Barriers And Obstacles To Cns Drug Delivery Physiological Barriers

There are several physiological or pathological factors preventing systemic drug delivery to CNS, including the BBB and the blood-cerebrospinal fluid barrier (BCB). Of these, the BBB is the most important barrier in the drug transport process.

The BBB can be defined as a physiological mechanism that alters the permeability of brain capillaries so that the majority of substances are prevented from entering brain tissue, although some molecules are allowed to enter freely. In the late 19th century, the German bacteriologist Paul Ehrlich observed that the certain dyes administered intravenously to small animals stained all the organs except the brain. His interpretation for the experiment was that the brain had a lower affinity for the dye than the other tissues. However, Edwin E. Goldmann, a student of Ehrlich, injected the dye trypan blue directly into the cerebrospinal fluid of rabbits and dogs. He found that the dye readily stained the entire brain but did not enter the bloodstream to stain the other internal organs. This experiment demonstrated that CNS is separated from the blood by a barrier. It is now well established that the BBB is a unique membranous barrier that tightly segregates the brain from the circulating blood (3,4). Through advances in experimental technology, brain capillaries, which comprise the BBB, can be visually observed using electron microscopy.

Physiologically, the BBB is found in all vertebrate brains, and in humans it is formed within the first trimester of life. The cellular locus of the BBB is the endothelial cell of the brain capillary. The structure of brain capillaries is unique, and this creates a permeability barrier between the blood and the extracellular fluid in brain tissue. Brain capillaries and the spinal cord do not have the small pores that allow solutes to circulate to other organs. These capillaries are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions (5). There are three types of ependymal cells lining the monolayer of endothelial cells in the BBB: astrocyte foot processes, pericytes, and neurons. Astrocytes form the structural framework for the neurons, and control their biochemical environment.

Astrocyte foot processes or limbs spread out and interconnect to encapsulate the capillaries. Pericytes are mesenchymal-like cells that are associated with the walls of small blood vessels. Neurons (also known as neurones, nerve cells and nerve fibers) are electrically excitable cells in the nervous system that function to process information and transmit signals. The cell biology of the BBB phenomenon is based on interactions among these different cell types, as demonstrated in Figure 1. The tight junctions between endothelial cells produce a very high trans-endothelial electrical resistance which limits aqueous based paracellular diffusion that is observed in other organs (6-8).

In addition to blocking paracellular pathways for solute transport across the BBB, pinocytotic mechanisms and cell fenestrations are virtually nonexistent across the brain capillary endothelium. As a result, transcellular bulk flow of solute does not circulate through the BBB. Under these conditions, solute can access brain interstitium via two pathways: lipid mediation and catalyzed transport. In lipid mediation, lipid-soluble solutes can diffuse through the capillary endothelial membrane and passively cross the BBB. Catalyzed transport is classified into three general categories: carrier-mediated transport, active efflux transport, and receptor-mediated transport.

Figure 1 Schematic representation of the brain capillary endothelial cell. These cells form the BBB, and possess tight junctions and low permeability. The cells lack fenestration, have limited pinocytosis, and contain a large volume of mitochondria. Astrocytic endfeet cover the endothelial cell surface. Due to the tightness of the endothelial barrier, paracellular transport of substances is negligible under physiological conditions. Drugs enter the brain only by passive transcellular diffusion, receptor transcytosis or through carrier-mediated transport. Source: Reproduced from Ref. 17 with permission.

Figure 1 Schematic representation of the brain capillary endothelial cell. These cells form the BBB, and possess tight junctions and low permeability. The cells lack fenestration, have limited pinocytosis, and contain a large volume of mitochondria. Astrocytic endfeet cover the endothelial cell surface. Due to the tightness of the endothelial barrier, paracellular transport of substances is negligible under physiological conditions. Drugs enter the brain only by passive transcellular diffusion, receptor transcytosis or through carrier-mediated transport. Source: Reproduced from Ref. 17 with permission.

As a general rule, only the lipophilic molecules less than ~ 600-700 Da can be transported passively across the BBB. The barrier effectively blocks the majority of hydrophilic molecules and small ions. Unfortunately, as a result, many drugs are excluded from the CNS, making it difficult to treat CNS diseases. Current drug therapies for brain disorders are primarily lipophilic and can readily cross the BBB. However, not all lipophilic drugs can penetrate the BBB. For example, anticancer drugs such as doxorubicin, vincristine and vinblastine are lipophilic molecules, but can hardly pass through the BBB. The presence of efflux transporters such as P-glycoprotein (P-gp) limits access of these medications to the CNS.

There are a number of transport systems on both luminal and abluminal membranes of the endothelial cell that mediate solute transcytosis from blood to brain. The transport systems are involved in the uptake of nutrients such as glucose, amino acids, choline, purine bases, or nucleosides. However, there is also enzymatic activity inside the BBB. Solutes are subject to degradation by enzymes present inside the endothelial cells. These cells contain large densities of mitochondria, metabolically highly active organelles. BBB enzymes also recognize and rapidly degrade most peptides, including naturally occurring neuropeptides (9,10).

The BBB determines whether or not a compound can reach the CNS, either by passive diffusion or through carrier-mediated or receptor-based transport systems. Considerable research has focused on the structural and physicochemical requirements favoring transport across the BBB as related to anatomical and physiological features. Such studies have had a significant effect on the design of CNS drugs with improved permeability across the BBB. The BBB should be regarded as a dynamic rather than a rigid barrier; it can be influenced by astrocytes and probably also by neuronal and hormonal stimuli, and its properties are also affected by diseases of the CNS. This may offer new strategies for targeting drugs to the brain (11).

Besides the BBB, another barrier that limits CNS accumulation of systemically administered is the BCB. The BCB can regulate the movement of molecules into the cerebrospinal fluid (CSF), due to fact that CSF can exchange molecules with the interstitial fluid of the brain parenchyma. Physiologically, the BCB is located in the epithelium of the choroids plexus, which works together with the arachnoid membrane to limit penetration of molecules into the CSF. The passage of substances from the blood through the arachnoid membrane is prevented by tight junctions (12). In addition, there are a number of transport systems in the choroids plexus that extrude compounds from the CSF into the plasma. For example, a variety of therapeutic organic acids (e.g., penicillin, methotrexate, zidovudine) are actively removed from the CSF by an organic anion transporter.

Furthermore, substantial inconsistencies exist between the composition of the CSF and the interstitial fluid of the brain parenchyma, suggesting the presence of what is sometimes called the CSF-brain barrier (13).

The long pathways that comprise this potential barrier may prevent drugs from migrating from the CSF to brain interstitial fluid, thereby preventing these compounds from achieving therapeutically effective concentrations in the brain.

In the case of a CNS tumor, the BBB in the microvasculature is an even more difficult barrier to overcome. While the BBB can be significantly compromised during the progression of disease, additional physiological barriers limit drug delivery into solid tumors. Due to heterogeneous micro-vasculature distribution, drug delivery to neoplastic cells in a solid tumor is usually not uniform. During the progression of a CNS tumor, decreased vascular surface area and increased diffusion pathway further reduce exchange of molecules. Additionally, high pressure in and adjacent to the tumor make the cerebral microvasculature in adjacent regions of normal brain even less permeable to drugs than normal brain endothelium, leading to exceptionally low extra-tumoral interstitial drug concentrations (14). Therefore, it is critical to optimize drug properties and formulations to overcome BBB and achieve therapeutical concentration inside the tumor.

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