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

• Published in: Advanced biology Vol. 6; no. 2; pp. e2101293 - n/a
• Main Authors: Haney, Matthew J., Yuan, Hong, Shipley, Steven T., Wu, Zhanhong, Zhao, Yuling, Pate, Kelly, Frank, Jonathan E., Massoud, Nicole, Stewart, Paul W., Perlmutter, Joel S., Batrakova, Elena V.
• Format: Journal Article
• Language: English
• Published: Germany 01-02-2022
• Subjects: Animals; Biomimetics; brain bioavailability; Drug Carriers - metabolism; drug delivery system; extracellular vesicles; Extracellular Vesicles - metabolism; Leukocytes, Mononuclear; Macaca mulatta; monocytes; nonhuman primates; Positron Emission Tomography Computed Tomography; Tissue Distribution; monocytes; brain bioavailability; extracellular vesicles; drug delivery system; nonhuman primates
• ISSN: 2701-0198; 2701-0198
• DOI: 10.1002/adbi.202101293

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. 64Cu‐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 64Cu‐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.
Living cells and EVs are evaluated for their potential for CNS drug delivery in rhesus macaques using longitudinal PET/MRI imaging. The data indicate that the optimal carrier depends on the administration route. Smaller carriers, EVs are superior for systemic administration; larger vehicles, such as cells, are more advantageous for local administration due to their lower clearance from the brain tissues.