Development of Gd(III)-Pt(II) MR Probes for Tandem Detection & Chemotherapy

顺铂是实体瘤最广泛使用的化疗药物之一。尽管它的临床效用， 顺铂具有显著的脱靶毒性。此外，它对化疗耐药性敏感， 几种机制，最常见的是减少积累。患者通常使用顺铂 在重新评估肿瘤的反应之前，进行两个周期的治疗（总共六周）。在此期间， 患者暴露于显著的毒性而不知道治疗是否有效。此外，如果肿瘤 对顺铂没有反应，浪费了一段关键的时间，而更有效的治疗方法可以 都是处方药如果有一种工具可以预测肿瘤是否会对铂（II）产生反应， 化疗，它可以减轻患者暴露于有害的副作用，并有助于确保最佳治疗 选项是规定的。目前，还没有这样的工具，这使得这一问题成为一个关键的未满足的需要在医学上。 临床批准的Gd（III）MR造影剂（CA）为开发Gd（III）-MR造影剂提供了一个通用平台。 Pt（II）治疗诊断剂，可以预测肿瘤是否对Pt（II）化疗敏感，并提供 同时抗癌治疗和通过MR成像检测。米德实验室是 开发生物响应性Gd（III）MR CA，通过调节弛豫率增加来“开启” 一个或多个内部球体参数。一个这样的参数是旋转相关时间（rotational correlation time）。𝜏大量增加 𝜏在CAs与大的生物分子结合时发生的CAs中，导致弛豫率急剧增加， 作为MR图像中更亮的对比度。通过将顺式-二氯铂（II）部分配位至Gd（III）CA， Gd（III）-Pt（II）化合物将模拟顺铂。因此，这些药物可以结合DNA，使其具有抗癌作用。 性能和增加弛豫更明亮的MR对比度。弛豫率的变化只发生在DNA 因此，这些试剂可用于预测感兴趣的肿瘤是否易受 顺铂治疗。如果没有观察到对比度增加，则试剂不能进入细胞并结合 因此，肿瘤可能对治疗没有反应。将在顺铂中对合成的所有药物进行体外测试 将获得敏感和抗性细胞系和MR图像。代理商将在额外的筛选 50+乳腺癌细胞系在西北大学的Dai Horiuchi教授实验室。代理商也将 在具有顺铂敏感性和抗性胁腹异种移植物的鼠模型中进行体内测试。 本项目符合NIH的使命声明和资助计划。研究 寻求开发新的分子成像探针作为预测肿瘤对顺铂治疗的反应的工具， 然后通过MR成像提供同时的抗癌治疗和监测。目前，没有有效的 一种预测肿瘤是否对顺铂治疗有反应的方法，因此该项目的成功将有助于解决 关键的未满足的需求。由于顺铂应用广泛且毒性高，因此本项目具有潜力， 大大提高了大量患者的治疗质量。

Cisplatin is one of the most widely used chemotherapeutics for solid tumors. Despite its clinical utility, cisplatin suffers from significant off target toxicity. Additionally, it is susceptible to chemoresistance through several mechanisms, most commonly by decreased accumulation. Patients prescribed cisplatin typically undergo two cycles of therapy (six weeks total) before the tumor is reevaluated for a response. During this time, patients are exposed to significant toxicity without knowing if the treatment is effective. Furthermore, if the tumor does not respond to cisplatin, a crucial period of time has been wasted when a more effective treatment could have been prescribed instead. If there were a tool that could predict whether or not a tumor will respond to Pt(II) chemotherapy, it could mitigate patient exposure to harmful side effects and help ensure the best treatment option is prescribed. Currently, there is no such tool, which makes this issue a critical unmet need in medicine. Clinically approved Gd(III) MR contrast agents (CAs) provide a versatile platform for developing Gd(III)- Pt(II) theranostic agents that can predict if tumors are susceptible to Pt(II) chemotherapy and provide simultaneous anti-cancer therapy and detection through MR imaging. The Meade lab is a pioneer in the development of bioresponsive Gd(III) MR CAs that “turn on” by an increase in relaxivity through modulation of one or more inner sphere parameters. One such parameter is 𝜏R, the rotational correlation time. A large increase in 𝜏R, which occurs when CAs bind to large biomolecules, results in a drastic increase in relaxivity, which is seen as brighter contrast in an MR image. By coordinating a cis-dichloroplatinum(II) moiety to Gd(III) CAs, the resulting Gd(III)-Pt(II) compounds will mimic cisplatin. As such, the agents can bind DNA, giving them anti-cancer properties and increasing the relaxivity for brighter MR contrast. The change in relaxivity occurs only when DNA is bound, therefore these agents can be used to predict whether or not tumors of interest are susceptible to treatment with cisplatin. If no contrast increase is observed, the agents were not able to enter the cells and bind DNA, therefore the tumor likely will not respond to therapy. All agents synthesized will be tested in vitro in cisplatin sensitive and resistant cell lines and MR images will be obtained. The agents will be screened in an additional 50+ breast cancer cell lines in the laboratory of Professor Dai Horiuchi at Northwestern. The agents will also be tested in vivo in murine models with cisplatin sensitive and resistant flank xenografts. This proposed project adheres to the mission statement and funding plans of the NIH. The research seeks to develop novel molecular imaging probes as tools to predict tumor response to cisplatin therapy and then provide simultaneous anti-cancer therapy and monitoring by MR imaging. Currently, there is no effective way to predict if a tumor will respond to cisplatin therapy, therefore success in this project would help solve a critical unmet need. Because cisplatin is widely used and has high toxicity, this project has the potential to drastically improve the quality of treatment for a large population of patients.