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New non-invasive technique controls the size of molecules penetrating the Blood-Brain Barrier.

A new technique developed by Columbia University has demonstrated for the first time that the size of molecules penetrating the blood-brain barrier (BBB) can be controlled using acoustic pressure, the pressure of an ultrasound beam, to let specific molecules through.  The study is being hailed as an important breakthrough in getting drugs delivered to specific parts of the brain precisely, non-invasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson’s and Alzheimer’s.

Most small, and all large, molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue.  As a result  all central nervous system diseases remain undertreated at best. For example, researchers know that Parkinson’s disease would benefit by delivery of therapeutic molecules to the neurons so as to impede their slow death. But because of the virtually impermeable barrier, these drugs can only reach the brain through direct injection and that requires anesthesia and drilling the skull while also increasing the risk of infection and limiting the number of sites of injection. And transcranial injections rarely work, only about one in ten is successful.

Focused ultrasound in conjunction with microbubbles, gas-filled bubbles coated by protein or lipid shells, continues to be the only technique that can permeate the BBB safely and non-invasively. When microbubbles are hit by an ultrasound beam, they start oscillating and, depending on the magnitude of the pressure, continue oscillating or collapse. While researchers have found that focused ultrasound in combination with microbubble cavitation can be successfully used in the delivery of therapeutic drugs across the BBB, almost all earlier studies have been limited to one specific-sized agent that is commercially available and widely used clinically as ultrasound contrast agents.  The team were convinced there was a way to induce a size-controllable BBB opening, enabling a more effective method to improve localized brain drug delivery.

The researchers targeted the hippocampus, the memory center of the brain, and administered different-sized sugar molecules (Dextran). The group found that higher acoustic pressures led to larger molecules accumulating into the hippocampus as confirmed by fluorescence imaging. This demonstrated that the pressure of the ultrasound beam can be adjusted depending on the size of the drug that needs to be delivered to the brain: all molecules of variant sizes were able to penetrate the opened barrier but at distinct pressures, i.e., small molecules at lower pressures and larger molecules at higher pressures.

Through this study the team have been able to show, for the first time, that the BBB opening size can be controlled through the use of acoustic pressure.  The researchers also learned much more about the physical mechanisms associated with the trans-BBB delivery of different-sized agents, and understanding the BBB mechanisms will help the medical community to develop agent size-specific focused ultrasound treatment protocols.

The team plan to continue to work on the treatment of Alzheimer’s and Parkinson’s in a range of models, and hope to test their technique in clinical trials within the next five years.

The team state that they’re really excited because now the medical community have a tool that could potentially change the current dire predictions that come with a neurological disorder diagnosis.

Source:  Columbia University

 

Reversible blood-brain barrier opening using focused ultrasound.  Shown are horizontal consecutive slices of the brain, corresponding to contrast enhanced T1 images from day 0 (when focused ultrasound was applied) to day 3 (when closing occurred). Overlaid with red color are the voxels where the MRI contrast agent (Gd-DTPA in this case) had diffused through the BBB. The left hippocampus was not sonicated and so the contrast agent remained in the vasculature, while in the sonicated hippocampus on the right, the contrast agent diffused into the brain parenchyma until the BBB completely closed on day 3. Source: Samiotaki et al. (2012)
Reversible blood-brain barrier opening using focused ultrasound. Shown are horizontal consecutive slices of the brain, corresponding to contrast enhanced T1 images from day 0 (when focused ultrasound was applied) to day 3 (when closing occurred). Overlaid with red color are the voxels where the MRI contrast agent (Gd-DTPA in this case) had diffused through the BBB. The left hippocampus was not sonicated and so the contrast agent remained in the vasculature, while in the sonicated hippocampus on the right, the contrast agent diffused into the brain parenchyma until the BBB completely closed on day 3.
Source: Samiotaki et al. (2012)

 

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