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: 8265545
• 负责人: Thomas J Meade
• 金额: $ 35.66万
• 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/8265545
• 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; 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. PUBLIC HEALTH RELEVANCE: 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 magnetic resonance imaging contrast agents that could provide a molecular profile of hormone receptor status in cells and tissues, validate responsiveness to therapy, and improve diagnoses. This is an innovative and far-reaching proposal that is likely to impact the fields of imaging, cancer diagnosis, and women's health.

描述（由申请人提供）：本研究计划的目的是开发一系列基于类固醇的磁共振成像（MRI）造影剂，以促进激素依赖性疾病和发展中类固醇受体的状态和功能的分子表征。检测细胞受体的位置及其在整个生物体中的浓度的能力至关重要，因为它可以进一步了解细胞信号传导机制。黄体酮和雌激素是类固醇激素，与其受体结合并在细胞核中充当转录因子。一种非侵入性 确定激素依赖性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，确定肿瘤的大小和确切位置，并在传统成像策略遗漏或混淆乳房和子宫病变时提供额外的工具。与荧光和光学显微镜不同，MRI 不受样本深度或透明度的限制。 MRI 不使用电离辐射或放射性，如正电子发射断层扫描 (PET) 和 X 射线/CT，并且它允许随着时间的推移进行 3D 重建和高分辨率成像，而无需牺牲生物体。该拨款提案的假设是，钆（III）结合的激素造影剂可以靶向并在激素受体阳性细胞中积累，以实现非侵入性图像受体状态。我们的初步研究已确定钆 (Gd) 结合的孕酮衍生物是能够穿过细胞膜、与孕酮受体结合、启动基因转录并增强使用磁共振体内成像的哺乳动物组织和肿瘤的对比度的化合物，这是最有前途的这被称为“ProGlo”。该提案重点关注 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.合成并测试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、电荷和水溶性，将选择性地探测膜结合受体或位于细胞和肿瘤内部的受体。目的 2. 探讨使用功能性激素 MR 药物是否可以将乳房和子宫的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、水溶性和多螯合激素 CA，对 CA 进行化学修饰，以增强体内弛豫性并降低毒性。类固醇受体因其在促进乳房和子宫病变生长中的作用而成为分子成像的有吸引力的靶标。该提案将开发类固醇造影剂，可以提供细胞中激素受体状态的分子特征，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提供有价值的工具，并可立即用于激素受体依赖性发育和疾病的动物模型，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。 公共健康相关性：类固醇受体因其在促进乳房和子宫病变生长中的作用而成为分子成像的有吸引力的目标。该提案将开发类固醇磁共振成像造影剂，可以提供细胞和组织中激素受体状态的分子概况，验证对治疗的反应并改善诊断。这是一项创新且影响深远的提案，可能会影响成像、癌症诊断和女性健康领域。