ADVANCED MR TECHNOLOGIES FOR PROBING THE TUMOR MICROENVIRONMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is a broad effort to improve our ability to monitor the microenvironment of a tumor. There are three sub-projects. First, It is well-known that hypoxic or even anoxic regions in solid-growing tumors may limit the efficacy of non-surgical therapy, including radiotherapy, photodynamic therapy, chemotherapy. Accurate assessment of tumor oxygenation at various stages of tumor growth and in response to interventions/therapy may provide a better understanding of tumor development and may serve as a prognostic indicator for treatment outcome, potentially allowing individualized cancer therapy. We have recently identified a 1H MRI probe of pO2: hexamethyldisiloxane (HMDSO). The PI has developed a new, HMDSO-based quantitative MR oximetry technique PISTOL (Proton Imaging of Silanes to Map Tissue Oxygenation Levels) for mapping of tissue interstitial pO2. This technique has been applied to study the tumor microenvironmenental response to therapy in this project. The goal of the first subproject is to optimize synthesis and characterization of HMDSO based nanoemulsions as pO2 nanoprobes (funding source 1) for 1H MRI based oximentry and uses them to study tumor response to combination chemotherapy. The goal of the second subproject (funding source 2) is to study the response of combining hyperbaric oxygen with pO2-sensitive photodynamic therapy of cancer with pO2 nanoprobes. In another area of technology development, three dimensional Chemical Shift Imaging (3D-CSI) is an MR-based non-invasive approach used in the clinic to quantify and monitor these metabolites. A major hurdle in routine clinical use of 3D-CSI is the long acquisition time and hence the time spent by the patient in the scanner. Therefore a strong need to address this problem exists to enable clinicians to make routine use of this powerful technology. The proposed project aims to overcome this limitation by the use of compressive sensing, which has been a revolutionary invention in the past few years. This technique has been successfully implemented for MRI and promises to be a new path for reducing acquisition times for MRI scans. We plan to conduct a retrospective analysis of brain and breast CSI data sets in order to compare metabolite maps obtained with conventional k-space reconstruction method to compressive sensing based reconstruction using undersampled data. We hypothesize that by exploiting the sparsity of k-space as well as the spectral data, we may be able to reduce CSI scan times for patients by a factor of 2 without significant reduction in the quality of data. A third area of investigation involves contrast agents for breast cancer. Small molecular contrast agents have a high sensitivity for breast cancer detection but a limited specificity for the characterization of the detected lesions. A similar approach, which uses large molecular (macromolecular) contrast agents, can provide this tissue differentiation but the sensitivity is low. One cannot use these two types of agents together as it would be impossible to distinguish between effects of the two. A novel class of contrast agents, called PARACEST agents, have been recently proposed for MRI applications and need to be urgently evaluated in vivo as the theoretically predicted sensitivity of these agents is higher than conventional Gd-based agents. These agents also have the advantage of having image contrast turned on at will using radio-frequency pulses. We planned to study the kinetics of such a macromolecular PARACEST agent albumin-EuDOTA-4Am-(Gly)2(OBz-Ser)2 in rat tumors and subsequently administer a conventional small molecular contrast agent Gd-DTPA. These two agents affect the image contrast using different mechanisms and hence administering the PARACEST agent before Gd-DTPA will not affect the subsequent Gd-DTPA contrast. Specific aims of this project are: 1) Optimization of PARACEST imaging sequence and contrast parameters. 2) Study dynamic PARACEST contrast enhancement (DPCE) kinetics in muscle tissue and tumors and develop kinetic model. 3) Use DPCE kinetics to study response to antiangiogenic therapy in two tumor lines.