Polymer-mediated assembly of MRI contrast agents and their use in imaging of vascular defects.

摘要

Defective, leaky vasculature is characteristic of a wide variety of diseases, including arthritis, cancer, and cardiovascular disease. The ability to locally highlight vascular defects via medical imaging may therefore provide a way to improve diagnosis and treatment of some of the most significant diseases worldwide. As magnetic resonance imaging (MRI) provides the highest spatial resolution and best soft tissue contrast among common imaging techniques, it remains an appealing approach to vascular imaging. MRI, however, has relatively low sensitivity to its contrast agents compared to other clinical modalities, which limits its use in targeted applications. To address this issue, this thesis investigates the use of polymer materials to control the size, morphology, spatial organization, and surface properties of MR imaging probes to improve their relaxivity and accumulation at sites of interest.;The first part of this thesis focuses on the design and development of gadolinium-based contrast agents. Chapter 2 describes the synthesis of a polymeric fastener to anchor gadolinium to the surface of a liposome through electrostatic and hydrophobic interactions. As a result, the probe provided greater contrast per dose than gadolinium chelates used clinically, and was able to beacon areas of vascular damage in in vivo models of ischemia. The strategy was then adapted to rapidly label stem cells for applications in cell tracking, as described in Chapter 3.;Secondly, methods to improve the in vivo performance of superparamagnetic iron oxide nanoparticle (SPION) contrast agents are investigated. Chapter 4 explores the use of hyperbranched polyglycerol (HPG) in assembling SPIONs in the form of spherical clusters. By controlling the cluster size and molecular architecture of the polymer coating, optimal relaxivity of the SPIONs was achieved for sensitive imaging. In Chapter 5, the SPION clusters are further improved with the incorporation of targeting ligands and by inducing a wormlike morphology. This allowed for greater accumulation in areas of defective vasculature. Overall, this work contributes to a better understanding of contrast agent design and may serve to expedite efforts to improve the diagnosis and treatment of vascular diseases.