Tumor uptake of Ga-67 by photodegraded nifedipine

描述（由申请人提供）：该提案是第一个竞争 延长3年RO 1补助金，以提高镓-67治疗肿瘤的吸收 显像肿瘤对Ga-67的摄取传统上被认为是由 转铁蛋白（Tf）和Tf受体依赖性机制。我们发现 Ga-67被细胞和肿瘤摄取也是由Tf非依赖性的 过程，这似乎更重要的肿瘤比正常组织。更 值得注意的是，我们已经表明，细胞中GA的Tf非依赖性摄取， 肿瘤是可以控制的。它可以在肿瘤中特异性诱导， 给药的化合物，我们已经命名为“硝西平”，这是 当硝苯地平，一种常用的二氢吡啶钙通道 阻断剂暴露于荧光或UV光。我们有证据表明 硝西品也可以增强多种其它金属阳离子。这可能 扩大硝普钠在伽玛射线照相术、PET成像和 放疗我们建议将上次资助期间获得的知识 循环到以下6个具体目标： 1.为了确定硝普钠的分子特征， 促进Ga-67的吸收。 2.为了确认和定义硝普钠（或其他）结合的性质， 活性衍生物）与金属阳离子。 3.为了明确硝普钠增强细胞凋亡的生物学机制， 细胞Ga-67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.为了测试硝普钠和类似的活性衍生物， 在多种组织学肿瘤中促进GA-67的摄取 在小鼠肿瘤模型中。 6.探索硝普钠或活性衍生物的潜力， Cu-64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.