Iron paraCEST MRI Contrast Agents for Monitoring Tumor Acidosis

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DESCRIPTION (provided by applicant): 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.