Characteristics of compounds that cross the blood-brain barrier

Abstract

Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.

Successful delivery of docetaxel to rat brain using experimentally developed nanoliposome: a treatment strategy for brain tumor

“…It has an efficient antineoplastic effect against a wide spectrum of solid tumors, such as ovarian, breast and lung cancer. It is found to be effective in the treatment of glioma in vitro but its in vivo efficacy is highly compromised due to its poor aqueous solubility and high molecular weight (Banks, 2009;Liu et al, 2011;Tan et al, 2012). Therefore, suitable design and development of appropriate vehicle for the transport of therapeutic payload is of prime importance in order to develop an effective therapy against glioma.…”

On the atomic structure of cocaine in solution

“…Other theories, however, have argued that drugs enter cells solely via carriers normally used for the transport of nutrients and intermediary metabo- 8,9 Nevertheless, in order to exert a pharmacological function, after crossing the BBB the drug must then partition into the aqueous environment of the interstitial brain fluid. 7 Highly lipid soluble molecules can be sequestered by the capillary bed and not reach the cells beyond the BBB. As a result, effective molecules must somehow achieve the correct balance between lipophilicity or hydrophobicity and hydrophilicity in order to penetrate deeply enough into the BBB in order to perform their function.…”

“…Molecules which successfully cross the BBB are traditionally thought to passively diffuse across this largely hydrophobic barrier, 6 usually being of low molecular weight (< 400 Da) 2,3 and high lipid solubility 3,7 . Other theories, however, have argued that drugs enter cells solely via carriers normally used for the transport of nutrients and intermediary metabo- 8,9 Nevertheless, in order to exert a pharmacological function, after crossing the BBB the drug must then partition into the aqueous environment of the interstitial brain fluid.…”

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“…The brain microvessel endothelial cells forming the blood-brain barrier (BBB) are structurally and functionally different from capillaries found in other organs. 17 The restrictive nature of the BBB is important for maintaining the proper extracellular fluid environment within the brain required for neuronal transmission. However, in terms of central nervous system therapy, an intact BBB presents a formidable obstacle to drug delivery to the brain.…”