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Blasting Your Way In

Getting drugs of any sort through the blood-brain barrier is never something that can be taken for granted, and if your therapeutic agents is well outside the usual size/polarity bounds, you can pretty much take it for granted that it’s not going in at all. The number of techniques that have been tried to get around this limitation is probably beyond counting, ranging from low-impact solutions like tagging things with groups designed to hitch a ride on transport proteins, all the way up to physical methods that begin to sound like neo-trepanation.

There’s a technique that’s been coming up into view the last few years that I can’t decide which class to assign to, because it’s sort of an elegant drill press approach. That’s focused ultrasound, which has been shown in numerous animal experiments (starting in 2001) to open up (through various mechanisms) the tight cellular junctions in the brain’s vasculature that are the physical wall forming the BBB. In the presence of microbubbles, you can use even lower ultrasound energy levels than otherwise, and the whole process can be done noninvasively and in a targeted manner.

This is becoming particularly interesting, given the number of biologics and biologic/small-molecule hybrids that one might find useful to get into the brain. Antibodies (and antibody conjugates), siRNA, viral vectors, PEGylated drugs – none of these cross very efficiently or predictably, and against something like glioma, throwing that sort of kitchen sink selection is actually pretty appropriate. And if we ever have anything decent against Alzheimer’s, the same outlook applies. (There was, though, a report earlier this year that ultrasound itself was effective at breaking up amyloid plaques and restoring some function in a mouse model, but that, I think, is a bit more vigorous approach, and probably rather more difficult to implement in a human-sized cranial cavity).

At any rate, there are a number of clinical trials ongoing (see here and the links therein). Given the ways in which molecular medicine is going, having a technique to blast things into the brain will probably come in handy. Let’s hope it works.

7 comments on “Blasting Your Way In”

  1. milkshake says:

    I bet if you microwave your head in the oven, drugs will go in even faster. Then there is IV mannitol that can open CNS barrier, but it is not pretty.

    Glioblastoma is a desperate scenario, and the current treatment options (chemo-releasing implant wafer, high-dose brain radiation) are all bad. But for any other indication, I would rather try to redesign small molecule ligands to make them smaller and greasier, and maybe little basic, to make them CNS penetrable. Proteins do not get directly taken into brain for a good reason. You can see what happens in hepatic encephalopathy, when the wrong kind of things get in the brain.

  2. PorkPieHat says:

    This stuff has the power to transform CNS medicine and therapeutics delivery, especially neuro-oncology. The use of MRI – guided high-intensity focus ultrasound (HIFU) and the application to stem-cell homing and activation is a space to be VERY mindful of in the very near future…its already here, in fact.

  3. Anon says:

    What happened to ocular delivery into thr brain that was all the rage a few years back?

  4. steven says:

    Some virus could pass through blood-brain barrier, so if we could dilevery the drug by the virus or not?

  5. Mark Thorson says:

    Here’s a study which makes a good case for the intranasal route bypassing the blood-brain barrier (BBB). In rodents, anyway.

    http://www.neurosurgery.uthscsa.edu/journal_club/journals/JOURNAL%20ARTICLES/Scranton_2011_rostral_migratory.pdf

  6. Falanx says:

    I think the class you’d put it under is “Sexy New Trepanning”.

  7. Vader says:

    The notion of opening the blood-brain barrier nonselectively makes me think of Chesterton’s fence.

    http://www.chesterton.org/taking-a-fence-down/

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