The overall Program Project focuses on the design and detection of bioorganic biodegradable Chemical Exchange Saturation Transfer (CEST) agents, with the ultimate goal of their practical application to cellular and molecular labeling and the imaging of drug delivery and gene expression in animals and humans. Much work is needed to make the use of such agents possible on a daily basis in the clinic. The overall goal of Project 1 is to develop quantitative IMRI approaches for detecting both exogenous and endogenous CEST agents in situ. As such, this project focuses on the design of new MRI pulse sequences to label and detect exchangeable protons, on the quantification of contrast generated by CEST agents, and on translation from phantoms to animal models and to humans. During these developments, we will be interacting closely with projects 2 and 3 to assure that we always have the best agents and that the technology is optimized for the actual agents being used under in vivo conditions. To accomplish our goal, we have set several specific aims:
In AIM 1. we will develop new magnetic labeling schemes for detecting exchangeable protons. Until now, magnetization transfer (MT) processes in vivo have only been detected using transfer of induced saturation, both radio-frequency (RF) induced and dephasing induced. We will develop and optimize novel approaches for magnetic labeling that do not employ RF saturation, but instead a series of so-called Label-Transfer Modules (LTMs), each including a labeling section and exchange transfer section. We will use these to design frequency-selective inversion and dephasing label-transfer approaches, as well as methods based on frequency modulation, such as can be induced using chemical shifts and scalar coupling and detected using approaches similar to multi-dimensional Fourier-Transform (FT) NMR.
In AIM 2. we focus on quantification of the water contrast caused by CEST agents. Proper quantification requires uncontaminated signal and thus selective detection of the effect of the agents through removal of the interfering effects of competing magnetization transfer processes and the detrimental effects of inhomogeneities in both static magnetic field (Bo) and applied radiofrequency field (Bi). Approaches to measure absolute concentrations will be designed and optimized and subsequently validated using known concentrations in phantoms. Finally, in AIM 3, we focus on translation of the developed exchange technologies to animal and human systems. This relates to the selective detection of both endogenous and exogenous CEST agents in vivo. The technologies developed in vitro in aims 1 and 2 will be implemented on both animal scanners (11.7T, 17.6T) and human scanners (3T, 7T). Both single-slice and multi-slice/3D MRI exchange-transfer technologies will be developed for this purpose. In the animal studies, we will evaluate endogenous effects as well as the exogenous systems developed in Projects 2 and 3. On the human scanners we will focus on endogenous compounds.
These aims are expected to result in the availability of quantifiable exchange transfer contrast MRI approaches in vivo, optimized with respect to the specific drug-delivery and gene expression systems in animals and ready for application in humans.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZEB1-OSR-C (J1))
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Liu, Guoying
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Hugo W. Moser Research Institute Kennedy Krieger
United States
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Li, Yuguo; Qiao, Yuan; Chen, Hanwei et al. (2018) Characterization of tumor vascular permeability using natural dextrans and CEST MRI. Magn Reson Med 79:1001-1009
Chen, Lin; Xu, Xiang; Zeng, Haifeng et al. (2018) Separating fast and slow exchange transfer and magnetization transfer using off-resonance variable-delay multiple-pulse (VDMP) MRI. Magn Reson Med 80:1568-1576
Chen, Lin; Wei, Zhiliang; Chan, Kannie W Y et al. (2018) Protein aggregation linked to Alzheimer's disease revealed by saturation transfer MRI. Neuroimage 188:380-390
Knutsson, Linda; Xu, Jiadi; Ahlgren, André et al. (2018) CEST, ASL, and magnetization transfer contrast: How similar pulse sequences detect different phenomena. Magn Reson Med 80:1320-1340
Liu, Jing; Bai, Renyuan; Li, Yuguo et al. (2018) MRI detection of bacterial brain abscesses and monitoring of antibiotic treatment using bacCEST. Magn Reson Med 80:662-671
Zhang, Jia; Li, Yuguo; Slania, Stephanie et al. (2018) Phenols as Diamagnetic T2 -Exchange Magnetic Resonance Imaging Contrast Agents. Chemistry 24:1259-1263
Jiang, Shanshan; Eberhart, Charles G; Lim, Michael et al. (2018) Identifying Recurrent Malignant Glioma after Treatment Using Amide Proton Transfer-Weighted MR Imaging: A Validation Study with Image-Guided Stereotactic Biopsy. Clin Cancer Res :
Banerjee, Sangeeta Ray; Song, Xiaolei; Yang, Xing et al. (2018) Salicylic Acid-Based Polymeric Contrast Agents for Molecular Magnetic Resonance Imaging of Prostate Cancer. Chemistry 24:7235-7242
van Zijl, Peter C M; Lam, Wilfred W; Xu, Jiadi et al. (2018) Magnetization Transfer Contrast and Chemical Exchange Saturation Transfer MRI. Features and analysis of the field-dependent saturation spectrum. Neuroimage 168:222-241
Yadav, Nirbhay N; Yang, Xing; Li, Yuguo et al. (2017) Detection of dynamic substrate binding using MRI. Sci Rep 7:10138

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