Empowered in-vivo functional brain imaging with Ferucarbotran-loaded red blood cells

Abstract

Our previous MPI data validated that engineered SPIO-loaded RBCs have improved in-vivo stability over the corresponding free SPIO-based contrast agents. We now demonstrate the efficiency of these biomimetic constructs in the field of functional brain imaging using Functional Magnetic Resonance Imaging (fMRI). Data was obtained in an anesthetised rodent model using a 7 Tesla preclinical MRI system (Bruker, Biospec 70/30). Responses to i) neuronal activation of the somatosensory barrel cortex (via repeated electrical stimulation of the whisker pad) and ii) respiratory challenge (10% increased FiCO₂) were recorded pre and post injection of 1.5 ml of human Ferucarbotran-loaded-RBCs (corresponding to 16 µmoles Fe) as an intravenous SPIO-based tracer. Post injection we found high contrast-to-noise, Cerebral Blood Volume (CBV) weighted signal changes in line with previous preclinical fMRI studies using free SPIO nanoparticles. CBV-fMRI offers functional sensitivity at cortical laminar resolutions as a significant advantage over routine Blood Oxygenation Level Dependent (BOLD) fMRI. Furthermore, RBCs are biocompatible and biodegradable iron oxide-carriers. Hence, our novel approach permits the easier targeting of CBV markers with higher contrast (over BOLD fMRI) and in the future could drive development of longitudinal assessment of brain function using safe and long half-life SPIO-based tracers.