Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Abstract

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage.

Brainpeps: the blood–brain barrier peptide database

“…Because selective and sufficient entry of drugs and their modification tools is important in CNS drug design, while still limiting the access of toxic compounds, knowledge about the BBB behaviour of drugs is highly researched (Chu et al 2006;Engelhardt 2006). Moreover, the addition of physical techniques to temporarily and spatial-selectively open the BBB, can even further extend the clinical possibilities (Campbell et al 2011;Liu et al 2010;Madsen and Hirschberg 2010;Rossi 2011).…”

Gene Transfection Enhanced by Ultrasound Exposure Combined with Drug Treatment Guided by Gene Chip Analysis

“…HTB-81) in RPMI-1640 medium (Cellgro, Mediatech, Herndon, VA) were cultured as monolayers in a humidified atmosphere of 95% air and 5% CO 2 at 37 C, as described previously [16]. The medium was supplemented with 10% heatinactivated fetal bovine serum (FBS, Atlanta Biologicals, Atlanta, GA) and 1% penicillin/streptomycin (Cellgro).…”

“…H-101) supplied with a matching resistance network allowing production of sound at 1 MHz, as described previously [16]. The transducer had a diameter of 70 mm, a 52 mm focal length and a 1.5 mm focal width at half-amplitude (À6 dB).…”

Ultrasound enhanced drug delivery to the brain and central nervous system

“…In vitro, endothelial cell permeability to hydrophobic molecules has been shown to increase with moderate ultrasound hyperthermia [13]. In a primate study, application of ultrasound to the brain following direct injection of a gadolinium-labelled liposome into the brain tissue increased diffusion of the agent within the parenchyma [14]. That study used a low duty cycle (around 5%), but long sonications (up to 4 h), thus a thermal mechanism could be possible.…”