Tumor uptake of Ga-67 by photodegraded nifedipine

描述(由申请者提供)：这是第一个竞争的提案 续签为期3年的RO1赠款，以改善肿瘤对镓-67的摄取 成像。肿瘤对Ga-67的摄取传统上被认为是由 转铁蛋白及其受体依赖机制。我们发现， 细胞和肿瘤对Ga-67的摄取也是由Tf非依赖的 过程，这在肿瘤中似乎比正常组织更重要。更多 值得注意的是，我们已经证明了细胞和细胞中不依赖于TF的GA摄取 肿瘤是可以被调控的。它可以通过以下方式在肿瘤中特异性地诱导 给药的化合物，我们已命名为“亚硝西平，”这是 硝苯地平产生时，一种常用的二氢吡啶类钙通道 阻滞剂，暴露在荧光或紫外线下。我们已经产生了证据表明 亚硝西平也可以增强其他多种金属阳离子。今年5月 扩大亚硝西平在伽马闪烁成像、正电子发射计算机断层成像和 放射治疗。我们建议将上一次融资中获得的知识应用于 实现以下6个具体目标： 1.确定亚硝西平的分子特征 促进镓-67的摄取。 2.确认和定义亚硝西平(或其他 活性衍生物)到金属阳离子。 3.明确亚硝西平增强小鼠心脏功能的生物学机制。 细胞对Ga-67的摄取。 4.确定体内动力学和最佳给药方法，以最大限度地提高 肿瘤的可视化。 5.为了测试硝西平及其类似活性衍生物的广谱效果， 在多种组织学肿瘤中促进GA-67的摄取 在小鼠肿瘤模型中分型。 6.探索亚硝西平或活性衍生物的潜力，以增强 对铜-的吸收。

DESCRIPTION (Provided by Applicant): This proposal is the first competing renewal of a 3-year RO1 grant to improve the uptake of gallium-67 for tumor imaging. Uptake of Ga-67 by tumors has traditionally thought to be mediated by transferrin (Tf) and Tf receptor-dependent mechanisms. We have found that uptake of Ga-67 by cells and tumors is also mediated by a Tf-independent process, which appears more important in tumors than normal tissues. More significantly, we have shown that the Tf-independent uptake of GA in cells and tumors can be regulated. It can be specifically induced in tumors by administration of compound, which we have named "nitrosipine," which is produced when nifedipine, a commonly used dihyropyridine calcium channel blocker, is exposed to fluorescent or UV light. We have generated evidence that nitrosipine may also enhance a variety of other metal cations as well. This may expand the utility of nitrosipine for gamma scintigraphy, PET imaging and radiotherapy. We propose to apply the knowledge gained during the last funding cycle to the following 6 specific aims: 1. To define the molecular features of nitrosipine that are necessary for promoting uptake of Ga-67. 2. To confirm and define the nature of the binding of nitrosipine (or other active derivatives) to metal cations. 3. To define the biological mechanism by which nitrosipine enhances the cellular Ga-67 uptake. 4. To define the in vivo kinetics and optimal method for dosing to maximize the visualization of tumors. 5. To test how broadly effective nitrosipine, and similar active derivatives, are in promoting uptake of GA-67 in tumors of a wide variety of histologic types in a murine tumor models. 6. To explore the potential for nitrosipine or active derivatives, to enhance the uptake of Cu-64.