; Estrogens; Etiology; Fluorescence; Gadolinium; Genetic Transcription; Growth; Hormone Receptor; Hormones; Human; Image; Imaging Techniques; Implant; In Vitro; Ionizing radiation; Knowledge; Lesion; Life; Location; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Mechanics; Membrane; Microscopy; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Mutagenesis; New Agents; Nuclear; Nude Mice; Oncogenic; Optics; Organism; Palpable; Pathologic Processes; Physiological Processes; Positron-Emission Tomography; Process; Progesterone; Progesterone Receptors; Property; Radioactivity; Receptor Cell; Research Proposals; Resolution; Rodent Model; Role; Safety; Series; Signal Transduction; Solubility; Specimen; Steroid Receptors; Steroids; Testing; Time; Tissues; Toxic effect; Tumor Tissue; Uterine Lesion; Uterus; Water; Women' s Health; X-Ray Computed Tomography; Xenograft procedure; base; breast lesion; cancer diagnosis; design; dimethylbenzanthracene; endometriosis; gadolinium oxide; improved; in vitro testing; in vivo; innovation; malignant breast neoplasm; molecular imaging; neoplastic cell; public health relevance; receptor; receptor binding; receptor function; recombinase; reconstruction; research study; single photon emission computed tomography; soft tissue; spatiotemporal; steroid hormone; tool; transcription factor; tumor; water solubility

DESCRIPTION (provided by applicant): The objective of this research proposal is to develop a series of steroid-based magnetic resonance imaging (MRI) contrast agents to facilitate molecular characterization of the status and function of steroid receptors in hormone-dependent disease and development. The ability to detect the location of cell receptors and their concentration throughout a living organism is of vital importance as it allows for further understanding of cell signaling mechanics. Progesterone and estrogen are steroid hormones that bind to their receptors and function as a transcription factors in the nucleus. A non-invasive means of determining the hormone receptor status of hormone-dependent tumors and benign lesions could assist with treatment options, identification of the size and exact location of the tumor, and provide additional tools when traditional imaging strategies miss or confuse lesions of the breast and uterus. Unlike fluorescence and optical microscopy, MRI is not limited by depth or transparency of the specimen. MRI does not use ionizing radiation or radioactivity like positron emission tomography (PET) and X-ray/CT, and it allows for 3D reconstructions and high resolution imaging over time without the need to sacrifice the organism. It is the hypothesis of this grant proposal that gadolinium(III) conjugated hormone-based contrast agents can target and accumulate in hormone receptor positive cells to non-invasively image receptor status. Our preliminary studies have identified gadolinium (Gd)-conjugated progesterone derivatives as compounds capable of traversing the cell membrane, binding to progesterone receptors, initiating gene transcription, and enhancing contrast in mammalian tissues and tumors imaged in vivo using magnetic resonance, the most promising of which is termed "ProGlo". This proposal focuses on the application and expansion of ProGlo to enhance the imaging of steroid receptor tumors and tissues in vivo. AIM 1. To synthesize and test a series of CAs that targets the estrogen receptor. Estrogen-based contrast agents will be designed and synthesized with varying polarities, charges, and water solubilities that will selectively probe membrane bound receptors or receptors located inside the cells and tumors. AIM 2. To investigate if hormone receptor disease of the breast and uterus can be classified as receptor positive using functional hormone MR agents. AIM 3. To chemically modify CAs to enhance in vivo relaxivity and reduce toxicity by developing and testing bio-orthogonal, water-soluble, and multi-chelated hormone CAs. Steroid receptors have emerged as attractive targets for molecular imaging due to their role in promoting the growth of breast and uterine lesions. This proposal will develop steroid contrast agents that could provide a molecular profile of hormone receptor status in cells, validate responsiveness to therapy, and improve diagnoses. Functional contrast agents will provide valuable tools for use in humans and for immediate use in animal models of hormone receptor dependent development and disease without the need to euthanize the animal thereby increasing knowledge about developmental biology, disease etiology, and progression.

描述(申请人提供)：这项研究计划的目标是开发一系列基于类固醇的磁共振成像(MRI)造影剂，以促进类固醇受体在激素依赖型疾病和发育中的状态和功能的分子表征。能够检测细胞受体的位置和它们在整个生物体中的浓度是至关重要的，因为它允许进一步了解细胞信号机制。黄体酮和雌激素是类固醇激素，它们与它们的受体结合，在细胞核内发挥转录因子的作用。一种非侵入性 确定激素依赖型肿瘤和良性病变的激素受体状态的方法可以帮助选择治疗方案，识别肿瘤的大小和确切位置，并在传统成像策略遗漏或混淆乳腺和子宫病变时提供额外的工具。与荧光显微镜和光学显微镜不同，磁共振成像不受标本深度或透明度的限制。MRI不使用正电子发射断层扫描(PET)和X射线/CT等电离辐射或放射性，它允许随着时间的推移进行3D重建和高分辨率成像，而不需要牺牲有机体。这项拨款提案的假设是，基于Gd(III)的基于激素的造影剂可以靶向并聚集在激素受体阳性细胞中，以非侵入性的方式成像受体状态。我们的初步研究发现，Gd偶联的孕酮衍生物能够穿透细胞膜，与孕酮受体结合，启动基因转录，并在活体磁共振成像的哺乳动物组织和肿瘤中增强对比度，其中最有希望的是ProGlo。这项建议侧重于ProGlo的应用和扩展，以增强体内类固醇受体肿瘤和组织的成像。目的1.合成和检测一系列针对雌激素受体的CA。基于雌激素的造影剂将被设计和合成，具有不同的极性、电荷和水溶解度，将选择性地探测膜结合的受体或位于细胞和肿瘤内的受体。目的2.探讨功能性激素MR试剂能否将乳腺和子宫激素受体疾病归类为受体阳性。目的3.通过开发和测试生物正交性、水溶性和多螯合激素的CA，对CA进行化学修饰，以提高体内松弛能力和降低毒性。由于类固醇受体在促进乳腺和子宫病变的生长方面的作用，它们已经成为吸引人的分子成像靶点。这项提议将开发类固醇造影剂，可以提供细胞内激素受体状态的分子图谱，验证对治疗的反应，并改善诊断。功能性造影剂将为人类使用和立即用于激素受体依赖发育和疾病的动物模型提供宝贵的工具，而无需对动物实施安乐死，从而增加对发育生物学、疾病病因学和进展的了解。