Kilogram scale facile synthesis and systematic characterization of a Gd-macrochelate as T1-weighted magnetic resonance imaging contrast agent.

ABSTRACT

To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r2/r1 ratio of the reported Gd macrochelates that is an important factor for T1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r1 value of 16.35 mM-1 s-1 and r2/r1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 â„ƒ or 1.8 cP at 37 â„ƒ, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications.