Focused ultrasound induced-blood-brain barrier opening in mouse brain receiving radiosurgery dose of radiation enhances local delivery of systemic therapy.
Authors: Wang S, Wu CC, Zhang H, Karakatsani ME, Wang YF, Han Y, Chaudhary KR, Wuu CS, Konofagou E, Cheng SK
Investigate the temporal effects of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening in post-radiotherapy mouse brains. C57B6 mice without tumors were used to simulate the scenario after gross total resection (GTR) of brain tumor. Radiation dose of 6 Gy x 5 was delivered to one-hemisphere of the mouse brain. FUS-induced BBB-opening was delivered to the irradiated and non-irradiated brain and was confirmed with MRI. Dynamic MRI was performed to evaluate blood vessel permeability. Two time points were selected: acute (2 days after radiation) and chronic (31 days after radiation). BBB opening was achieved after FUS in the irradiated field as compared to the contralateral non-irradiated brain without any decrease in permeability. In the acute group, a trend for higher gadolinium concentration was observed in radiated field. Localized BBB-opening can be successfully achieved without loss of efficacy by FUS as early as 2 days after radiotherapy. Adjuvant radiation after GTR is commonly used for brain tumors. Focused ultrasound facilitated BBB-opening can be achieved without loss of efficacy in the post-irradiated brain as early as 2 days after radiation therapy. This allows for further studies on early application of FUS-mediated BBB-opening.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether focused ultrasound can effectively and safely induce blood–brain barrier opening at acute (2 days) and chronic (31 days) time points after cranial radiotherapy in mice.
Animal model / Human subject
Mouse (Mus musculus), strain C57B6, age 6-7 weeks old, sex male
Disease model
Post-radiotherapy brain (simulating post-gross total resection of brain tumor)
MRI or image guidance method
9.4 T small-animal system MRI; dynamic contrast-enhanced T1-weighted imaging
Targeted brain region(s)
One Hemisphere (Irradiated Hemisphere / Irradiated Field)
Cargo name and characteristics
Gadolinium-based contrast agent (small molecule MRI contrast agent)
Route of administration
Intraperitoneal
Outcomes and Safety
Summary of Outcomes
Focused ultrasound (FUS) reliably opened the blood–brain barrier (BBB) in irradiated mouse brains without loss of permeability, effective as early as 2 days after radiotherapy with a trend toward higher gadolinium concentration in the acute irradiated field. The paper did not report testing multiple FUS parameter sets or specify parameter-dependent successes.
Duration of biological effect
2 days
Safety-related matter
No adverse effects were reported; focused ultrasound (FUS)-induced BBB opening was achieved in irradiated brain tissue without loss of efficacy, including as early as 2 days after radiotherapy.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Single element focused ultrasound transducer (Imasonic, France)
FUS Pressure
0.72 Mpa
FUS Mode
pulsed
Pulse duration
5 ms
Duration of a single FUS session
2 minutes
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
Multiple
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