Therapeutics Delivery Behind, Through and Beyond the Blood Brain Barrier

Abstract

The brain has five protective barriers (BPB) that hinder the delivery of therapeutic drugs. They describe the five main interfaces between the central nervous system (CNS) and the periphery. These include: the blood brain barrier (BBB) that extends down the spinal cord; the brain cerebrospinal fluid (CSF) barrier (B[CSF]B]; the brain-inner CSF barrier (B[iCSF] b); the brain-outer CSF barrier B[oCSF]B; and the brain retinal barrier (B[R]B). We shall mostly be concerned with the BBB and use the denomination BBB as if it applied (though erroneously) to all BPBs.All interfaces are formed by tight junctions. In the case of the BBB, the tight junctions are between the endothelial cells of the primary vasculature with primary manifestation being the impermeability of the capillary wall due to the presence of the junctions and a low endocytic activity. For B [CSF] B, the tight junctions are between the epithelial cells of the choroid plexus. In the case of the B[iCSF]B, the junctions are between the neuroependymal cells lining the ventricular surfaces. As for B[oCSF] B, the junctions are between endothelial cells of the arachnoid vessels (the pia arachnoid). The BPBs hinder the delivery of most pharmaceuticals (diagnostic, therapeutic agents) to the brain. a. Some brain diseases and their effects on the Blood Brain BarrierThere are approximately 400 neural disorders some which being cognitive. Table 1 below shows only some of these, specifically those due to a failure of the BBB as a result of disruption, breakdown, opening, failure, damage (inflammatory) and increased permeability, but also some diseases for which the effect on the BBB is still unknown.. Neurological disorders are

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“…Primary tumors: Of unclear cause, primary tumors can start from normal brain cells in the cerebral white matter then grow quickly, infiltrate small areas of the tumor, spread to other areas, and can become very large before producing symptoms (this is consistent with our current understanding of cancer as braided in our genome [15][16][17][18][19][20][21].…”

“…The niche protects these cells against therapy by maintaining a relatively hypoxic environment. A biomarker for cells in GBs that exhibits cancer stem cell properties (the transcription factor HES3) has been shown to regulate their number when placed in culture [19][20][21]. Figures 1 & 2 provide a schematic illustration of Glioblastoma and its surgical resection.…”

Antiangiogenic Targeting of Early Developing Glioblastoma Behind a Weakened Blood Brain Barrier

“…d) The inner CSF-brain barrier formed by strap junctions between the neuro-ependymal cells lining the ventricular surfaces. It is present only in early development and absent in the adult [18,19]. The above barriers and the blood retinal barrier (not studied here) are parts of a whole realm of barriers.…”

“…As a result, chemotherapy has historically provided little durable benefit as the tumors recur within several months even in the case of the more accessible tumors that are located outside the brain. For brain tumors, the access is even more challenging because of the presence of the brain protective barriers (BPBs), chiefly the BBB, compounding the difficulties [18,19].…”