Getting stuff across the BBB & exactly where you want it in the brain - through the nose, with ultrasound (in mice)

[Rhyothemis]

Getting stuff (name your favorite bioactive molecule) into the brain, especially exactly where you want it to go, can be very difficult. Here's an innovative approach to the problem using intranasal drug delivery combined with ultrasound. The study was on mice of course, but all technological development has to start somewhere (though I do feel sorry for all those poor mice). Free full-text from PLoS.

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A New Brain Drug Delivery Strategy: Focused Ultrasound-Enhanced Intranasal Drug Delivery

Chen et al. 2014

journals.plos.org/plosone/a...

Abstract

"Central nervous system (CNS) diseases are difficult to treat because of the blood-brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (IN) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+IN) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After IN administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (IV) drug injection is employed, FUS was also applied after IV injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+IN enhanced drug delivery within the targeted region compared with that achieved by IN only. Despite the fact that the IN route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+IN was not significantly different from that of FUS+IV. As a new drug delivery platform, the FUS+IN technique is potentially useful for treating CNS diseases."

[Rhyothemis]

Brand new, full-text review article on focused ultrasound (with fancy color graphics!):

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Theranostic Strategy of Focused Ultrasound Induced Blood-Brain Barrier Opening for CNS Disease Treatment

Chen et al. Front Pharmacol. 2019; 10: 86.

ncbi.nlm.nih.gov/pmc/articl...

"The BBB blocks nearly 98% of drug compounds from accessing the CNS, and the use of focused ultrasound raises the potential for developing a drug delivery platform (Pardridge, 2005). The permeability of the BBB can be transiently increased using low-energy burst-tone focused ultrasound following an administration of intravenous microbubbles (Hynynen et al., 2001, 2003; Park et al., 2012; Chai et al., 2014). A physical cavitation effect is created from circulating microbubbles, significantly reducing the ultrasound pressure to produce an equivalent acoustic cavitation effect (concepts see Figure 1). The subsequent application of ultrasonic energy can achieve a local detachment of tightly sealed junctions on the capillary wall without inducing neuronal damage (Hynynen et al., 2005). Due to its spherically concaved transducer design, ultrasonic energy focused at the geometrical center can be sharply cascaded, allowing ultrasonic energy to be tightly deposited deeply within the brain tissue while minimizing skull energy absorption (Clement et al., 2000). Since the BBB blocks nearly 98% of drugs from accessing the CNS, the use of focused ultrasound raises a potential therapeutic delivery platform to the CNS (Pardridge, 2005)."

[Hidden]

What drugs would you want to get through the BBB?

[Rhyothemis in reply to Hidden]

Pretty much anything that could help with PD or any number of other awful diseases. Here's a video that explains the BBB problem and offers another innovative approach - the use of exosomes (aka extracellular vesicles), sometimes in conjunction with viral entry mechanisms:

youtube.com/watch?v=FxyXZD_...(Not working as expected?)

[Hidden in reply to Rhyothemis]

Current medication for PD is able to cross the BBB so this technology may be improved before it is needed.

[Rhyothemis in reply to Hidden]

There are currently no disease modifying drugs for PD (or at least, ones approved by any of the major government agencies). A disease modifying drug is one that actually affects the course of the disease, not one that just helps control symptoms (e.g., l-Dopa).

Nilotinib may be a disease modifying drug, but it is not currently approved by the FDA for its use in PD. Perhaps high dose-thiamine is disease modifying, but as with nilotinib, that has not yet been established. If it turns out that nilotinib or high-dose thiamine are effective disease modifying treatments for PD, there are any number of other diseases (e.g, Alzheimer's) which would benefit from improved drug delivery to the brain. Even for drugs that can cross the BBB and are in current use, side effects could theoretically be diminished by the ability to target specific brain regions. This technology (or the ultrasound approach) is most definitely needed.

[Hidden in reply to Rhyothemis]

As I said, this is a technology awaiting a use once new or repurposed drugs are identified and would benefit from this method of delivery.

[Rhyothemis in reply to Hidden]

Fair enough, though there are a number of substances that are currently in the 'it would work if only we could get enough in there' bin - good old curcumin* for one (or at least that's one reason often given for their poorer-than-hoped-for results in trials).

[Hidden in reply to Rhyothemis]

Curcumin is able to cross the BBB. I have had a quick search and cannot find research results indicating that bypassing the BBB would make curcumin a useful disease modifying drug.

[Rhyothemis in reply to Hidden]

Curcumin can cross the BBB, but in relatively small amounts - the dose makes the treatment, as well as the poison. Efforts have been made to improve bioavailability. Micronized "nano" curcumin has been investigated in relation to PD as an HDAC inhibitor:

michaeljfox.org/foundation/...

"We anticipate that nanocurcumin formulations simultaneously preventing worsening of Parkinson symptoms through activating the neural repair pathways to restore the balance between the signature neurotransmitter, dopamine and endogenous neuro-chemicals in the brain. "

J147, a curcumin derivative, has been reported to be much more bioavailable:

cen.acs.org/articles/90/i31...

"Not much of the curcumin gets into the bloodstream, let alone past the blood-brain barrier, in its pure, active form, he adds."

The target of the drug is mitochondrial dysfunction, which is at the root of neurodegeneration (and aging, generally):

salk.edu/news-release/alzhe...

"The results, the researchers say, are not only encouraging for moving the drug forward as an Alzheimer’s treatment, but also suggest that J147 may be useful in other age-associated diseases as well.

People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke” says Schubert. “But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated.”

[Rhyothemis]

Some speculation here - chronic inflammation is known to increase blood brain barrier permeability and in general is a bad thing - the BBB is there for a reason. Exercise is known to increase BBB function and decreases chronic inflammation. However, after a bout of exercise, there is an increase in inflammatory markers such as IL-6. Many exercise adaptations are mediated through this transient increase in inflammatory markers. I wonder if BBB permeability is increased after a bout of exercise, and if timing drug dosing such that peak plasma levels coincide with peak IL-6 levels would improve bioavailability.

Later I'll do some looking into the literature, but if anyone already has information on this, please do post.

[Rhyothemis]

Another possible way around the BBB is ocular delivery - eye drops. Ocular administration of Nerve Growth Factor (NGF) appears to get to various brain regions in rats:

ncbi.nlm.nih.gov/pubmed/215...

The first person to try ocular NGF was its discoverer, Rita Levi-Montalcini:

blog.adafruit.com/2017/11/1...

[Rhyothemis in reply to Rhyothemis]

Ocular NGF was found to decrease experimentally-induced inflammation int he cerebellum and hippocampus (but not the frontal cortex) of rats:

ncbi.nlm.nih.gov/pubmed/266...

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NGF eye drops are now being sold as a treatment for neurotrophic keratitis, a rare eye disease, under the name Oxervate:

healio.com/ophthalmology/co...

[Rhyothemis in reply to Rhyothemis]

Another example of eye application being used to get through the BBB - leptin applied to the eyes of rats makes its way to the hypothalamus:

iovs.arvojournals.org/artic...