Multi-layer surface modification of pancreatic islets for magnetic resonance imaging using ferumoxytol

Ferumoxytol is the only clinically available ultrasmall superparamagnetic iron oxide. However, the labeling efficacy of islet magnetic resonance imaging (MRI) using ferumoxytol is not suitable for use in clinical pancreatic islet transplantation (PIT). We evaluated the feasibility of pancreatic islet MRI using ferumoxytol through multi-layer surface modification. A four-layer nanoshield with poly (ethylene) glycol (PEG, 2 layers), ferumoxytol, and heparin was formed on the pancreatic islets. We compared pancreatic islet function, viability, and labeling efficacy of control, ferumoxytol alone-labeled, heparin-PEGylated, and ferumoxytol-heparin-PEGylated islets. With optimization of the ferumoxytol concentration during the ferumoxytol-heparin-PEGylation process, the labeling contrast in ex vivo MRI of ferumoxytol-heparin-PEGylated pancreatic islets was stronger than that of pancreatic islets labeled with ferumoxytol alone, without decreasing ex vivo islet viability or function. In a syngeneic mouse renal subcapsular PIT model, heparin-PEGylation and ferumoxytol-heparin-PEGylation delayed the revascularization of pancreatic islet grafts but did not impair glucose tolerance or revascularization of pancreatic islet grafts four weeks post-transplantation. Pancreatic islet visibility after labeling was also confirmed in a syngeneic mouse intraportal PIT model and in preliminary analysis of a non-human primate intraportal PIT model. In conclusion, multi-layer islet surface modification is a promising option for pancreatic islet MRI in intraportal PIT.