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.

顺铂是应用最广泛的实体肿瘤化疗药物之一。尽管它有临床用途，