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.
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.
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| 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 |
| 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 |
| 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 |
| 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 |
