A variety of gadolinium-based MRI contrast agents continue to be used clinically as non-specific extracellular agents but none report on specific metabolic indices of cancer. Although many responsive gadolinium agents have been reported in the literature, none are moving toward clinical approval largely because they are never truly silent and their response to biological events or tissue physiology is only modest. A novel class of MRI agents, the paramagnetic chemical exchange saturation transfer (paraCEST) agents, is better suited for the design of responsive MR agents because they are inherently more sensitive to changes in tissue physiology and metabolism. The extreme sensitivity of proton exchange rates to tissue environment makes these complexes an ideal platform for the design of responsive MR agents. Despite this potential, paraCEST agents have not shown much success in vivo at this point because 1) the field is small and only a few labs have tried to implement them in vivo and 2) their sensitivity in vivo is disappointingly low compare to in vitro. We are now convinced that the low in vivo sensitivity of paraCEST agents is because most agents were designed similar to Gd-based agents with an exchanging inner-sphere water molecule and this exchange adds substantial line- broadening to the tissue water signal by a T2exch mechanism. In this grant, we will focus on applications of paraCEST reporter molecules that lack an inner-sphere water exchange site thereby eliminating the detrimental T2exch effect on the bulk water signal. We will demonstrate the utility of these new agents for imaging common hallmarks of cancer in vivo before the end of the next 5 year grant cycle.
In Aim 1, we will use paraCEST sensors to image the extracellular pH of multiple tumor types by detecting the frequency of the CEST signals arising from multiple ligand -OH groups. The agents we propose will have ?OH signals that shift frequency with changes in pH.
In Aim 2, we will implement nitroimidazole-based MRI sensors for imaging hypoxic regions of tumors using agents that accumulate to high levels in hypoxic tissues. We have already shown that the Gd-derivatives of these agents are trapped only in hypoxic tumors and can be detected in T1- weighted images. The corresponding Yb- and Tm-derivatives will show a CEST signal that will also report the intracellular pH in those same hypoxic regions.
In Aim 3, we outline a general strategy for improving the sensitivity of paraCEST agents by using pH-responsive block copolymer micelles as carriers that incorporate paraCEST centers in the hydrophobic block. The overarching goal of this grant is to implement responsive paraCEST agents in tumor-bearing animals at concentrations acceptable for translation to humans. We will show for the first time that two important hallmarks of cancer, pH and hypoxia, can be imaged routinely in vivo.

Public Health Relevance

Magnetic resonance imaging (MRI) is widely used to detect tumors but provides very little information about tumor metabolism or microenvironment. This project involves developing a new class of responsive MR imaging agents as highly specific reporters of tumor biomarkers such as low pH and highly reduced tissue oxidation state. These indices are all hallmarks of rapidly proliferating cells so having a stable of responsive agents capable of sensing these tissue biomarkers would be extremely valuable for monitoring tumor progression and response to treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115531-12
Application #
9402058
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Menkens, Anne E
Project Start
2005-08-15
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Zhang, Lei; Evbuomwan, Osasere M; Tieu, Michael et al. (2017) Protonation of carboxyl groups in EuDOTA-tetraamide complexes results in catalytic prototropic exchange and quenching of the CEST signal. Philos Trans A Math Phys Eng Sci 375:
Zhang, Lei; Martins, André F; Mai, Yuyan et al. (2017) Imaging Extracellular Lactate In Vitro and In Vivo Using CEST MRI and a Paramagnetic Shift Reagent. Chemistry 23:1752-1756
Singh, Jaspal; Rustagi, Vineeta; Zhang, Shanrong et al. (2017) On-bead combinatorial synthesis and imaging of europium(III)-based paraCEST agents aids in identification of chemical features that enhance CEST sensitivity. Magn Reson Chem 55:747-753
Farashishiko, Annah; Plush, Sally E; Maier, Karley B et al. (2017) Crosslinked shells for nano-assembled capsules: a new encapsulation method for smaller Gd3+-loaded capsules with exceedingly high relaxivities. Chem Commun (Camb) 53:6355-6358
Zhang, Lei; Martins, André F; Zhao, Piyu et al. (2017) Enantiomeric Recognition of d- and l-Lactate by CEST with the Aid of a Paramagnetic Shift Reagent. J Am Chem Soc 139:17431-17437
Wu, Yunkou; Zhang, Shanrong; Soesbe, Todd C et al. (2016) pH imaging of mouse kidneys in vivo using a frequency-dependent paraCEST agent. Magn Reson Med 75:2432-41
Kumas, Cemile; Fernando, W Shirangi; Zhao, Piyu et al. (2016) Unexpected Changes in the Population of Coordination Isomers for the Lanthanide Ion Complexes of DOTMA-Tetraglycinate. Inorg Chem 55:9297-305
Xing, Yixun; Jindal, Ashish K; Regueiro-Figueroa, Martín et al. (2016) The Relationship between NMR Chemical Shifts of Thermally Polarized and Hyperpolarized 89 Y Complexes and Their Solution Structures. Chemistry 22:16657-16667
Funk, Alexander M; Clavijo Jordan, Veronica; Sherry, A Dean et al. (2016) Oxidative Conversion of a Europium(II)-Based T1 Agent into a Europium(III)-Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging. Angew Chem Int Ed Engl 55:5024-7
Fernando, W Shirangi; Martins, André F; Zhao, Piyu et al. (2016) Breaking the Barrier to Slow Water Exchange Rates for Optimal Magnetic Resonance Detection of paraCEST Agents. Inorg Chem 55:3007-14

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