Cross-Linked and Biodegradable Polymeric System as a Safe Magnetic Resonance Imaging Contrast Agent

Owing to the low efficacy of clinically used small-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) agents, we designed and explored biodegradable macromolecular conjugates as MRI contrast agents. The linear polymeric structure and core-cross-linked formulation possessed different characteristics and features, so we prepared and comparatively studied the two kinds of Gd-based <i>N</i>-(2-hydroxypropyl) methacrylamide (HPMA) polymeric systems (the core-cross-linked pHPMA–DOTA-Gd and the linear one) using the clinical agent diethylene-triamine pentaacetic acid-Gd­(III) (DTPA-Gd) as a control. This study was aimed to find the optimal polymeric formulation as a biocompatible and efficient MRI contrast agent. The high molecular weight (MW, 181 kDa) and core-cross-linked copolymer was obtained via the cross-linked block linear copolymer and could be degraded to low-MW segments (29 kDa) in the presence of glutathione (GSH) and cleaned from the body. Both core-cross-linked and linear pHPMA–DOTA-Gd copolymers displayed 2–3-fold increased relaxivity (<i>r</i>₁ value) than that of DTPA-Gd. Animal studies demonstrated that two kinds of macromolecular systems led to much longer blood circulation time, higher tumor accumulation, and much higher signal intensity compared with the linear and clinical ones. Finally, in vivo and in vitro toxicity studies indicated that the two macromolecular agents had great biocompatibility. Therefore, we performed preliminary but important studies on the Gd-based HPMA polymeric systems as biocompatible and efficient MRI contrast agents and found that the biodegradable core-cross-linked pHPMA–DOTA-Gd copolymer might have greater benefits for the foreground