Development of safe and effective magnetic resonance contrast agents for blood pool imaging and cancer diagnosis

The current commercialized Gd(III)-based magnetic resonance (MR) contrast agents are small molecules characterized with short blood half-life and nonspecific tissue distribution. The accuracy of MR diagnosis involving clinical contrast agents is often hindered because of a short diagnostic window and low selectivity of target tissues. Macromolecular Gd(III)-based contrast agents are more effective than small molecular agents for blood pool imaging with high relaxivity and limited vascular extravasation. However, the clinical translation of macromolecular contrast agents is impeded by the potential safety concerns associated with their slow excretion and prolonged tissue retention. Polydisulfide Gd(III) complexes have been developed as biodegradable macromolecular MR contrast agents to facilitate the excretion of Gd(III) chelates and alleviate the safety concerns. The agents can be readily degraded and excreted via renal filtration with minimal tissue retention. However, the reported polydisulfide Gd(III) complexes are based on linear Gd(III) chelates of a DTPA derivative, which has poor kinetic stability. In this research, two alternative polydisulfides have been developed to minimize the stability issue of the linear Gd(III) ligand. Firstly, polydisulfide Mn(II) complexes were developed as gadolinium-free biodegradable macromolecular MRI contrast agents. Two polydisulfide Mn(II) complexes based on Mn-DTPA and Mn- EDTA were synthesized and characterized. Both agents showed comparable relaxivity to the reported polydisulfide Gd(III) complexes. The degradations of both polydisulfide iv Mn(II) complexes were demonstrated through in vitro incubation with endogenous free thiols. In vitro transmetallation study revealed higher kinetic inertness of the Mn-DTPAbased agent. In vivo MR evaluation showed preferential contrast enhancement of Mn(II) agents in the liver and myocardium. Secondly, polydisulfides based on the more stable macrocyclic Gd(III) chelates were developed and evaluated. Two polydisulfide Gd- DOTA conjugates with charge differences were synthesized and characterized. Both agents showed improved relaxivity, and efficient degradability. Both in vitro and in vivo transmetallation study revealed higher kinetic inertness of the macrocyclic polydisulfide agents than the previously reported linear agents. The effect of charge on pharmacokinetics and biodistribution was compared and discussed.