A research and career development plan is proposed to transition from a background in chemistry to an independent research program in biomedical imaging and cancer biology. A two-tiered research plan will first focus on developing new MRI contrast agents, and then focus on applying these MRI contrast agents to mouse models of breast cancer. This research plan is founded on the development and application of new types of MRI contrast agents that can monitor multiple cancer biomarkers during a single MRI scan session. Our objectives of the proposed research are A) to develop a new T1 relaxation agent that can accurately measure the acidic extracellular pH of metastatic breast tumor tissues, while also accounting for the concentration of the agent by including a PARACEST MRI contrast agent;B) to develop a new PARACEST agent that targets v3 cell integrin;C) to combine these agents with a new PARACEST agent that can measure vascular permeabilities in order to assess tumor angiogenesis and D) to assess therapeutic responses in breast cancer mouse models by measuring extracellular pH, detecting v3 expression and evaluating vascular permeability during a single MRI scan session. Our deliverable consists of nano-sized dendrimers that can carry the MRI contrast agents for improved detection sensitivity, and for improved specificity for tumor tissues through the Enhanced Permeability and Retention effect. Successful completion of these specific aims will lead to evaluations of therapeutic efficacies that change tumor pH or v3 expression levels using our new MRI methods. This unique combination of nanoparticles and molecular imaging constitutes a platform technology for many other biomedical applications. A two-tiered career development plan will also be established. Training in biomedical imaging will be achieved through guidance by experts in biomedical engineering and radiology. A mentor committee will also provide guidance while navigating the activities required to establish a new research program. During the second year, senior mentors in cancer biology will provide guidance in cancer research applications and professional development activities. A progressive plan is also proposed to develop skills as a mentor, leader, networker, presenter, writer, collaborator, and entrepreneur throughout this process, in order to develop an independent, staffed and fully resourced research program in biomedical imaging and cancer research.
The results of this project will provide a direct method to measure in vivo pH non-invasively. Thus, the extracellular pH (pHe) within tumor tissues will be used as a diagnostic biomarker to determine the prognosis of pathology, to evaluate the efficacy of pHe-altering therapies and to predict the efficacy of pHe-dependent chemotherapies. Besides, multifunctional nano-sized MRI probes will be used to assess multiple, tumor specific biomarkers in a single MRI scan session and this novel technology will significantly enhance in the early diagnosis and treatment of breast cancer. In addition, a structured career development plan will make project PI as an independent investigator.
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