Editors' ChoiceDrug Delivery

“Captain, Shields Are Down, We Can’t Survive Another Hit”

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Science Translational Medicine  18 May 2011:
Vol. 3, Issue 83, pp. 83ec75
DOI: 10.1126/scitranslmed.3002641

Many tumor-killing drugs are useless against brain tumors because the blood-brain barrier (BBB) “force field” blocks their entrance. The BBB impedes treatment of many brain conditions because it only allows molecules <500 daltons and with good lipid solubility to cross. Much like how photon torpedoes can damage a starship’s shields, the application of focused ultrasound, combined with microbubble contrast agents, can transiently disrupt the BBB, thus allowing drugs to access these hard-to-reach tumors.

Continuous-wave ultrasound can create intracranial standing waves, which confound estimates of pressures generated by these waves and lead to high variability between in vitro and in vivo experimental results. O’Reilly et al. therefore used ultrasound bursts containing short (3 µs) cycles to eliminate these standing waves. They varied the time between cycles within a burst and also varied the time between bursts. These bursts were applied to rat brains in vivo, along with intravenous infusion of a microbubble contrast agent. Whole rat-brain sections were then analyzed ex vivo for leaky blood vessels. One of the authors’ key findings was that a single-cycle burst can cause BBB disruption, as evidenced by histology showing red blood cells that had escaped their vessels. Short bursts could reduce the treatment time for a single lesion; or if there are multiple lesions, these could be targeted during a single bolus injection of microbubble contrast agent.

Much work remains to translate this technique into the clinic, but the potential applications to drug delivery and imaging are limitless. For example, it has been shown by others that the chemotherapeutic herceptin (~150 kD) can be delivered to the brain with ultrasound-induced BBB disruption. Similarly, ultrasound has been used to deliver amyloid-β antibodies to the brain in a mouse model of Alzheimer’s disease, resulting in a reduction in plaques. O’Reilly et al. have set the stage for discovering the optimal torpedo (or ultrasound burst) to bring the BBB shields down and open wide the possibilities for treatment of various neurological diseases.

M. A. O’Reilly et al., Focused-ultrasound disruption of the blood-brain barrier using closely-timed short pulses: Influence of sonication parameters and injection rate. Ultrasound Med. Biol. 37, 587–594 (2011). [PubMed]

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