Brain Distribution of Drugs: Brain Morphology, Delivery Routes, and Species Differences

Exit pathways of therapeutic antibodies from the brain and retention strategies

“…The mammalian CNS is isolated from the periphery by unique anatomical structures: 1) The BBB, which limits direct access of substances in the blood to the brain parenchyma 1 ; 2) a distinctive barrier formed between spinal cord parenchyma and the surrounding vasculature 2 ; 3) the cerebrospinal fluid (CSF)-brain barrier and 4) the blood-CSF barrier, which separate the brain parenchyma from the CSF space and the CSF from the blood, respectively. 3 , 4 Furthermore, in the vicinity of the cribriform plate and along the cranial nerves and venous sinuses of the dura mater run the meningeal lymphatic vessels, which drain CSF to the regional lymph nodes.…”

“…A different type of blood-CSF barrier exists within the choroid plexus: Blood vessel endothelial cells in this organ express carrier receptors, but, in contrast to the endothelium of the BBB, are fenestrated and do not form tight junctions, thus allowing macromolecule permeability. 1 The barrier function is in this case ensured by the choroid plexus epithelium, which is also responsible for the secretion of CSF into the ventricles. Those epithelial cells, in addition to various transporters, also express FcRn.…”

“…Within the ventricles, the brain parenchyma is loosely separated from CSF by a lining of ependymal cells, which do not form tight junctions and permit exchange of macromolecules between brain interstitial fluid and CSF. 1 , 3 , 6 …”

“…As only small and lipophilic molecules passively cross the BBB, it is inherently difficult to bring biologics into the CNS parenchyma. 1 , 28 , 29 Nonetheless, there are various approaches to overcome this limitation. We summarize four fundamental methods for biologics: (1) induction of BBB permeability, (2) charge-optimization to allow adsorption-mediated transcytosis (AMT), (3) receptor-mediated transcytosis (RMT), and (4) bypassing the BBB via direct CNS delivery.…”

Efficient in vivo neuronal genome editing in the mouse brain using nanocapsules containing CRISPR-Cas9 ribonucleoproteins

“…The vasculature of the CNS forms the blood brain barrier (BBB), which controls brain homeostasis by tightly regulating the movement of ions, molecules, and cells between the bloodstream and the brain. For systemic administration, compounds targeting the CNS need to have specific properties to cross the BBB 8 . High dosages of these compounds may be required that could produce unwanted side effects 9 .…”