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.
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.
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|Townsend, Taryn R; Moyle-Heyrman, Georgette; Sukerkar, Preeti A et al. (2014) Progesterone-targeted magnetic resonance imaging probes. Bioconjug Chem 25:1428-37|
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|Hung, Andy H; Holbrook, Robert J; Rotz, Matthew W et al. (2014) Graphene oxide enhances cellular delivery of hydrophilic small molecules by co-incubation. ACS Nano 8:10168-77|
|Heffern, Marie C; Matosziuk, Lauren M; Meade, Thomas J (2014) Lanthanide probes for bioresponsive imaging. Chem Rev 114:4496-539|
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