Studies On Water-soluble Tumor And Brain-targeting Magnatic Resonace Imaging Contrast Agents Containing Porphyrin Or Dopamine Groups

In recent years, magnetic resonance imaging (MRI) is a rapidlydeveloping medical diagnostic modality, which has been widely applied inclinical medicine, biology and material sciences, etc. MRI contrast agents area unique class of pharmaceuticals that enhance the image contrast betweennormal and diseased tissue and indicate the status of organ function or bloodflow after administration by increasing the relaxation rates of water protons intissue in which the agent accumulates.Gd-DTPA was the first contrast agent approved for use in clinical MRI forcontrast enhancement. However, the short imaging time and nonspecificdistribution in vivo limit its utility in focal lesion detection and diagnosis.Moreover, its ionic characteristic leads to some side effects associated withthe hyperosmolality. An ideal method to overcome these insufficiencies is todesign and synthesize a series of nonionic, low-toxicity and site-specificcontrast agents. The main contents of this thesis were summarized as fellows:The research progress of MRI techniques was reviewed briefly. Theprinciple, classification and influencing factors, and development trend ofMRI contrast agents were described in detail.Water soluble5-(4-aminophenyl)-10,15,20-tris(4-sulfonatopheny-l)-porphyrin (Na3APTSPP) was chosen as the tumor-targeting groups. Thewater-soluble and low molecular weight tumor-targeting ligand wassynthesized by the reaction between diethylenetriaminepentaaceticdianhydride (DTPAA) and Na3APTSPP. Its gadolinium (Ⅲ) complexe wasfurther prepared by the chelation of this ligand with gadolinium chloride(GdCl3). The ligand and gadolinium (Ⅲ) complex were characterized by1HNMR, FT-IR, UV and EI MS. The longitudinal relaxivity test indicated thatthe complex possessed higher R1relativities than that of Gd-DTPA. MRimaging demonstrated that gadolinium (Ⅲ) complex obviously enhanced thecontrast of MR images of VX-2carcinoma in the lower limb of New Zealandwhite rabbits during the detection time and had a prolonged durationcompared with the clinically used Gd-DTPA.Poly-α,β-[N-(2-hydroxylethy1)-L-aspartamide](PHEA) and its derivatives are water-soluble polymers which have been used as plasmaexpanding agents and drug carriers due to low-cytotoxicity andnon-immunogenicity, good biocompatibility and biodegradability, ease tochemical modification. The water soluble tumor-targeting MRI contrastagents were synthesized by the incorporation of5-(4-amino-phenyl)-10,15,20-tris(4-sulfonatophenyl)-porphyrin (Na3APTSPP) as thetumor-targeting groups and Gd-DTPA into the side chains of PHEA carriers.These compounds obtained were further characterized by FT-IR,1H NMR,and UV and in vitro properties were also evaluated. The results of in vitrocytotoxicity assay and relaxivity test showed that these macromolecular MRIcontrast agents possessed lower cytotoxicities to HeLa cells and obviouslyhigher relaxation effectiveness than that of Gd-DTPA.The brain-targeting compound was synthesized by the reaction betweendiethylenetriaminepentaacetic dianhydride (DTPAA) and dopamine as thebrain-targeting groups. Subsequently, this ligand obtained was clelated withgadolinium chloride (GdCl3) to make the corresponding gadolinium (Ⅲ)complexes as the brain-targeting MRI contrast agent. The gadoliniumcomplex and ligand were characterized by1H NMR, FT-IR, UV and EI MS.The longitudinal relaxivity studies indicate that the complex possessed higherrelaxation effectiveness than that of Gd-DTPA.