Safe and potent MRI contrast agents by complexing gadolinium with enzyme/reduction dual-sensitive branched polymers

To address the issue of inefficient signal enhancement by polymeric magnetic resonance imaging (MRI) contrast agents, herein, we have prepared a high molecular-weight (MW) branched and gadolinium (Gd)-labeled N-(1,3-dihydroxypropyl)methacrylamide (DHPMA) copolymer (branched-pDHPMA-SS-Gd, 192 kDa, about 110 nm) by linking each branched chain by an enzyme-sensitive tetrapeptide (GFLG), and small molecule DOTA-Gd was conjugated to the carrier with a reduction-sensitive disulfide bond to obtain an enzyme/reduction dual-sensitive contrast agent. For control studies, DOTA-Gd was conjugated to an enzyme-sensitive branched carrier without a disulfide bond, resulting in a single sensitive branched copolymer (branched-pDHPMA-Gd, 198 kDa, about 110 nm). The longitudinal relaxivities of branched-pDHPMA-SS-Gd (r(1) = 12.48 mM(-1) s(-1)) and branched-pDHPMA-Gd (r(1) = 14.37 mM(-1) s(-1)) were 3-4 folds of clinical DTPA-Gd (r(1) = 3.53 mM(-1) s(-1)). The in vivo imaging signal enhancement by branched-pDHPMASS-Gd (about 130%) was similar to that of branched-pDHPMA-Gd (120%), which was 2.4 to 2.6-fold higher than that of clinical DTPA-Gd (about 50%). Although branched copolymers had the similar capability in enhancing MRI signals, enzyme/reduction dual-sensitive branched-pDHPMA-SS-Gd released low MW Gd-chelates at a more rapid rate, rendering it better biosafety and biodegradability. In conclusion, this study provides an important theoretical and experimental foundation for construction of Gd-based multi-sensitive polymeric MRI contrast agents with great biosafety and high efficiency. (C) 2019 Published by Elsevier Ltd.