Modular High Relaxivity Contrast Agents for Cellular and Molecular Imaging.

摘要

The use of contrast agents is a common method of enhancing MR imaging and 30% of all MRI’s utilize a paramagnetic contrast agent. Current clinical contrast agents are limited in their sensitivity and limit the full potential of the technique. Therefore, new and improved agents must be developed to improve selectivity and sensitivity. To address these problems, this thesis describes the development of molecular and cellular probes for magnetic resonance imaging and their application to the imaging of pancreatic islets. Gadolinium contrast agents were used as molecular and cellular probes to improve the sensitivity of the technique. Paramagnetic gadolinium complexes were determined to be a viable means to accomplish our molecular and cellular imaging goals.;This thesis describes three approaches to the development and application of two new classes of MR contrast agents towards biological questions (Chapters 2, 3 & 4). These classes of MR contrast agents are based on small modular multiplexed clusters of contrast agents and larger nanoparticle based agents. The first approach (Chapter 2) improves performance versus clinical agents by 1500%. Here, the development and synthesis of a new multifunctional MR contrast agent is described. These agents are constructed using click chemistry as a means to attach together several small molecule contrast agents into a rigid system that is much more than the sum of its parts. Such optimization in the performance of our agents is necessary to develop the best imaging probes, and we studied how rigidity affects performance by varying the linker length between the scaffold and contrast agents.;The second approach (Chapter 3) is the synthesis of a nanoparticle based contrast agent in which small molecule contrast agents are coupled to the surface of nanodiamonds. These highly functionalized nanoparticles are being explored for use in imaging as well as in drug delivery and sensors. This thesis examines the effect of the addition of gadolinium contrast agents onto the surface of the nanodiamonds. The results have shown a more than 10 fold improvement in efficiency and sensitivity over commercial agents.;The third approach applies the optimized system of Chapter 1 to the imaging of pancreatic islets (Chapter 4). These cells produce insulin within the body. If these cells are compromised and insulin fails to be produced the result is the onset of type 1 diabetes. The utilization of both cellular and molecular imaging techniques was examined to track the fate of islets in a mouse model system. Chapter 4 describes the development of a lipophilic agent that allows for the rapid labeling of cells and, in particular, pancreatic islets for transplant. Following transplant we will be able to monitor the location and fate of the cells via MRI. This chapter also explores the development of a molecularly targeted system that is known to specifically bind to islets. In this system, DTBZ is attached for the VMAT2 receptor on the islets.;Appendix 1discusses the synthesis and challenges surround the development of an activateable core shell nanoparticle. The goal of this project was to develop a system that would deliver a dose of chemotherapeutics and indicate the delivery with an activation of a MR contrast agent. This agent was designed to be responsive to a decrease in pH which is commonly seen in a tumor mass. The main challenge here was the synthesis of a dendrimer core. Two approaches were taken to make the core but neither met with success.;Appendix 2 discusses a project to conjugate together a therapeutic drug, cisplatin, in this case, a MR contrast agent and a fluorescent dye. While several multifunctional scaffolds to attach each of these compounds were constructed we were unable to conjugate the cisplatin derivative to it. It was concluded that the reactivity of the cisplatin derivative was so poor at to not continue down that route. A new proposed synthesis on resin is included.