A Safe MRI- and PET-guided Method for Increasing Osmotic Blood-Brain Barrier Permeability

Background Given the current lack of widely adopted strategies for facilitating drug penetration into the brain, developing new techniques to increase blood-brain barrier (BBB) permeability is essential to address the increasing burden of central nervous system disorders. Osmotic blood-brain barrier opening (OBBBO), achieved through intra-arterial delivery of 25% mannitol to the cerebral vasculature, is a pioneering strategy demonstrating both safety and partial efficacy. Purpose To investigate the potential of 25% mannitol with 4% NaCl, a combination that doubles the osmotic power, to safely increase OBBBO efficacy. Materials and Methods To visualize penetration into the brain, OBBBO with intra-arterial, intravenous, or intraperitoneal infusion of molecules was performed in mice (<i>n</i> = 44). Brain penetration of small molecules (gadolinium-based contrast agent) and the safety of the infusion procedure were assessed via MRI and histologic examination. Brain penetration of large molecules (zirconium 89-radiolabeled antibodies) was assessed via PET imaging. A head-to-head comparison was performed of brain penetration of both these molecules using the standard approach (25% mannitol) versus the combination of 25% mannitol with 4% NaCl. The Wilcoxon signed rank test, Mann-Whitney <i>U</i> test, and mixed-model analysis were used for the statistical analyses. Results The findings showed robust OBBBO across the entire targeted hemisphere of mouse brains following administration of 4% NaCl in 25% mannitol (<i>n</i> = 9), surpassing that achieved with 25% mannitol alone (<i>n</i> = 8) (ratio of OBBBO area to intact BBB area, 1.99 ± 0.17 vs 1.41 ± 0.15; <i>P</i> < .001). Follow-up MRI and postmortem histologic examination confirmed the safety of this procedure. PET imaging revealed that brain uptake of radiolabeled antibodies was significantly improved using this new method. Conclusion Combining 4% NaCl with 25% mannitol showed promise for improving the safe delivery of therapeutic agents to the brain through the endovascular route. © RSNA, 2025 <i>Supplemental material is available for this article.</i> See also the editorial by Clement and Gaultier in this issue.