Synthesis And Physicochemical Characterization Of New PEG/β-Cyclodextrin Modified Gd-DTPA As Macromolecular Contrast Agent For Mr Imaging

Nuclear magnetic resonance imaging (MRI) has become a useful technique in clinical diagnostics. With the help of blood-pool contrast agent, MRI can provide minimally invasive angiography, assess angiogenesis, quantify the number and spacing of blood vessel, and measure blood bolume and blood flow. Blood-pool contrast agents are paramagnetic gadolinium (Gd) chelates of high-molecular-weight polymers ideally. However, clinically approved contrast agents for MRI are low weight molecular chelates of Gd often complexed with MagnevistTM (Gd-DTPA) and DotaremTM (Gd-DOTA). These agents can rapidly extravasate out of blood vessels into extracellular matrix which cannot allow the complex mathematical models and prolonged imaging time. In this study, the conjugation of low molecular weight chelates (Gd-DTPA) to pCD/PEG (Gd-DTPA-PEG2000-βCD-OCH3, Gd-DTPA-βCD, Gd-DTPA-PEG2000-βCD-SA) change the biophysical and pharmacological properties of low weight agents, due to the relaxation theory. The conjugates were characterized with regard to GPC,1H NMR, ICP, IR relaxivity and MR imaging.The relaxivity of Gd-DTPA-PEG2000-βCD-OCH3(R1=9.55mmol/L·s-1) and Gd-DTPA-PEG2000-βCD-SA (R1=6.16mmol/L·s-1) was increase67%and7.7%which compare to MagnevistTM (R1=5.72mmol/L·s-1).Preliminary results show significant contrast enhancement in the liver, heart and kidney and blood vessel, especially in IVC, of mice for higher relaxitivy with the Gd-DTPA-PEG2000-βCD-OCH3compared to the clinically used low molecular weight agent (Gd-DTPA) after2min injection, still showing acceptable clearance. Then, the signals return to the original level240min later. The result resolves the problem that MRI macromolecular contrast agent can’t self-metabolize in the body. Furthermore, low toxicity of Gd-DTPA-PEG2000-βCD-OCH3(15～100μg/mL) has been resulted by MTT cytotoxicity test in the human liver cells (L-02) and human liver cancer cells (SMMC-7721). Though the viability of cell decrease in high gadolinium content (100～1000μg/mL), it was higher than77%. In acute toxicity studies, Gd-DTPA-PEG2000-βCD-OCH3also showed the low death rate after twice [Gd3+] injection to KM mice, lung cancer mice and skin cancer mice. Consider the results of the test, the products which synthesis in this study are hoped to be used in clinical.