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Overcoming the Brain Barrier
than 25 million patients. Although great progress has been made in recent years toward the understanding of neurode- generative diseases, few effective treatments, and no cures, are currently available.
Moreover, aging greatly increases the risk of neurodegen- erative disease, and the average age of Americans is steadily increasing. Today, over 35 million Americans are over the age of 65. Within the next 30 years, this number is likely to double, putting more and more people at increased risk of neurodegenerative disease. Alzheimer’s disease, which has emerged as one of the most common brain disorders, se- verely affects the memory center of the brain, with pathol- ogy gradually spreading to most brain areas as the disease progresses. This pathology is characterized partly by deposi- tion of protein deposits (amyloid plaques) in the brain tissue but also in the blood vessels themselves (Iadecola, 2004).
By acting as a permeability barrier, the BBB impedes entry from blood to the brain, thus rendering many potent, neuro- logically active substances and drugs ineffective simply because they cannot be delivered to where they are needed to treat dis- eases in the brain. As a result, traversing the BBB remains the rate-limiting factor in brain drug delivery development.
A variety of approaches have been, and are being, developed to overcome the BBB for selective therapeutic treatment of brain pathologies. Over the past decade, numerous small- and large-molecule products have been developed for treat- ment of neurodegenerative diseases with mixed success. When administered systemically in vivo (e.g., by injection into the bloodstream or intravenously), the BBB inhibits their delivery to the regions affected by those diseases.
Indeed, a review of the Comprehensive Medicinal Chemis- try database indicates that only 5% of the more than 7,000 small-molecule drugs can be used to treat the central ner- vous system (CNS; Pardridge, 2015). With these, only four CNS disorders can be treated: depression, schizophrenia, ep- ilepsy, and chronic pain (Ghose et al., 1999; Lipinski, 2000). Moreover, despite the availability of pharmacological agents that could, hypothetically, treat potentially devastating CNS disorders including brain tumors and age-related neurode- generative diseases, they remain undertreated mainly be- cause of the impermeability of the BBB.
To be successful, a drug delivery system that overcomes the BBB requires transient, localized, and noninvasive targeting of a specific tissue region. These factors are critical in devel- oping such a system because the drugs of choice are likely
to be very powerful and could damage healthy tissue, with significant consequences for the brain and the body.
To date, none of the techniques clinically used or currently under research address these issues within the scope of the treatment of neurodegenerative diseases. As a result, the present situation in neurotherapeutics enjoys few success- ful treatments for most CNS disorders. Several pharmaceu- tical companies use the technique known as “lipidization,” which is the addition of lipid groups to the polar ends of molecules to increase the permeability of the agent (Fischer et al., 1998). However, the effect is not localized because the permeability of the drug increases not only in the targeted region but also throughout the entire brain and body. There can thus be a limit to the amount absorbed before the side effects become deleterious (Fischer et al., 1998).
A second set of techniques under study is neurosurgically based drug delivery methods that involve the invasive im- plantation of drugs into a region with a needle (Blasberg et al., 1975). The drug spreads through diffusion and is often localized to the targeted region because diffusion does not allow molecules to travel far from their point of release. However, such invasive procedures traverse untargeted brain tissue to get to the target region, potentially causing unnecessary damage.
Other techniques utilize solvents mixed with drugs or adju- vants (pharmacological agents) attached to drugs to disrupt the BBB through dilation and contraction of the blood ves- sels (Pardridge, 2015). However, this disruption is not local- ized within the brain, and the solvents and adjuvants used are potentially toxic. Although this technique may consti- tute a delivery method specific to the brain, it requires spe- cial attention to each type of drug molecule and a specific transport system, resulting in a time-consuming and costly process while still not being completely localized to the tar- geted region. As a result, none of the brain drug delivery techniques are routinely used in the clinic and the state of the art in the treatment of brain diseases remains stagnant.
Focused Ultrasound with Microbubbles
BBB thus remains a formidable obstacle in treating CNS disorders and millions of patients are undertreated at best. However, another approach, focused ultrasound (FUS), pro- vides that unique combined advantage of extracorporeal ap- plication with the capability of focalization through the in- tact skull, thus offering an unprecedented highly localizable drug delivery system.
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