Treatments that alkalinize the acidic extracellular space of tumors are under development as inexpensive anticancer alternatives that reduce metastasis and malignancy. One of these alkalinizing therapies, oral bicarbonate, has been shown to be particularly effective and has been recently approved by the FDA as an investigational new drug for clinical cancer trials. A drawback of this therapy is that high doss of bicarbonate impair kidney function, making it important to optimize bicarbonate treatments. We propose to develop a new class of small molecule MRI contrast agents for the registration of pH in tumor tissue to monitor and optimize alkalinizing treatments. These efforts will use pH sensitive paraCEST MRI contrast agents with two different exchangeable protons that can be used for ratiometric concentration independent pH monitoring in tissue. (paraCEST = paramagnetic chemical exchange saturation transfer). This approach is under development for lanthanide (Ln(III)) containing contrast agents, but is problematic because of the lack of different types of exchangeable protons with large paramagnetic induced proton shifts. Work in the Morrow laboratory has shown that iron (Fe(II)) complexes can be developed into paraCEST MRI contrast agents. Fe(II) complexes have sharper and more highly shifted proton resonances for CEST than the Ln(III) complexes currently under development. In addition, the iron complexes may be potentially be less expensive and less toxic. We will develop these new iron based agents both as small molecule imaging agents and as dendrimers to control retention and tumor uptake. These agents will be tested in mouse mammary tumors.

Public Health Relevance

Treatments that alkalinize the acidic extracellular space of tumors are under development as inexpensive anticancer alternatives that reduce metastasis and malignancy. One of these alkalinizing therapies, oral bicarbonate, has been shown to be particularly effective and has been recently approved by the FDA as an investigational new drug for clinical cancer trials. We propose to develop iron based MRI contrast agents for the registration of tumor acidosis and with the long term goal of monitoring and optimize alkalinizing treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA173309-01
Application #
8431063
Study Section
Special Emphasis Panel (ZRG1-SBIB-Q (03))
Program Officer
Menkens, Anne E
Project Start
2013-01-22
Project End
2014-12-31
Budget Start
2013-01-22
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$78,708
Indirect Cost
$28,708
Name
State University of New York at Buffalo
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Olatunde, Abiola O; Cox, Jordan M; Daddario, Michael D et al. (2014) Seven-coordinate Co(II), Fe(II) and six-coordinate Ni(II) amide-appended macrocyclic complexes as ParaCEST agents in biological media. Inorg Chem 53:8311-21
Dorazio, Sarina J; Olatunde, Abiola O; Tsitovich, Pavel B et al. (2014) Comparison of divalent transition metal ion paraCEST MRI contrast agents. J Biol Inorg Chem 19:191-205
Dorazio, Sarina J; Olatunde, Abiola O; Spernyak, Joseph A et al. (2013) CoCEST: cobalt(II) amide-appended paraCEST MRI contrast agents. Chem Commun (Camb) 49:10025-7
Tsitovich, Pavel B; Spernyak, Joseph A; Morrow, Janet R (2013) A redox-activated MRI contrast agent that switches between paramagnetic and diamagnetic states. Angew Chem Int Ed Engl 52:13997-4000