Synthesis And Property Of Dendrimer-based Magnetic Resonance Imaging Contrast Agents

Magnetic resonance imaging (MRI) is a new and rapid developing clinical diagnostic modality that relies on the detection of NMR signals of water protons in human body. MRI contrast agents are paramagnetic materials that can increase the proton relaxation rates of water, thus enhance the contrast between the normal and abnormal tissue pathologically. The most challenging aspects in the development of MRI contrast agent are high relaxivity, low toxicity as well as tissue targeting.Dendrimers are an attractive platform for macromolecular contrast agents due to the presence of multiple terminal groups on the exterior of the molecule. Through entroducing appropriate metal ion chelates, a large numbers of metal ions for imaging and therapy may be conjugated to the dendrimer in combination with a targeting vector by classic organic synthetic techniques. Thus, a large amount of these metal ions potentially may be site specifically delivered directly into the body with the dendrimer as the vehicle with the targeting vector directing the modified dendrimer. The development of targeted macromolecular agents with acceptable blood retention times and selective organ uptake then has the potential for various biological applications. The main comparative studies of dendrimers with various externally appended imaging and as targeting agents were reviewed in this thesis.We have developed three series of combined gadolinium complexes of dendrimers as new MRI contrast agents. Polyamidoamine (PAMAM) dendrimers were diethylamine, ammonia and 1,4-benzendicarboxylic acid as cores. The ligands were prepared from the polyamidoamine form of Starburst? dendrimers in which free amines have been conjugated to the chelator diethylenetriamine pentaacetic acid monoanhydride. The corresponding Gd(III) complexes were synthesized by the reaction of these ligands with GdCl3?H2O. All ligands were confirmed by FT-IR and NMR, and the complexes were characterized by FT-IR. The longitudinal relaxation time (T1) was measured, and all relaxivity values (R1) of these dimeric Gd(III) complexes are higher than that of Magnivest (Gd-DTPA). One of these complex, which has the highest relaxivity in three series, was chosen to test the acute toxicity and T1-weighted imaging. It has been found that this dimeric Gd(â…¢) complex exhibits no acute toxicity, and offers highly enhanced MRI signal and increases intention time in the rat liver tissue compared to Gd-DTPA. Our results suggest that these new and powerful classes of contrast agent have the potential for diverse and extensive application in MRI.