GETTING DRUGS THROUGH THE BLOOD-BRAIN BARRIER 2 treat brain mets, tumors w aid of US

[Lani]

US=ultrasound


Ultrasound Crosses Last Frontier: The Blood-Brain Barrier
— A novel ultrasound device has been shown to enhance drug distribution in the rat brain, owing to its ability to cross the blood–brain barrier (BBB). This and a study that investigated the mechanism of the ultrasound-related opening of pores in the BBB were reported here at the American Institute of Ultrasound in Medicine 2011 Annual Convention.

In the first proof-of-concept presentation, George K. Lewis MS, a PhD graduate student at Cornell University in Ithaca, New York, described an experiment to determine the efficacy and safety of ultrasound-enhanced drug distribution in the rat brain.

"The purpose here is to address the problem of treating glioblastomas — high-grade forms of brain cancer that have very poor outcomes," Mr. Lewis said. Few drugs have been found to be effective in this cancer type, he added, if for no other reason than the inability of systemic administration to gain access to the tumor because of the BBB.

For operable tumors, the current standard of treatment is removal of the tumor. However, because tumor margins for surgical purposes must remain necessarily limited in the central nervous system (CNS), tumor cells inevitably remain on the periphery of the tumor site. Thus, direct exposure to chemotherapy follows the surgical procedure.

"This is done with either implantation of encapsulated, drug-laden wafers (i.e., polifeprosan 20 with carmustine implant)," said Mr. Lewis, "or convection-enhanced delivery (CED), where you actually insert a needle into the region and infuse [the drug] under high pressure to cover the area with the drug." With either method, however, drug penetration is limited.

"Our approach is to infuse the drug, and then use 2 different methods to distribute it." The first approach uses a low-profile transducer cannula assembly, and the second uses a novel construction — a so-called time-reversal acoustics drug delivery cannula. "It's not as dramatic as plane wave, but it's more tightly focused," said Mr. Lewis. These methods were previously shown to have promise in ex vivo investigations.

The current study exposed anesthetized rats with craniotomies to a tracer dye, using both methods described above, both with and without stabilized microbubbles. After animal sacrifice, frozen sectioning and histology were performed for a 3-dimensional reconstruction to measure the infusion volume and to assess possible tissue damage to the brain.

Results showed that the application of ultrasound CED did indeed enhance tracer distribution, compared with control; further, this was accomplished without any apparent tissue damage. "We actually got a 2 to 3 times increase in the distribution volume covering the whole caudate region," said Mr. Lewis, however, "what was surprising to us was that when you combined CED and ultrasound with microbubbles, we did not see this effect. We thought they would actually oscillate in the field and enhance the penetration of the tracer, but that wasn't the case."

Mr. Lewis and colleagues surmise that the microbubbles formed were on a scale much larger than CNS endothelial pores, and that "we might have been clogging it up."

Given these results, the Cornell scientist is looking to repeat this investigation with larger animals.

Getting at the Mechanism of Microbubble Action

Delving into the basic science behind microbubble activity in the CNS and permeability of the BBB, Yao-Sheng Tung, MS, from the Department of Biomedical Engineering at Columbia University in New York City, reported on his work with microbubbles and focused ultrasound.

Mr. Tung and colleagues used a cylindrically focused hydrophone, confocal with the focused ultrasound transducer, as a passive cavitation detector to identify the threshold of inertial cavitation in the presence of Definity (Perflutren Lipid Microsphere) microbubbles.

Results showed that the inertial cavitation response could be detected transcranially during the BBB opening, and that the inertial cavitation pressure threshold lay at 0.45 MPa. "However, the BBB was opened at 0.30 MPa, so the BBB can be opened without requiring inertial cavitation."

Importantly, these activities did not cause any tissue damage, Mr. Tung added.

Dr. Lewis has been granted a US provisional patent (No. 61311064) for technology related to this study. Dr. Tung has disclosed no relevant financial relationships.

American Institute of Ultrasound in Medicine (AIUM) 2011 Annual Convention: Abstracts 989301 and 990294. Presented April 17, 2011.

[hutchibk]

Fascinating. Please hurry!