PhD

dissertationMagnetic resonance imaging (MRI) assists clinical diagnostics by providing high resolution images. Incorporation of contrast agents will enable MRI to detect diseases on the molecular level. The first part of the thesis describes the development and evaluation of two such contrast agents. A dendrimer-based biodegradable magnetic resonance (MR) contrast agent, PAMAM-G6-cystamine-(Gd-D03A), was developed for tumor imaging. This agent introduced higher contrast enhancement in the tumor area than the non-degradable control. Moreover, it showed faster renal excretion and lower uptake by liver tissue, suggesting favorable pharmacokinetics. The other degradable contrast agent, Nanoglobule-G4-cystamine-(Gd-D03A), was developed for dynamic contrast enhanced (DCE) MR urography. The carrier of this agent, generation 4 nanoglobule, provides a globular backbone whose size is large enough to prevent leakage in normal vasculature and small enough to allow for rapid renal elimination. The degradability, provided by disulfide bond, would further accelerate renal excretion and create a high concentration of contrast agent in the urinary tract. Images acquired by DCE-MR urography showed that this agent, although used at l/3rd the dose of Gd(DTPA-BMA), exhibited faster renal elimination kinetics, and generated significantly more contrast enhancement in the bladder than the low molecular weight Gd(DTPABMA). Meanwhile, it was rapidly removed from circulation and only allowed low liver deposition. Advances in molecular biology have conjured nucleic acids, such as plasmid DNA and siRNA, into powerful therapeutic agents. However, nucleic acid delivery exists as a paramount barrier. As a second part of the thesis, a series of multifunctional carriers (MFCs) were developed. The preliminary studies showed that one of the carriers, SKACO, could conduct luciferase expression on U87 cells up to 425 times higher than Lipofectamine-2000. This carrier also introduced green fluorescent protein expression in 71.29% of U87 cells, much higher than 6.16% by Lipofectamine-2000. Another carrier, SKAHCO, effectively delivered Luc siRNA to silence luciferase activity up to 84.6% in U87- Luc cells. It also mediated green fluorescent protein expression-knocking out in approximately 61.29% of CHO-EGFP cells, in contrast to 40.40% of Lipofectamine-2000. In summary, these carriers provide a new type of system with high delivery efficiency and are therefore worth further investigation