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 ?R, the rotational correlation time. A large increase in ?R, 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.
This project seeks to develop Gd(III)-Pt(II) theranostic contrast agents for predicting tumor response to Pt(II) chemotherapy and simultaneous MR detection and anti-cancer treatment. If successful, these agents will predict whether a tumor is susceptible to treatment with Pt(II) compounds and then provide simultaneous anti- cancer therapy and monitoring by MR with increased contrast. Predicting response to chemotherapy is a critical unmet need in medicine, thus this project involves high impact translational research.
