Liver-targeting MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan.

Commercial gadolinium (Gd)-based contrast agents (GBCAs) play important role in clinical diagnostic of hepatocellular carcinoma, but their diagnostic efficacy remained improved. As small molecules, the imaging contrast and window of GBCAs is limited by low liver targeting and retention. Herein, we developed a liver-targeting gadolinium (Ⅲ) chelated macromolecular MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan, namely, CS-Ga-(Gd-DTPA)n, to improve hepatocyte uptake and liver retention. Compared to Gd-DTPA and non-specific macromolecular agent CS-(Gd-DTPA)n, CS-Ga-(Gd-DTPA)n showed higher hepatocyte uptake, excellent cell and blood biocompatibility in vitro. Furthermore, CS-Ga-(Gd-DTPA)n also exhibited higher relaxivity in vitro, prolonged retention and better T1-weighted signal enhancement in liver. At 10 days post-injection of CS-Ga-(Gd-DTPA)n at a dose of 0.03 mM Gd/Kg, Gd had a little accumulation in liver with no liver function damage. The good performance of CS-Ga-(Gd-DTPA)n gives great confidence in developing liver-specifc MRI contrast agents for clinical translation.

A novel manganese chelated macromolecular MRI contrast agent based on O-carboxymethyl chitosan derivatives.

Currently used Gd-based and Mn-based small molecular MRI contrast agents fail to meet the requirements for the long-term monitoring, and the potential safety risk under high administration dose or repeat dosing needs to be considered. In the present study, a biocompatible macromolecular magnetic resonance imaging (MRI) contrast agents based on O-carboxymethyl chitosan (CMCS), CMCS-(Mn-DTPA)n was designed and synthesized. The relaxivity of CMCS-(Mn-DTPA)n is approximately 3.5 and 5.5 times higher than that of Gd-DTPA and Mn-DPDP in aqueous solution, respectively. The MRI signal intensity in the kidney and liver of Sprague Dawley (SD) rats is significantly increased at a dose of 0.03 mM Mn/kg b.w. CMCS-(Mn-DTPA)n accompanied by a long effective imaging window. According to in vitro studies, CMCS-(Mn-DTPA)n exhibits good cellular and blood biocompatibility at the dose necessary for MRI imaging. Based on the results from in vivo studies, manganese (Mn) is completely excreted from SD rats within ten days after administration and does not exert a pathological effect on the liver. CMCS-(Mn-DTPA)n represents a potentially novel MRI contrast agent due to its excellent relaxivity, long effective imaging window and good biocompatibility.