Diseases that primarily affect the brain, often resulting in dementia, are some of the most prevalent, devastating, and yet poorly treated of all diseases. Despite advances in our knowledge of basic neurosciences, the failure rate for new drugs targeting important central nervous system (CNS) diseases still exceeds most other areas of drug discovery. A significant barrier to drug development for these diseases is presented by the blood-brain barrier (BBB).
The BBB is a dynamic diffusion barrier essential for the protection and maintenance of brain homeostasis. In contrast with blood vessels elsewhere in the body, relatively few molecules can passively diffuse across endothelial cells of the brain and, conversely, many more molecules are actively transported. This selective permeability arises from the high transendothelial electrical resistance imposed by the special junctions of the BBB, along with a low rate of transcytosis.
Only a small number of polar molecules with low molecular weight (<400 Da) and less than 8 hydrogen bonds have been found to cross the BBB under physiological conditions. Although these properties are the main physiological hurdles that impede the entrance of harmful toxins and viruses that are potentially in the bloodstream, they also stop ~98% of therapeutic molecules—including not only proteins drugs but also many small molecules.
Tight junctions (TJs) are the main protein complexes that control the property of low paracellular permeability by sealing the paracellular route between adjacent brain microvascular endothelial cells. In fulfillment of this vital role, TJs have been proposed as the main obstacle that greatly restricts paracellular diffusion of polar molecules, non-lipophilic drugs, macromolecules, and xenobiotics into the CNS.
TJs present themselves as highly dynamic structures, in which the localization of their structures is modified in response to pathophysiological stressors that may induce downstream modifications. TJs dysregulation at the BBB has also been shown to contribute to the pathogenesis of many CNS disease states. However, research has shown that modulation of TJs may also allow increased brain delivery of drugs through the paracellular route.
Apart from the permeability concern, even if a compound is able to transverse the barrier, it also has to remain in a therapeutically relevant concentration at the target site to elicit its desired action. The presence of many influx/efflux transporters at the BBB may alter their ability to enter the CNS, regardless of their lipophilicity. Additionally, the putative role of the BBB as a drug-metabolizing barrier that is capable of inactivating therapeutics has received little attention.
Therefore, for the drug to reach the target site at efficient concentrations, it is necessary to raise drug levels by substantially enhanced dose or extended administration. However, as most therapeutics for CNS diseases are administered intravenously, the risk of systemic toxicity is high. Therefore, researchers are looking for more ways to transfer therapeutic agents into the CNS without the need for increasing the systemic levels of these agents.
Over the past decade, a number of delivery strategies have been tested to increase BBB paracellular permeability to improve drug delivery to the brain in vivo. In addition to the common miscellaneous techniques, various invasive and non-invasive techniques—as reviewed in this article—have been developed to enhance brain drug uptake.
Among them, the use of nanocarriers as drug-delivery systems has emerged as one of the most promising ways forward in treating a variety of brain diseases. In recent years, there has been a significant increase in the number of novel nanocarriers with unique compositions and properties. For example, extracellular vesicles (EVs) may represent a potential breakthrough in targeted CNS disease treatment, as they inherently are cell targeting, protective of their drug cargo, non-immunogenic, noncytotoxic, and can be easy to load.
There has been growing interest in the development of exosomes as vehicles to deliver therapeutic substances to brain tissues and alter CNS functions. Being natural delivery vehicles for genetic material, several proof-of-concept studies have concluded that exosomes derived from the CNS and circulating in the blood have a BBB permeability similar to liposomes. But unlike liposomes, they accumulate in endothelial cells. Ultimately, the fulfillment of exosomal therapy may hinge on the development of suitable strategies for exosome production, characterization, targeting, and loading.
The use of monocytes as molecular Trojan horses to shuttle cargos across the BBB has also been demonstrated. Monocytes may be loaded with drug cargos either in the blood, following intravenous injection, or by harvesting from patients and introducing the cargo ex-vivo before returning the loaded monocytes to the patient. Using this technique may allow the efficient delivery of large molecules such as antibodies.
While there is emerging insight into viable solutions for drug delivery across the BBB, very little is known about how aging—the greatest risk factor for neurodegenerative disorders— may affect BBB function. There is also the issue of BBB disruption, (loss of the BBB effect), under various pathological conditions of diseases.
As more effective strategies to address the BBB are developed, and as more drug companies focus on novel therapeutics for the CNS, the terrible tide of increasing CNS-related mortality in an aging population may start to recede.