PEGylated amphiphilic polymeric manganese(ii) complexes as magnetic resonance angiographic agents

Abstract

Currently, the most commonly used clinical magnetic resonance imaging (MRI) contrast agents, Gd(III) chelates, have been found to be associated with nephrogenic systemic fibrosis (NSF) in renally compromised patients. Toxicity concerns related to Gd(III)-based agents prompted intensive research toward the development of safe, efficient, and long-cycle non-Gd contrast agents. Herein, three amphiphilic polymeric manganese (Mn) ligands (mPEG_1k-P(L-a-HMDI)-mPEG_1k, mPEG_2k-P(L-a-HMDI)-mPEG_2k and mPEG_4k-P(L-a-HMDI)-mPEG_4k) were synthesized, and then end-capped respectively with different molecular weights of polyethylene glycol monomethyl ether (mPEG 1 kD, 2 kD and 4 kD) to obtain amphiphilic polymer Mn ligands. After being chelated with Mn(II), these amphiphilic polymer Mn complexes show significantly higher T₁ relaxivity than the small molecule Mn complex (MnL) at 0.5 T, 1.5 T and 3.0 T magnetic fields, respectively. Then, mPEG_2k-P(MnL-a-HMDI)-mPEG_2k with relatively high T₁ relaxivities (23.2, 14.4 and 9.7 mM⁻¹s⁻¹ at 0.5 T, 1.5 T and 3.0 T, respectively), low CMC (4.7 mg L⁻¹), reasonable size (48 nm) and excellent stability among these three polymer Mn complexes was selected for in vivo MR imaging of vascular vessels. The results suggest that mPEG_2k-P(MnL-a-HMDI)-mPEG_2k has an excellent and relatively long time-window vascular enhancement effect even at a low dose of 0.05 mmol Mn kg⁻¹ BW, and could play a role in the diagnosis of vascular diseases (0.1 mmol Mn kg⁻¹ BW). Therefore, mPEG_2k-P(MnL-a-HMDI)-mPEG_2k may be considered as a potential blood pool contrast agent.