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: 9759560
• 负责人: Casey Adams
• 金额: $ 3.98万
• 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/9759560
• 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.

顺铂是目前应用最广泛的实体瘤化疗药物之一。尽管它在临床上很有用， 顺铂具有明显的非靶向毒性。此外，它还容易通过以下途径产生化疗耐药性 有几种机制，最常见的是累积减少。患者通常会开顺铂 接受两个周期的治疗(总共六周)，然后重新评估肿瘤的反应。在此期间， 患者暴露在严重的毒性中，而不知道治疗是否有效。此外，如果肿瘤 对顺铂没有反应，已经浪费了一段关键的时间，因为更有效的治疗方法可以 却被开了处方。如果有一种工具可以预测肿瘤是否对铂有反应(II) 化疗，它可以减轻患者暴露于有害副作用，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，这使得这个问题成为医学上一个严重的未得到满足的需求。 临床批准的Gd(III)磁共振造影剂(CA)为开发Gd(III)提供了一个通用的平台- PT(II)治疗药物，可以预测肿瘤是否对铂(II)化疗敏感，并提供 同时进行抗癌治疗和通过磁共振成像进行检测。米德实验室是该领域的先驱 生物响应性Gd(III)磁流变液的研究进展 一个或多个内部球体参数。一个这样的参数是𝜏R，即旋转相关时间。大幅增长 在𝜏R中，当CA与大的生物分子结合时发生，导致弛豫度急剧增加，如图所示 在MR图像中的对比度更高。通过将顺式二氯铂(II)部分配位到Gd(III)CaS上，得到 Gd(III)-Pt(II)化合物将模拟顺铂。因此，这些试剂可以与DNA结合，从而使它们具有抗癌作用 属性，并增加松弛，以实现更明亮的MR对比度。弛豫度的变化只有当DNA 是结合的，因此这些试剂可以用来预测感兴趣的肿瘤是否易感。 用顺铂治疗。如果没有观察到对比度增加，试剂就不能进入细胞并结合 DNA，因此肿瘤很可能对治疗没有反应。所有合成的药物都将在体外进行顺铂试验。 将获得敏感和耐药的细胞系和磁共振图像。这些特工将在另一份 西北大学戴厚内教授的实验室里有50多个乳腺癌细胞株。特工们也将 在顺铂敏感和耐药侧翼异种移植的小鼠模型中进行体内测试。 这一拟议的项目符合美国国立卫生研究院的使命声明和资金计划。这项研究 寻求开发新的分子成像探针作为工具来预测肿瘤对顺铂治疗的反应 然后同时提供抗癌治疗和磁共振成像监测。目前，还没有有效的 预测肿瘤对顺铂治疗是否有效的方法，因此该项目的成功将有助于解决 严重的未得到满足的需求。由于顺铂应用广泛且毒性高，该项目有可能 极大地提高了大量患者的治疗质量。