A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery

BACKGROUND AND PURPOSE Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the b rain. The apparent global delivery of viral-sized iron oxide particles to t he rat brain after BBB opening as seen on MR images was compared with the c ellular and subcellular location and distribution of the particles. METHODS: Two dextran-coated superparamagnetic monocrystalline iron oxide na noparticle contrast agents, MION and Feridex, were administered intraarteri ally in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB wi th hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the bra in was evaluated first with MR imaging then by histochemical analysis and e lectron microscopy to assess perivascular and intracellular distribution. RESULTS: After BBB opening, MR images showed enhancement throughout the dis rupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells bu t did not cross beyond the basement membrane. In contrast, after MION deliv ery, iron histochemistry was detected within cell bodies in the disrupted h emisphere, and the electron-dense MION core was detected intracellularly an d extracellularly in the neuropil. CONCLUSION: MR images showing homogeneous delivery to the brain at the macr oscopic level did not indicate delivery at the microscopic level. These dat a support the presence of a physiological barrier at the basal lamina, anal ogous to the podocyte in the kidney, distal to the anatomic (tight junction ) BBB, which may limit the distribution of some proteins and viral particle s after transvascular delivery to the brain.