Nanodroplets used with Ultrasound Acoustics to Induce Drug Delivery across the Blood-Brain Barrier

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A. (Source: Wiedemair et. al, 2009)                                          B. (Perkins, 2015) 

Image Title: Image (A) depicts the blood-brain barrier surrounding capillaries. Image (B) shows ultrasonic waves oscillating a nanodroplet in the capillary allowing molecules to cross the barrier.

The blood brain barrier (BBB) is a permeable wall of tight protein junctions between small blood vessels that protect the brain by preventing harmful molecules like viruses and bacteria from reaching the brain from the surrounding bloodstream.  While the BBB provides vital protection, it presents a challenge when treating neurological diseases such as Parkinson’s and Alzheimer’s [1]. Most drugs that are designed to treat neurological diseases are unable to cross this protective barrier to have their intended effect. Injections into the brain have been used to directly deliver treatments across the BBB, but these procedures are invasive and increase risk of infection. Nanodroplets oscillated at high speeds using focused ultrasound (FUS) to create an opening in the BBB offer a noninvasive treatment that avoids brain injections [2].

Droplets composed of lipids and a perfluorobutane core are pressurized to reduce the molecules to the nano-scale [5]. The nanodroplets create an opening in the BBB through rapid changes in pressure, induced by the FUS induced oscillation, which causes vapor cavities within a liquid to appear [6]. These cavities allow active transportation across the BBB and this facilitates the delivery of drugs used to treat neurological diseases into the tissue. The acoustic emissions generated by the oscillating nanodroplets need to be applied within a safe range that does not harm the BBB and rather provides a temporary opening for drug delivery. At a certain level of acoustic pressure, the nanodroplets risk collapse and create a shockwave, potentially causing tissue damage. Dangerous levels of acoustic emissions can be detected using a spectroscopic monitor before inertial cavitation occurs, making the procedure safe and effective. The level of acoustic emissions also correlates to the size of the opening being created in the BBB. As acoustic emissions increase with pressure, so does the permeability of the BBB, allowing treatment to be specific to the size of the therapeutic agent being delivered and decrease the opportunity for larger, unwanted molecules to also cross the BBB while the FUS is applied [3]. 

References

  1. Arvanitis, Costas D. et al. “Controlled Ultrasound-Induced Blood-Brain Barrier Disruption Using Passive Acoustic Emissions Monitoring.” Ed. Arrate Muñoz-Barrutia. PLoS ONE 7.9 (2012): e45783. PMC. Web. 3 Mar. 2015.
  2. Chen, Cherry C. and Sheeran, Paul S. and Wu, Shih-Ying and Olumolade, Oluyemi O. and Dayton, Paul A. and Konofagou, Elisa E. "Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoutstically-activated nanodroplets." Journal of Controlled Release 172.3 (2013): 795-804. 
  3. Chen, Hong and Konofagou, Elisa E. "The size of blood-brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure." Journal of Cerebral Blood Flow Metabolism 34.7 (2014): 1197-1204.
  4.  Columbia University. Non-invasive method controls size of molecules passing blood-brain barrier. 14 08 2014. 03 03 2015 <http://www.rdmag.com/news/2014/08/non-invasive-method-controls-size-mole....
  5. Paproski, Robert J., and Roger J. Zemp. "Comparing Nanodroplets and Microbubbles for Enhancing Ultrasound-mediated Gene Transfection."2013 IEEE International Ultrasonics Symposium (IUS) (2013): n. pag. Web.
  6. Blake, J. R. "Cavitation and Bubble Dynamics . By C. E. B RENNEN . Oxford University Press, 1995. 282 Pp. ISBN 0 19 509409. £60." J. Fluid Mech. Journal of Fluid Mechanics 316.-1 (1996): 376. Web.

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Functional Enhancement: This treatment is the only known localized and reversible method to open the blood-brain barrier. It is noninvasive and can control the size of the BBB opening to be specific to the therapeutic agent [3].  The nanodroplets are able to circulate through the entire bloodstream and target specified areas in the brain. This allows the FUS to target multiple regions of the brain that cannot be reached with direct injections. It thus, may provide localized delivery of therapeutic drugs [4]. 

Benefit Summary: 

The use of microbubbles and FUS would allow reversible, localized, and controlled delivery of therapeutic agents to the brain. This technique may provide a safer mechanism to treat brain diseases and disorders than current techniques like transcranial injections (drilling through the skull and directly injecting drugs into the desired region of the brain), which are rarely successful and risk infection [4]. This system of drug delivery can also monitor the levels of nanodroplet oscillation to prevent tissue damage using the acoustic emissions of the droplet. 

Risk Summary: 

This technique can not only cause tissue damage upon nanodroplet collapse, but also result in harming the integrity of the BBB and causing leakage of red blood cells and damage to vesicles (small vessels in the brain). However, unstable cavitation of nanodroplets such as inertial cavitation is one of the only known ways to achieve BBB openings of a size that allows larger therapeutic molecules to pass into the tissue (offering openings of up to 500 kilodaltons (mass of a band separating in a gel)  and stable cavitation can achieve up to 70 kilodaltons) [1]. 

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