Biodistribution of Biomimetic Drug Carriers, Mononuclear Cells, and Extracellular Vesicles, in Nonhuman Primates

Discovery of novel drug delivery systems to the brain remains a key task for successful treatment of neurodegenerative disorders. Herein, the biodistribution of immunocyte-based carriers, peripheral blood mononuclear cells (PBMCs), and monocyte-derived EVs are investigated in adult rhesus macaques using longitudinal PET/MRI imaging. Cu-64-labeled drug carriers are introduced via different routes of administration: intraperitoneal (IP), intravenous (IV), or intrathecal (IT) injection. Whole body PET/MRI (or PET/CT) images are acquired at 1, 24, and 48 h post injection of Cu-64-labeled drug carriers, and standardized uptake values (SUVmean and SUVmax) in the main organs are estimated. The brain retention for both types of carriers increases based on route of administration: IP < IV < IT. Importantly, a single IT injection of PBMCs produces higher brain retention compared to IT injection of EVs. In contrast, EVs show superior brain accumulation compared to the cells when administered via IP and IV routes, respectively. Finally, a comprehensive chemistry panel of blood samples demonstrates no cytotoxic effects of either carrier. Overall, living cells and EVs have a great potential to be used for drug delivery to the brain. When identifying the ideal drug carrier, the route of administration could make big differences in CNS drug delivery.

Automated summary

This study investigated the biodistribution and brain retention of PBMCs and EVs in adult rhesus macaques using PET/MRI imaging. The route of administration had a significant impact on brain retention of the carriers, with PBMCs showing higher brain retention when administered intrathecally. EVs demonstrated superior brain accumulation when administered intraperitoneally and intravenously, respectively. No cytotoxic effects were observed for either carrier in blood samples. Overall, living cells and EVs have great potential for drug delivery to the brain, and the route of administration plays a crucial role in CNS drug delivery.