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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB005866-07
Application #
8286073
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Liu, Christina
Project Start
2005-09-23
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$313,888
Indirect Cost
$97,618
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Preslar, Adam T; Tantakitti, Faifan; Park, Kitae et al. (2016) (19)F Magnetic Resonance Imaging Signals from Peptide Amphiphile Nanostructures Are Strongly Affected by Their Shape. ACS Nano 10:7376-84
MacRenaris, Keith W; Ma, Zhidong; Krueger, Ruby L et al. (2016) Cell-Permeable Esterase-Activated Ca(II)-Sensitive MRI Contrast Agent. Bioconjug Chem 27:465-73
Hung, Andy H; Lilley, Laura M; Hu, Fengqin et al. (2016) Magnetic barcode imaging for contrast agents. Magn Reson Med :
Vistain, Luke F; Rotz, Matthew W; Rathore, Richa et al. (2016) Targeted delivery of gold nanoparticle contrast agents for reporting gene detection by magnetic resonance imaging. Chem Commun (Camb) 52:160-3
Rotz, Matthew W; Culver, Kayla S B; Parigi, Giacomo et al. (2015) High relaxivity Gd(III)-DNA gold nanostars: investigation of shape effects on proton relaxation. ACS Nano 9:3385-96
Carney, Christiane E; MacRenaris, Keith W; Meade, Thomas J (2015) Water-soluble lipophilic MR contrast agents for cell membrane labeling. J Biol Inorg Chem 20:971-7
Harrison, Victoria S R; Carney, Christiane E; MacRenaris, Keith W et al. (2015) Multimeric Near IR-MR Contrast Agent for Multimodal In Vivo Imaging. J Am Chem Soc 137:9108-16
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
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

Showing the most recent 10 out of 60 publications