Magnetic resonance probes for in vivo tracking of transplanted cells

Cellular transplantation is a promising technique that will be used in the future to treat a variety of diseases. Establishing a method to assess the fate and viability of transplanted cells would be extremely valuable to developing biomedical applications for cellular therapies. One useful application for cellular therapy is pancreatic islet transplantation as a treatment for type 1 diabetes. This therapy has been studied extensively in animals and successfully used in the clinic to reverse diabetes in humans. There are, however, many questions to be answered before islet transplantation becomes a routinely used clinical treatment.;This dissertation describes the progression in the design and testing of a series of probes designed for tracking cells using magnetic resonance imaging (MRI). MRI has several characteristics that make it an ideal modality for cellular tracking. In order to use MRI to its full capability, contrast agents for cellular labeling must be developed to maximize the sensitivity and optimize probe utility. In vitro cell culture and a mouse islet transplant model of type 1 diabetes were used to assess the efficacy of a series of MRI contrast agents designed for cellular labeling. Chapter 2 compares the advantages and disadvantages of two classes of multimodal MRI probes; iron oxide nanoparticles and multinuclear gadolinium chelates. GdIII based agents hold several advantages over iron oxide agents. However, the main disadvantage of GdIII agents is that they are less sensitive than iron oxide agents. This can be overcome by employing refined synthetic techniques that incorporate multinuclear designs. Chapter 3 describes the testing of cyclic multinuclear GdIII contrast agents that have improved characteristics due to the enhanced rigidity of the complex. Although the designs of the agents presented in chapter 3 were not ideal for islet labeling, they have provided a framework for the next generation of agents that incorporate a covalently attached functional side group. Chapter 4 and appendix A discuss the design of cyclic multinuclear GdIII contrast agents that contain a membrane labeling moiety and a beta cell targeting ligand, respectively. The sophisticated designs described represent important progress toward the optimization of an imaging agent for in vivo cellular tracking of transplanted islets.