The goal of this project is to develop bioactivated magnetic resonance(MR) contrast agents for the imaging of in vivo processes, ranging from gene expression to secondary messenger activation. This project is focused on obtaining insights into the interrelated problems of developmental biology and clinical diseases by i. generating MR probes that function as real-time in vivo enzyme reporters, ii. Track gene expression in whole animals and correlate this information with ongoing developmental events, and iii. develop biocompatible scaffolds for the efficient delivery of these agents in experimental animals and potentially humans. In order to maximize the impact of this technique, functional contrast agents must be investigated and developed. Further, the study of developmental biology in whole animals will result in a deeper understanding of the role of spatial organization with mechanism. Therefore, to create an in vivo assay of enzymatic activities and detection of secondary messengers, MR contrast agents will be designed and synthesized with removable protection groups that largely prevent the access of water to a paramagnetic center. By limiting the access of bulk water (q- modulation) the unprocessed agent is designed to be an ineffective contrast agent. We have defined 5 primary objectives: 1.Synthesize and characterize MRI contrast agents with enzyme substrates as blocking groups of water (q-modulation) 2. Use computational modeling to direct synthetic efforts towards new q-modulated agents. 3.Develop targeted contrast agents and methods of amplifying the contrast signal. 4. Investigate delivery and the uptake mechanisms by which the agents are internalized by cells. 5. Evaluate the effectiveness of the agents in preclinical rodent models and other in vivo systems. Several tetraazamacrocyclic architectures will be synthesized and investigated. We will focus on the schematically represented structures I- V where the arrows represent the site of enzymatic attack for the irreversibly activated agents (I-III).
This project is relevant to public health because the results will directly impact current methods of diagnosis and treatment of clinical disease. The development of bioactivated contrast agents for tracking gene expression is a powerful tool for developmental biology which has wide-ranging applications in areas such as prevention of cancer metastasis.
|Heffern, Marie C; Velasco, Pauline T; Matosziuk, Lauren M et al. (2014) Modulation of amyloid-? aggregation by histidine-coordinating Cobalt(III) Schiff base complexes. Chembiochem 15:1584-9|
|Harrison, Victoria S R; Carney, Christiane E; Macrenaris, Keith W et al. (2014) A multimeric MR-optical contrast agent for multimodal imaging. Chem Commun (Camb) 50:11469-71|
|Carney, Christiane E; MacRenaris, Keith W; Mastarone, Daniel J et al. (2014) Cell labeling via membrane-anchored lipophilic MR contrast agents. Bioconjug Chem 25:945-54|
|Trivedi, Evan R; Ma, Zhidong; Waters, Emily A et al. (2014) Synthesis and characterization of a porphyrazine-Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model. Contrast Media Mol Imaging 9:313-22|
|Preslar, Adam T; Parigi, Giacomo; McClendon, Mark T et al. (2014) Gd(III)-labeled peptide nanofibers for reporting on biomaterial localization in vivo. ACS Nano 8:7325-32|
|Heffern, Marie C; Matosziuk, Lauren M; Meade, Thomas J (2014) Lanthanide probes for bioresponsive imaging. Chem Rev 114:4496-539|
|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|
|Raitsimring, A; Astashkin, A V; Enemark, J H et al. (2013) Optimization of pulsed DEER measurements for Gd-based labels: choice of operational frequencies, pulse durations and positions, and temperature. Appl Magn Reson 44:649-670|
|Hung, Andy H; Liang, Taiyang; Sukerkar, Preeti A et al. (2013) High dynamic range processing for magnetic resonance imaging. PLoS One 8:e77883|
|Jensen, Samuel A; Day, Emily S; Ko, Caroline H et al. (2013) Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Sci Transl Med 5:209ra152|
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