Sensitivity enhanced MRI imaging of receptor binding in breast cancer

癌症仍然是工业化世界的主要死亡原因之一。近年来， 由于乳酸盐与肿瘤转移有关， 癌症患者预后差。最近的研究发现，细胞表面的乳酸受体 HCA 1与肿瘤发生和转移相关，因此是一个有吸引力的成像靶点， 治疗靶点然而，由于乳酸盐表现出低亲和力和快速周转率， 分子成像技术不太适合于对这些类型的目标成像。我们已经开发出一种新颖 用于检测天然（无化学修饰）底物与 分子靶和独特的分子泵方案，提高了两到三个数量级的灵敏度， 因此使该技术适用于体内研究。重要的是，这种方法可以 在标准MRI硬件上实现，从而快速转化为临床。我们建议发展， 优化和验证这种方法用于成像乳酸与乳腺癌中HCA 1受体的结合。 在AIM 1中，我们将验证体外检测乳酸-HCA 1结合的特异性， 表达不同水平HCA 1受体的乳腺癌细胞，和（ii）MRI脉冲序列 优化.在AIM 2中，我们将在体内验证乳酸与乳腺癌细胞的特异性结合。我们将 使用L-乳酸盐或D-葡萄糖（代谢为乳酸盐）输注进一步探测乳酸盐结合，两者均为FDA 批准用于人体静脉注射。 这些目标预期将导致用于成像低亲和力配体与靶分子结合的MRI方法。 一个细胞目标由于标记方法的性质，这些MRI方法将是高度可调的，以适应不同的应用。 广泛的其他底物-靶标对。

Cancer remains one of the leading causes of death in the industrialized world. In recent years, there has been a resurgence of interest in tumor lactate metabolism since lactate has been associated with metastases and poor prognosis in cancer patients. Recent discoveries have identified that the cell surface lactate receptor HCA1 is associated with tumorigenesis and metastasis and thus an attractive imaging target and possible therapeutic target. However, because lactate exhibits low affinity and a fast turnover rate, current in vivo molecular imaging techniques are not well suited to image these types of targets. We have developed a novel MRI based approach for detecting the low affinity binding of natural (no chemical modification) substrates to molecular targets and a unique molecular pump scheme that enhances the sensitivity two to three orders of magnitude thus making this technology applicable for in vivo studies. Importantly, this method can be implemented on standard MRI hardware and thus rapidly translated to the clinic. We propose developing, optimizing, and validating this approach for imaging the binding of lactate to HCA1 receptors in breast cancer. In AIM 1, we will validate the specificity of detecting lactate-HCA1 binding in vitro using (i) perfused breast cancer cells that express different levels of the HCA1 receptor, and (ii) MRI pulse sequence optimization. In AIM 2, we will validate the specific binding of lactate to breast cancer cells in vivo. We will further probe lactate binding using the infusion of L-lactate or D-glucose (metabolized to lactate), both FDA approved for iv use in humans. These aims are expected to result in a MRI method for imaging the binding of low-affinity ligands to a cell target. Due to the nature of the labelling approaches, these MRI methods will be highly tunable to a broad range of other substrates-target pairs.