Noninvasive and transient blood-brain barrier opening in the hippocampus of Alzheimer's double transgenic mice using focused ultrasound.
The spatio-temporal nature of focused ultrasound-induced blood-brain barrier (BBB) opening as a brain drug delivery method was investigated in Alzheimer's disease model mice. The left hippocampus of transgenic (APP/PS1, n = 3) and nontransgenic (n = 3) mice was sonicated (frequency: 1.525 MHz, peak-negative pressure: 600 kPa, pulse length: 20 ms, duty cycle: 20%, duration: 1 min) in vivo, through their intact skin and skull, after intravenous injection of microbubbles (SonoVue; 25 microl). Sequential, high-field MR images (9.4 Tesla) were acquired before and after injection of gadolinium (Omniscan, 0.75 ml, molecular weight: 573.7 Da) on two separate days for each mouse. Gadolinium deposits through the ultrasound-induced BBB opening in the left hippocampus revealed significant contrast-enhancement in the MRI. On the following day, MRI revealed significant BBB closure within the same region. However, the BBB opening extent and BBB closing timeline varied in different regions within the same sonicated location. This indicates that opening and closing were dependent on the brain region targeted. No significant difference in BBB opening or closing behaviors was observed between the APP/PS1 and the nontransgenic mice. In conclusion, a BBB-impermeable molecule was noninvasively, transiently and reproducibly delivered to the hippocampus of Alzheimer's APP/PS1 mice.
Choi
James J
JJ
Department Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Wang
Shougang
S
Brown
Truman R
TR
Small
Scott A
SA
Duff
Karen E K
KE
Konofagou
Elisa E
EE
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D019786:Gadolinium DTPA / Q000008:administration & dosage; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D010743:Phospholipids / Q000008:administration & dosage; D013459:Sulfur Hexafluoride / Q000008:administration & dosage; D014464:Ultrasonic Therapy / Q000379:methods*
D003287:Contrast Media; D010743:Phospholipids; C420843:contrast agent BR1; C064925:gadodiamide; D019786:Gadolinium DTPA; D013459:Sulfur Hexafluoride