Enhanced permeability of tumor blood vessels in brain using focused ultrasound with microbubbles

Several studies have demonstrated that focused ultrasound (FUS) in the presence of microbubbles is able to temporarily disrupt the blood-brain barrier (BBB) and deliver drugs to the central nervous system. While magnetic resonance-guided FUS (MRgFUS) treatments have shown promising results in targeted drug delivery, one question still remains how much the blood vessel permeability can be enhanced in tumors. This study was designed to investigate the FUS-induced enhancement of the blood vessel permeability in a specific tumor in the brain. Human breast cancer cells (BT 474) were inoculated directly into the brain of nude (nu/nu) rats (n = 15) as a metastatic tumor model. Guided by the MR images, the tumors were sonicated using a single element focused transducer at a frequency of 690 kHz for 60 s after the injection of microbubbles (Definity, 10 μl/kg). From the contrast-enhanced Tl-weighted MR images compared to Tl-weighted images, the average signal intensity in the tumor was found to increase by 14.3 ± 0.8% and 1.9 ± 0.3% with and without the FUS treatment, respectively. Two different larger molecule, dextrans (each 70 kD) were also tested. Compared to controls, the dextran uptake of the tumor increased 104.5 ± 0.4 times for Tetramethylrhodamine. For Texas Red, the uptake increased 29.5 ± 0.3 times. These results suggest a size-dependence on drug delivery enhancement in this tumor model. Small molecules might be transported across the blood-tumor barrier (BTB) without disruption of the barrier since tumors generally have leaky blood vessels. However, there are additional barriers to effective drug delivery in tumors, such as increased interstitial pressures, and even small molecule delivery may be enhanced. Large molecules may not leak freely from leaky tumor vessels and benefit more from ultrasound-enhancement.. Overall, these results suggest that the ultrasound bursts used to disrupt the BBB also enhance delivery of agents- - to tumors.