Linear and Core-Crosslinked Glycopolymer-Gadolinium Conjugates: Preparation and Their Behaviors as Nanoscale Magnetic Resonance Imaging Contrast Agents.

Abstract

In this study, a linear glycopolymer-gadolinium conjugate (pGAEMA-DOTA-Gd) was prepared via the reversible addition fragmentation chain transfer (RAFT) polymerization. In addition, a crosslinked polymer-gadolinium conjugate (Crosslinked pGAEMA-DOTA-Gd) was prepared via a two-step RAFT polymerization approach, and its core was composed of the biodegradable oligopeptide GFLG. The features of the two glycopolymer-gadolinium conjugates as highly efficient and safe nanoscale contrast agents were discussed. These two glycopolymer-DOTA-Gd conjugates have aqueous dynamic particle sizes of 4.8 nm and 21.3 nm with neutral charges. Longitudinal relaxivity (r1) of these two glycopolymer-gadolinium conjugates were three to four times higher than that of clinical agent DTPA-Gd. Animal studies showed that pGAEMA-DOTA-Gd and Crosslinked pGAEMA-DOTA-Gd demonstrated higher signal intensity and the relative change in T1 value (ΔT1) in mouse liver and kidney, and prolonged blood circulation time compared to DTPA-Gd. Notably, the performance of the core-crosslinked glycopolymer conjugate was better than that of the linear polymer. Inductively coupled plasma mass spectrometry (ICP-MS) results showed that polymeric contrast agents, especially the crosslinked one, showed higher aggregation in mouse liver and kidney, and were mainly excreted through renal routes eventually. In vitro and in vivo toxicity studies in healthy mice including cytotoxicity, blood compatibility and systemic toxicity indicated the absence of significant toxicity. Therefore, the prepared glycopolymer-DOTA-Gd conjugates may have significant potential as highly efficient and safe nanoscale MRI contrast agents.