A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery.
OBJECTIVE
Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles.


METHODS
Two dextran-coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution.


RESULTS
After BBB opening, MR images showed enhancement throughout the disrupted 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 but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil.


CONCLUSIONS
MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain.
Muldoon
L L
LL
Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, USA.
Pagel
M A
MA
Kroll
R A
RA
Roman-Goldstein
S
S
Jones
R S
RS
Neuwelt
E A
EA
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000098:blood supply / Q000378:metabolism*; D002196:Capillaries; D002199:Capillary Permeability; D002339:Carotid Arteries; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics; D003911:Dextrans; D004730:Endothelium, Vascular / Q000502:physiology; D005290:Ferric Compounds / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics; D052203:Ferrosoferric Oxide; D006651:Histocytochemistry; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D007501:Iron / Q000008:administration & dosage / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D008353:Mannitol / Q000008:administration & dosage / Q000494:pharmacology; D009994:Osmolar Concentration; D010087:Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics; D010316:Particle Size; D051381:Rats
D003287:Contrast Media; D003911:Dextrans; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; D010087:Oxides; C000499:ferric oxide; D008353:Mannitol; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide