Opening of the Blood Brain Barrier for Molecular Imaging R33-EB000705
The blood-brain barrier (BBB) is a specialized structure of the blood vessel wall that limits transport and diffusion from the vasculature to the central nervous system, thereby making it difficult to deliver many therapeutic and imaging agents into the central nervous system. Specifically, a functional and structural barrier at the level of the basal lamina and intercellular attachments of the endothelial cells known as "tight junctions" limit passage. Factors that affect passage through the barrier are lipid solubility, molecular size, and charge.
For the past several years, the NCIGT investigators along with Kullervo Hynynen of the University of Toronto have been investigating the use of low-intensity focused ultrasound exposures combined with an ultrasound contrast agent to selectively and temporarily disrupt the BBB. Use of these agents that consist of preformed microbubbles limits the interaction of the ultrasound to the endothelial cells, reducing the chance of damage to other brain structures. Using animal models, investigators characterize the size of agents that can be delivered to the brain using commercially-available fluorescent microspheres. In these experiments, researchers inject the microspheres immediately after sonication and then investigate the time course of the resealing of the BBB. Based on this work, investigators are developing an automated system that uses the emission signals in real-time to control ultrasound bursts. The hope is to determine the correct ultrasound intensities to use to maximize BBB disruption without inducing inertial cavitation. Having such a method to guide the procedure will be important because, especially when the sonications are delivered through the intact skull, it is difficult to determine acoustic intensity when focusing deep into living tissue.
To date the collaboration's work has shown:
- ultrasound-induced BBB disruption is possible using an ultrasound contrast agent;
- the number and location of various proteins at tight junctions are temporarily altered after ultrasound-induced BBB disruption;
- the mechanisms by which BBB disruption occurs;
- therapeutic agents can be delivered into the brain (clinically relevant doses of a chemotherapy agent (liposomal doxorubicin – Doxil®) have been administered to the rat brain as well as the delivery of antibodies);
- the results of tests of different ultrasound parameters on BBB disruption;
- that active transport of agents occurs through the BBB in arterioles, venules, and capillaries; and
- that a procedure can be optimized so that a practical clinical device can be constructed.
Over the past year, this collaboration resulted in a paper in PLoS One that details how collaborators at the Massachusetts General Hospital have demonstrated that large molecule agents can bind to amyloid plaques in Alzheimer's model mice and can be delivered through the disrupted BBB. This technique can be applied in disease models. It holds promise as a means to deliver agents that can detect and/or treat Alzheimer's disease.
- Vykhodtseva N, McDannold N, Hynynen K. Progress and problems in the application of focused ultrasound for blood-brain barrier disruption. Ultrasonics. 2008 Aug;48(4):279-96. PMID: 18511095.
- Raymond S, Treat L, Dewey J, McDannold N, Hynynen K, Bacskai B. Ultrasound Enhanced Delivery of Molecular Imaging and Therapeutic Agents in Alzheimer's Disease Mouse Models. PLoS ONE. 2008 May 14;3(5):e2175. PMID: 18478109. PMCID: PMC2364662.
- McDannold N, Vykhodtseva N, Hynynen K. Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med Biol. 2008 May;34(5):834-40. PMID: 18207311.
- McDannold N, Vykhodtseva N, Hynynen K. Effects of acoustic parameters and ultra-sound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med Biol. 2008 Jun;34(6):930-7. PMID: 18294757.
- Sheikov N, McDannold N, Sharma S, Hynynen K. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008 Jul;34(7):1093-104. PMID: 18378064.
- Sassaroli E, Hynynen K. Cavitation threshold of microbubbles in gel tunnels by focused ultrasound. Ultrasound Med Biol. 2007 Oct;33(10):1651-60. PMID: 17590501.
- McDannold N, Vykhodtseva N, Hynynen K. Use of ultrasound pulses combined with Definity for targeted blood-brain barrier disruption: A feasibility study. Ultrasound Med Biol. 2007 Apr;33(4):584-90. PMID: 17337109.
- Sheikov N, McDannold N, Jolesz F, Zhang YZ, Tam K, Hynynen K. Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier. Ultrasound Med Biol. 2006 Sep;32(9):1399-409. PMID: 16965980.