An albumin-binding Gd-HPDO3A contrast agent for improved intravascular retention

Abstract

Gadolinium contrast agents that bind to human serum albumin (HSA) can achieve significantly higher relaxivity values and show improved vascular retention time. Most contrast agents of this design are linear agents, which have demonstrated lower kinetic stability and can cause gadolinium deposition. However, the macrocyclic agent Gd-HPDO3A has been found to display the lowest levels of gadolinium retention in the body and therefore demonstrates a useful contrast agent scaffold. We studied the properties of the first Gd-HPDO3A HSA-binding contrast agent, including analysis of isomer composition, water-exchange rates, relaxivity profiles, and in vivo distribution. The relaxivity values of the complex were found to be limited by the slow water exchange rate and reduced hydration state of the albumin-bound complex, compared to previous albumin-binding agents. However, the complex displayed significantly enhanced vascular retention time, which allows for a longer imaging window, and showed enhanced contrast efficiency in a murine tumor model and in mouse models for stable and vulnerable atherosclerotic plaques. This complex therefore presents the opportunity to utilise the benefits of the Gd-HPDO3A structure in blood-pool imaging.