Novel Gadolinium Based Magnetic Resonance Imaging Agents: From Bench To Bedside

As a hot research direction in clinical medicine, translational medicine also attracts great attentions in the biological, materials and chemical areas, which shows close relationship to biomaterials especially nano-bio materials. At present, translational medicine is realized as one of the research focus full of challenges. In this thesis, according to the demand of pre-clinical applications, we designed and fabricated a series of magnetic nanocomposites with high quantity and MR imaging ability. Furthermore, we focused on the biocompatibility of these nanomaterials including cellular, hematological safety and the in vivo distribution and metabolism, which were necessary for their further preclinical study. The major research results can be summarized as following:1. Calcium carbonate as the most prominent biomineral has been extensively investigated due to its abundance in nature and good biocompatibility, and amorphous calcium carbonate (ACC) actually plays a key role in the early stage of biogenic calcium carbonate. It is distributed widely in animals, plants and sea urchin spine, and a large amount of calcites with complicated structure are formed via a controlled transformation from ACC. Herein, a series of gadolinium stabilized amorphous calcium carbonate nanoparticles (ACC-Gd NPs) were synthesized by rapid mixing of the solutions of calcium chloride, sodium carbonate and gadolinium chloride. In order to enhance the aqueous solubility of the prepared ACC-Gd, polyacrylic acid (PAA) was introduced into the process of ACC-Gd synthesis, which could circumvent the coalescence of colloid particles and help to stabilize the ACC-Gd NPs. The SEM and TEM images reveal that the as-prepared ACC-Gd-PAA nanoparticles had nearly spherical shapes with an average diameter less than 100 nm, and it could be dispersed in water homogeneously. ACC-Gd-PAA NPs showed high MR contrast enhancement, and the r1 value was 2.4 and 9.4 times higher than those of the gadolinium chloride and clinically used Gd-DTPA. Moreover, its outstanding MR imaging abilities especially the MR angiography (MRA) performance was demonstrated from SD rat to rabbit and finally beagle dog at low injectable dose. In addition, the dynamic distribution analysis of ACC-Gd-PAA NPs in mice and beagle dog indicted the quick clearance from blood vessels after the i.v. injection, leading to reduction of the NSF risk from gadolinium based MR contrast agent (GBCA) in synergy with its higher contrast imaging ability.2. Inorganic nonmetallic biomaterials, including the silicon frustule of unicellular diatom, the carbonate shell of mollusk and the calcium skeleton of the vertebrate, which are the main constituent part of organism, serve as the supportive and protective components of soft tissue. Among them, hydroxyapatite, which primarily makes up the enamel and bone, are widely used in tissue engineering. Recently, the inorganic nonmetallic biomaterials, especially the applications of hydroxyapatites attract great attentions. In this part, we reported a novel synthesis method of magnetic functionalized hydroxyapatite nanocomposites. By simply tuning the ratios of reactants, a series of hydorxyapatite-Fe3O4 worm-shaped nanocomposites (HAP-ION nanoworms) were prepared. In addition, layer-by-layer surface modifications with chitosan (CH) and sodium alginate (SA) were employed to improve the solubility and biocompatibility, and low cytotoxicity and no hemolysis were observed. With the increasing of iron oxide nanocrystals, the magnetic properties of the magnetic assembled nanoworms were enhanced, which resulted in better performance of magnetic resonance (MR) imaging. Owing to the intravenous injection of HAP-ION nanoworms, the contrast to noise ratio (CNR) of hepatic MR imaging in vivo was enhanced obviously, which should be benefit for the hepatic injury grading and further therapeutic treatment. 3. In this part, we fabricated a novel gadolinium (Gd)-based attapulgite (ATP) nano-composites (Gd-ATP) via aqueous suspension method, which showed good dispersion stability in water, uniform size distribution and cellular and hematological compatibility. Then, the MRI contrast enhancement effect in vitro was investigated using 3.0T clinical MR scanner. Furthermore, Gd-based nano-composites exhibited good contrast enhancement ability for the MR angiography (MRA) on rabbit.