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

用于串联检测的 Gd(III)-Pt(II) MR 探针的开发

• 批准号: 9921198
• 负责人: Casey Adams
• 金额: $ 4.03万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921198
• 关键词: Antineoplastic Agents; Apoptosis; Area; Binding; Biological; Biological Assay; Biological Models; Bladder; Breast; Breast Cancer cell line; Cancer Detection; Cell Line; Cells; Cervical; Chad; Circular Dichroism; Cisplatin; Clinical; Complex; Contrast Media; Cytoplasm; DNA; DNA Binding; DNA Binding Agent; DNA Repair; Detection; Development; Developmental Therapeutics Program; Ensure; Evaluation; Exposure to; Failure; Funding; Head and neck structure; Hemolysis; Homidium Bromide; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Injections; Laboratories; Life; Lung; Magnetic Resonance Imaging; Measures; Medicine; Metals; Mission; Modeling; Molecular; Monitor; Mus; Nonionizing Radiation; Ovarian; Patients; Penetration; Property; Proteins; Reporting; Research; Research Project Grants; Resistance; Resolution; Rotation; Solid Neoplasm; Stimulus; Structure; Temperature; Time; Toxic effect; Translational Research; United States National Institutes of Health; Xenograft Model; Xenograft procedure; anti-cancer; anticancer treatment; calf thymus DNA; cancer cell; cancer therapy; chemotherapy; cytotoxicity; design; effective therapy; experimental study; hearing impairment; imaging probe; improved; in vitro testing; in vivo; in vivo evaluation; in vivo monitoring; interest; magnetic field; melting; metal complex; molecular imaging; mouse model; novel; patient population; predicting response; professor; renal damage; response; side effect; soft tissue; spatiotemporal; stem; success; theranostics; tool; translational impact; tumor; uptake

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.

顺铂是实体瘤最广泛使用的化学治疗剂之一。尽管有临床实用性， 顺铂患有明显的OFF靶毒性。此外，它容易通过化学抗性 几种机制，最常见的是高级积累。患者开处方顺铂通常 在对肿瘤进行重新评估之前，要经过两个治疗周期（总共六周）以进行反应。在此期间， 患者在不知道治疗是否有效的情况下暴露于明显的毒性。此外，如果肿瘤 没有对顺铂的反应，当更有效的治疗可能 改为开处方。如果有一个工具可以预测肿瘤是否会对PT做出反应（II） 化学疗法，它可以减轻患者暴露于有害的副作用，并有助于确保最好的治疗 规定选项。当前，没有这样的工具，这使该问题成为医学上的至关重要的需求。 临床认可的GD（III）MR对比剂（CAS）为开发GD（III）提供了多功能平台 - PT（II）可以预测肿瘤是否易受PT（II）化疗的疗法剂 简单的抗癌治疗和通过MR成像检测。米德实验室是 Biorpsissive GD（III）MR CAS的开发，该MR CAS通过调制而增加了松弛性的“打开” 一个或多个内部球体参数。一个这样的参数是𝜏R，是旋转相关时间。大幅增长 在CA与大型生物分子结合时发生的𝜏R中，会导致松弛性急剧增加，从而看到 MR图像中的对比度更明​​亮。通过坐标为dichloroplatinum（ii）部分到GD（iii）CAS，由此产生 GD（III）-PT（II）化合物将模仿顺铂。因此，代理可以结合DNA，给他们抗癌者 性质并提高松弛性，以使MR对比度更明​​亮。放松性的变化仅在DNA时发生 受约束，因此这些药物可用于预测感兴趣的肿瘤是否容易受到影响 用顺铂治疗。如果未观察到对比度增加，则代理将无法进入细胞并结合 DNA，因此肿瘤可能不会对治疗反应。所有合成的试剂将在顺铂进行体外测试 将获得敏感和抗性细胞系和MR图像。代理商将额外筛选 西北部的戴·霍里奇（Dai Horiuchi）教授实验室中的50多个乳腺癌细胞系。代理商也将是 在带有顺铂敏感和抗性侧面饰面的鼠模型中进行了体内测试。 该拟议项目遵守NIH的任务声明和资金计划。研究 试图开发新的分子成像问题，以预测肿瘤对顺铂治疗的反应和 然后通过MR成像提供简单的抗癌治疗和监测。目前，没有效力 预测肿瘤是否会对顺铂治疗反应的方法，因此该项目的成功将有助于解决 关键的未满足需求。由于顺铂被广泛使用并且具有较高的毒性，因此该项目有可能 大大提高大量患者的治疗质量。