Non-invasive pH and temperature mapping is needed for cancer research because these parameters are exploited in tumor diagnosis or therapy. To that goal, smart contrast agents (SCAs) composed of paramagnetic lanthanide ion (Ln3+) with derivatives of 1,4,7,10 tetraazacyclododecane (cyclen) have been developed for MR. We have shown that two commercial Tm3+-based SCAs, TmDOTP5 and TmDOTMA, provide extracellular pH/temperature maps with biosensor imaging of redundant deviation in shifts (BIRDS). These types of SCAs are used as MRS shift agents to separate resonances of endogenous molecules (or ions). However BIRDS maps the 1H signals from non-exchangeable protons (i.e., CHx) of the SCA itself, which is in contrast to the paramagnetic chemical exchange saturation transfer (PARACEST) agent that features exchangeable protons (e.g., OH or NHx). Detection of the non-exchangeable protons by BIRDS provides redundancy to extract temperature/pH, the chemical shift imaging (CSI) data are acquired rapidly for superior signal-to-noise ratio (SNR), and quantification is nearly insensitive to the magnetic field strength (Bo), poor Bo shim conditions, and the SCA's concentration. BIRDS with high speed 2D CSI at 11.7T allows spatial resolution of ~10

Public Health Relevance

Novel paramagnetic lanthanide macrocyclics will be synthesized and translated for tumor imaging in rat brain. Agents will feature non-exchangeable protons, detectable by biosensor imaging of redundant deviation in shifts (BIRDS), for pH and temperature mapping, where quantification is independent of agent concentration and magnetic field. Each agent, designed for superior sensitivity of BIRDS, will undergo assays for kinetic inertness, brain access, cytotoxicity, and distribution. Results will identify structural features with toxicology and biodistribution suitable for future pre-clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140102-04
Application #
8408792
Study Section
Special Emphasis Panel (ZRG1-SBIB-U (50))
Program Officer
Zhang, Huiming
Project Start
2010-07-05
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$328,540
Indirect Cost
$97,345
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Coman, Daniel; Huang, Yuegao; Rao, Jyotsna U et al. (2016) Imaging the intratumoral-peritumoral extracellular pH gradient of gliomas. NMR Biomed 29:309-19
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Huang, Yuegao; Coman, Daniel; Herman, Peter et al. (2016) Towards longitudinal mapping of extracellular pH in gliomas. NMR Biomed 29:1364-72
Coman, Daniel; Sanganahalli, Basavaraju G; Jiang, Lihong et al. (2015) Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") exposure. NMR Biomed 28:1257-66
Strohbehn, Garth; Coman, Daniel; Han, Liang et al. (2015) Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance. J Neurooncol 121:441-9
Huang, Yuegao; Coman, Daniel; Hyder, Fahmeed et al. (2015) Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Bioconjug Chem 26:2315-23
Huang, Yuegao; Coman, Daniel; Ali, Meser M et al. (2015) Lanthanide ion (III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate for dual biosensing of pH with chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS). Contrast Media Mol Imaging 10:51-8
Maritim, Samuel; Huang, Yuegao; Coman, Daniel et al. (2014) Characterization of a lanthanide complex encapsulated with MRI contrast agents into liposomes for biosensor imaging of redundant deviation in shifts (BIRDS). J Biol Inorg Chem 19:1385-98
Scafidi, Joseph; Hammond, Timothy R; Scafidi, Susanna et al. (2014) Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 506:230-4

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