An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles

Abstract

The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable.

Overcoming the Blood–Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases

“…However, the permeability of the BBB has been reported to increase under various pathological stimuli, and this may offer a potential opportunity for drug delivery. [174] Nevertheless, this increase in permeability as part of the pathology of brain disorders is a widely variable phenomenon, and therefore may not be completely reliable for the consistent delivery of therapeutics into the brain. [40]…”

Nanotherapeutics engineered to cross the blood-brain barrier for advanced drug delivery to the central nervous system

“…At the BBB, tight junctions of the endothelium block the passage of molecules larger than ~ 4 nm, whereas small and water solutes can penetrate through paracellular transportation [19]. Studies have attempted to disrupt intercellular junctions to enhance the paracellular delivery of molecules using internal or external stimuli [20,21]. This review does not include these BBB-disrupting or 'invasive' approaches.…”

Elucidating the Inability of Functionalized Nanoparticles to Cross the Blood–Brain Barrier and Target Specific Cells in Vivo

“…All procedures were approved by the Animal Ethics Committee of The University of Western Australia (RA3/100/1485) and were conducted in accordance with the National Health and Medical Research Council of Australia Guidelines on the Use of Animals in Research. For cell culture, rat pups were euthanized with intraperitoneal injection of pentobarbital sodium (Provet®, Western Australia).Cortices from five animals were pooled together for each independent experiment.For in vivo imaging, adult rats (n = 5/group) were IV -administered a 5 mg/kg dose hydroxyethyl)-1piperazineethanesulfonic acid) (HEPES) buffer (50 mM, pH 7.4) via tail vein injection, and left in their home enclosures for 4 h to allow NP circulation 36. Rats were euthanized with pentobarbital sodium at 160 mg/kg dosage, transcardially perfused with 100 mL of 0.9 % saline, and dissected to remove the brain and major reticuloendothelial organs including the spleen, one kidney, and one liver and lung lobe.…”