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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Yu, Tao; Chan, Kannie W Y; Anonuevo, Abraham et al. (2015) Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI). Nanomedicine 11:401-5
Song, Xiaolei; Xu, Jiadi; Xia, Shuli et al. (2015) Multi-echo length and offset VARied saturation (MeLOVARS) method for improved CEST imaging. Magn Reson Med 73:488-96
Yang, Xing; Yadav, Nirbhay N; Song, Xiaolei et al. (2014) Tuning phenols with Intra-Molecular bond Shifted HYdrogens (IM-SHY) as diaCEST MRI contrast agents. Chemistry 20:15824-32
Chan, Kannie W Y; Yu, Tao; Qiao, Yuan et al. (2014) A diaCEST MRI approach for monitoring liposomal accumulation in tumors. J Control Release 180:51-9
Chan, Kannie W Y; Liu, Guanshu; van Zijl, Peter C M et al. (2014) Magnetization transfer contrast MRI for non-invasive assessment of innate and adaptive immune responses against alginate-encapsulated cells. Biomaterials 35:7811-8
Lin, Chien-Yuan; Yadav, Nirbhay N; Ratnakar, James et al. (2014) In vivo imaging of paraCEST agents using frequency labeled exchange transfer MRI. Magn Reson Med 71:286-93
Liu, Guanshu; Qin, Qin; Chan, Kannie W Y et al. (2014) Non-invasive temperature mapping using temperature-responsive water saturation shift referencing (T-WASSR) MRI. NMR Biomed 27:320-31
Xu, Jiadi; Yadav, Nirbhay N; Bar-Shir, Amnon et al. (2014) Variable delay multi-pulse train for fast chemical exchange saturation transfer and relayed-nuclear overhauser enhancement MRI. Magn Reson Med 71:1798-812
Yadav, Nirbhay N; Xu, Jiadi; Bar-Shir, Amnon et al. (2014) Natural D-glucose as a biodegradable MRI relaxation agent. Magn Reson Med 72:823-8
Bar-Shir, Amnon; Liu, Guanshu; Chan, Kannie W Y et al. (2014) Human protamine-1 as an MRI reporter gene based on chemical exchange. ACS Chem Biol 9:134-8

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