Iron paraCEST MRI Contrast Agents for Monitoring Tumor Acidosis

描述（由申请人提供）：将肿瘤的酸性细胞外空间碱化的治疗方法正在开发中，作为减少转移和恶性肿瘤的廉价抗癌替代方法。其中一种碱化疗法，口服碳酸氢盐，已被证明特别有效，最近已被FDA批准作为临床癌症试验的研究性新药。这种疗法的一个缺点是高剂量的碳酸氢盐会损害肾功能，因此优化碳酸氢盐治疗非常重要。我们建议开发一类新的小分子MRI造影剂，用于肿瘤组织pH的登记，以监测和优化碱化治疗。这些工作将使用pH敏感的paraCEST MRI造影剂，具有两种不同的可交换质子，可用于组织中不依赖于比例浓度的pH监测。（paraCEST =顺磁化学交换饱和转移）这种方法正在开发用于含有对比剂的镧系元素（Ln(III)），但由于缺乏不同类型的可交换质子和大的顺磁诱导质子位移，因此存在问题。莫罗实验室的工作表明，铁（Fe(II)）配合物可以开发成paraCEST MRI造影剂。与目前正在开发的Ln（III）配合物相比，Fe（II）配合物在CEST中具有更锐利和更高位移的质子共振。此外，铁配合物可能更便宜，毒性更小。我们将开发这些新的铁基药物作为小分子显像剂和树状大分子来控制滞留和肿瘤摄取。这些药物将在小鼠乳腺肿瘤中进行试验。

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.