Enhancing drug delivery for boron neutron capture therapy of brain tumors with focused ultrasound

Glioblastoma is a notoriously difficult tumor to treat because of its relative sanctuary in the brain and infiltrative behavior. Therapies need to penetrate the CNS but avoid collateral tissue injury. Boron neutron capture therapy (BNCT) is a treatment whereby a B-10-containing drug preferentially accumulates in malignant cells and causes highly localized damage when exposed to epithermal neutron irradiation. Studies have suggested that B-10-enriched L-4-boronophenylalanine-fructose (BPA-f) complex uptake can be improved by enhancing the permeability of the cerebrovasculature with osmotic agents. We investigated the use of MRI-guided focused ultrasound, in combination with injectable microbubbles, to noninvasively and focally augment the uptake of BPA-f. With the use of a 9L gliosarcoma tumor model in Fisher 344 rats, the blood-brain and blood-tumor barriers were disrupted with pulsed ultrasound using a 558 kHz transducer and Definity microbubbles, and BPA-f (250 mg/kg) was delivered intravenously over 2 h. B-10 concentrations were estimated with imaging mass spectrometry and inductively coupled plasma atomic emission spectroscopy. The tumor to brain ratio of B-10 was 6.7 0.5 with focused ultrasound and only 4.1 0.4 in the control group (P .01), corresponding to a mean tumor [B-10] of 123 25 ppm and 85 29 ppm, respectively. B-10 uptake in infiltrating clusters treated with ultrasound was 0.86 0.10 times the main tumor concentration, compared with only 0.29 0.08 in controls. Ultrasound increases the accumulation of B-10 in the main tumor and infiltrating cells. These findings, in combination with the expanding clinical use of focused ultrasound, may offer improvements in BNCT and the treatment of glioblastoma.