Focused ultrasound system for localized drug delivery across the blood brain barrier

The brain is protected by a unique vascular system known as the blood-brain barrier (BBB), which acts as a defense system to prevent the entry of large molecules. While the BBB can protect the brain from toxins, it also represents a major impediment to drug delivery for therapeutic purposes. In research, the BBB also hinders large-scale screening for new drug candidates, since the best method for molecular delivery is surgical creation of a cranial aperture. This technology makes cooperative use of focused ultrasound (FUS) and microbubble technologies to achieve localized, transient, and non-invasive molecular delivery into the brain. The technology reversibly opens the BBB, both transcranially and transdermally, allowing drugs to pass from the blood vessels into targeted brain regions. Thus, more molecules may be screened and potentially used for treating diseases of the central nervous system (CNS).

Microbubbles enable focused ultrasound transducers to precisely open localized areas of the blood brain barrier

The technology employs FUS at a low intensity to locally create an opening in the BBB. The location of the opening in the BBB is accurately positioned by a computer-controlled FUS transducer. The size of the opening in the BBB is determined by using optimally-sized microbubbles, which also influences the duration of the opening. Using a brain atlas or previous magnetic resonance (MR) scans, the optimal orientation and positioning of a single element ultrasound transducer can be determined, offering a less expensive alternative to current multi-element, MR guided techniques.

The capability of this technology to induce a localized BBB opening at the center of a targeted region has been demonstrated on both primate and human skulls.

Lead Inventor:

Elisa E. Konofagou, Ph.D.

Applications:

• Recurrent drug delivery in Alzheimer's, Parkinson's and other central nervous system diseases.
• Localized delivery of toxic drugs to a tissue site of interest.
• Research tool for finely controlled membrane manipulation.
• High throughput drug screening in vivo.

Advantages:

• Minimally invasive due to transient creation of small BBB opening.
• Safe and quick relative to techniques such as cranial surgery.
• Non-toxic compared to drug-based methods for BBB disruption.
• Highly localized and cost-effective for access to specific regions of the brain.
• Enables single element transducer, MR guidance-free procedures.

Patent information:

• Patent Pending (US 20090005711)
• Patent Pending (WO/2011/035312%2520&maxRec=863))
• Patent Pending (WO/2011/079177%2520&maxRec=868 ))
• Patent Pending (US 20110295105)

Tech Ventures Reference: IR 2039

Related Publications:

• Choi JJ, Wang S, Tung YS, Morrison B 3rd, Konofagou EE. "Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo," Ultrasound Med Biol. 2010 Jan;36(1):58-67.
• Y.S. Tung, F. Vlachos, J.J. Choi, T. Deffieux, K. Selert, E.E. Konofagou. In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice. Phys Med Biol, Vol. 55, Issue 20, Oct 2010, pp. 6141-55.
• T.Deffieux, E.E.Konofagou. Numerical study of a simple transcranial focused ultrasound system applied to blood-brain barrier opening. IEEE Trans Ultrason Ferroelectr Freq Control, Vol. 57, Issue 12, Dec 2010, pp.2637-53.
• B. Baseri, J.J. Choi, T. Deffieux, M. Samiotaki, Y, Tung, O, Olumolade, S.A. Small, B. Morrison, E.E.Konofagou. Activation of signaling pathways following localized delivery of systemically-administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles. Phys Med Biol, Vol. 57, Issue 7, April 2012, pp. N65-N81.