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.

顺铂是最广泛使用的实体瘤化疗药物之一。尽管它具有临床实用性， 顺铂具有显着的脱靶毒性。此外，它还容易产生化学耐药性 有多种机制，最常见的是减少积累。患者通常服用顺铂 在重新评估肿瘤的反应之前，接受两个治疗周期（总共六周）。在此期间， 患者在不知道治疗是否有效的情况下暴露于显着的毒性。此外，如果肿瘤 对顺铂没有反应，当更有效的治疗可以时，已经浪费了关键的一段时间 已被处方。如果有一种工具可以预测肿瘤是否会对 Pt(II) 产生反应 化疗，它可以减轻患者遭受有害副作用的风险，并有助于确保最佳治疗 选项已规定。目前，还没有这样的工具，这使得这个问题成为医学上未得到满足的关键需求。 临床批准的 Gd(III) MR 造影剂 (CA) 为开发 Gd(III)- 提供了一个多功能平台 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 通过 MR 成像同时进行抗癌治疗和检测。米德实验室是该领域的先驱 开发生物响应性 Gd(III) MR CA，通过调节来增加弛豫度来“开启” 一个或多个内球参数。其中一个参数是 𝜏R，旋转相关时间。增幅较大 在 𝜏R 中，当 CA 与大生物分子结合时发生，导致弛豫度急剧增加，这一点可见 MR 图像中的对比度更亮。通过将顺式二氯铂 (II) 部分与 Gd(III) CA 配位，得到 Gd(III)-Pt(II) 化合物将模拟顺铂。因此，这些药物可以结合 DNA，从而具有抗癌作用 特性并增加弛豫度以获得更亮的 MR 对比度。仅当DNA 结合，因此这些试剂可用于预测感兴趣的肿瘤是否易受 用顺铂治疗。如果没有观察到对比度增加，则药剂无法进入细胞并结合 DNA，因此肿瘤可能不会对治疗产生反应。所有合成的药物都将在顺铂中进行体外测试 将获得敏感和耐药细胞系和 MR 图像。代理人将接受额外筛选 西北大学 Dai Horiuchi 教授实验室中的 50 多种乳腺癌细胞系。代理商也将 在具有顺铂敏感性和耐药性侧翼异种移植物的小鼠模型中进行了体内测试。 该拟议项目遵循 NIH 的使命宣言和资助计划。研究 寻求开发新型分子成像探针作为预测肿瘤对顺铂治疗的反应的工具 然后同时提供抗癌治疗和 MR 成像监测。目前尚无有效的 预测肿瘤是否会对顺铂治疗产生反应的方法，因此该项目的成功将有助于解决 未满足的关键需求。由于顺铂用途广泛且毒性较大，本项目具有潜在的 大大提高大量患者的治疗质量。