PEGylated Amphiphilic Gd-DOTA Backboned-Bound Branched Polymers as Magnetic Resonance Imaging Contrast Agents

Abstract

MRI contrast agents with high kinetic stability and relaxivity are the key objectives in the field. We previously reported that Gd-DOTA backboned-bound branched polymers possess high kinetic stability and significantly increased T 1 relaxivity than traditional branched polymer contrast agents. In this work, non-PEGylated and PEGylated amphiphilic Gd-DOTA backboned-bound branched polymers [P­(GdDOTA-C6), P­(GdDOTA-C10), mPEG-P­(GdDOTA-C6), and mPEG-P­(GdDOTA-C10)] were obtained by sequential introduction of rigid carbon chains (1,6-hexamethylenediamine or 1,10-diaminodecane) and mPEG into the structure of Gd-DOTA backboned-bound branched polymers. It is found that the introduction of both rigid carbon chains, especially the longer one, and mPEG can increase the kinetic stability and T 1 relaxivity of Gd-DOTA backboned-bound branched polymers. Among them, mPEG-P­(GdDOTA-C10) possesses the highest kinetic stability (significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol) and T 1 relaxivity (42.9 mM–1 s–1, 1.5 T), 11 times that of Gd-DOTA and 1.4 times that of previously reported Gd-DOTA backboned-bound branched polymers. In addition, mPEG-P­(GdDOTA-C10) showed excellent MRA effect in cardiovascular and hepatic vessels at a dose (0.025 or 0.05 mmol Gd/kg BW) far below the clinical range (0.1–0.3 mmol Gd/kg BW). Overall, effective branched-polymer-based contrast agents can be obtained by a strategy in which rigid carbon chains and PEG were introduced into the structure of Gd-DOTA backbone-bound branched polymers, resulting in excellent kinetic stability and enhanced T 1 relaxivity.

Lipophilic Group-Modified Manganese(II)-Based Contrast Agents for Vascular and Hepatobiliary Magnetic Resonance Imaging

“…Contrast agents (CAs) are indispensable in magnetic resonance imaging (MRI) in order to improve the sensitivity for detecting lesions, and in fact, more than one-third of MRIs are performed with the assistance of CAs . Due to their excellent T1 enhancement effect, gadolinium-based contrast agents (GBCAs) with linear or macrocyclic ligands have been the focus in both preclinical and clinical applications. , However, the extensive usage has revealed potential safety concerns with GBCAs. − The leakage of gadolinium ions from the ligands has caused nephrogenic systemic fibrosis in patients with chronic kidney disease, and the subsequent discovery of gadolinium deposition in the brain and bones led to additional restrictions with strict regulation. , Despite the suspension of several linear GBCAs by the European Medicines Agency, Gd-EOB-DTPA and Gd-BOPTA with linear ligands continue to be used in clinics for hepatobiliary imaging . This makes it increasingly attractive to design novel macrocyclic GBCAs or to find gadolinium-free alternatives with hepatobiliary-specific imaging capabilities. ,− …”