Exchange Transfer based Molecular MRI

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In this project, the overall goal is to design novel molecular MRI methods that are minimally invasive or totally noninvasive and, as such, have a high potential of being translated rapidly into the clinic to be used for tumor assessment and monitoring of treatment. Towards this goal, we exploit so-called chemical exchange saturation transfer (CEST) contrast, which is generated through magnetic labeling of exchangeable protons (such as NH and OH) on either exogenous or endogenous agents, followed by a physical transfer (chemical exchange) of this label to water protons, which allows detection using MRI. To reach our ultimate goal of fast human translation, we will focus our efforts on diamagnetic, biodegradable, non-metallic compounds. Specifically, we will exploit the body's own building blocks, proteins and carbohydrates as CEST biomarkers and develop MRI technology to detect these markers. Tumors are generally characterized by an increased content of small mobile proteins and peptides, rapid glucose metabolism, and increased permeability between blood vessels and extravascular extracellular space. The overall goal therefore is to develop MRI pulse sequence technology and theory for detecting mobile protein content, glucose delivery and metabolism, and tumor perfusion. Our first aim is to assess protein content by employing nuclear interactions within these macromolecules (cross-relaxation) combined with the exchange ofthe protein's amide protons to water protons. In the second aim, glucose metabolism and tumor perfusion will be assessed by monitoring the uptake of non-labeled D-glucose using CEST. These technologies are expected to be applicable for most tumor types, but to demonstrate their applicability, we will apply them first to two human breast cancer lines: less aggressive (MCF-7) and highly aggressive and metastatic (MDA-MB-231). This will be done both ex vivo, in perfused cells and, in vivo, on xenografts in mice. As a third aim, we will perform pilot studies in patients to show feasibility of rapid translation. These aims are expected to result in the availability of molecular MRI technologies in vivo that are suitable for immediate application in humans. Once established, we expect that these methods can be used for tumor detection, imaging tumor perfusion and metabolism, assessing tumor malignancy, and monitoring tumor treatment. This is expected to reduce false-positive detection rates by functioning as an add-on for current high-volume screening approaches and to improve treatment monitoring by MRI.