Abstract
We investigated controlled blood-brain barrier (BBB) disruption using a low-frequency clinical transcranial MRI-guided focused ultrasound (TcMRgFUS) device and evaluated enhanced delivery of irinotecan chemotherapy to the brain and a rat glioma model. Animals received three weekly sessions of FUS, FUS and 10 mg/kg irinotecan, or irinotecan alone. In each session, four volumetric sonications targeted 36 locations in one hemisphere. With feedback control based on recordings of acoustic emissions, 98% of the sonication targets (1045/1071) reached a pre-defined level of acoustic emission, while the probability of wideband emission (a signature for inertial cavitation) was than 1%. BBB disruption, evaluated by mapping the R1 relaxation rate after administration of an MRI contrast agent, was significantly higher in the sonicated hemisphere (P < 0.01). Histological evaluation found minimal tissue effects. Irinotecan concentrations in the brain were significantly higher (P < 0.001) with BBB disruption, but SN-38 was only detected in <50% of the samples and only with an excessive irinotecan dose. Irinotecan with BBB disruption did not impede tumor growth or increase survival. Overall these results demonstrate safe and controlled BBB disruption with a low-frequency clinical TcMRgFUS device. While irinotecan delivery to the brain was not neurotoxic, it did not improve outcomes in the F98 glioma model.
Highlights
Disrupting the blood-brain barrier (BBB) with focused ultrasound (FUS) and circulating microbubbles has been investigated to noninvasively and locally enhance drug delivery to the central nervous system[1]
We show that the large geometric gain achieved with a hemispherical transducer results in FUS-induced BBB disruption that can be reliably and repeatedly used in rats
There was no significant difference in the acoustic energy applied, the acoustic emissions recorded during sonication, or in the resulting BBB disruption between the FUS + IN and the FUS-Only animals
Summary
Disrupting the blood-brain barrier (BBB) with focused ultrasound (FUS) and circulating microbubbles has been investigated to noninvasively and locally enhance drug delivery to the central nervous system[1]. Preclinical studies have shown that FUS can increase the permeability of the partially-intact blood-tumor barrier (BTB) and enhance the delivery of chemotherapy to CNS tumors[11,12,13,14,15]. Perhaps more important is the prospect of getting drugs to surrounding areas where tumor cells are infiltrating into healthy brain where the BBB is intact. This infiltration, which often cannot be fully resected, leads to recurrence and is one of the main challenges in treating patients with brain tumors. If the geometric gain of the transducer is not high enough, the size of the focal region will exceed the dimensions of the brain, leading to high acoustic intensities near the skull due to internal reflections. Regulatory agencies may require preclinical data be obtained with the same equipment planned for human use
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