Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening.
Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.
1 Department of Biomedical Engineering, Ultrasound and Elasticity Imaging Laboratory, Columbia University, New York, NY, USA.
Carlos
C
Sierra
1 Department of Biomedical Engineering, Ultrasound and Elasticity Imaging Laboratory, Columbia University, New York, NY, USA.
Camilo
C
Acosta
1 Department of Biomedical Engineering, Ultrasound and Elasticity Imaging Laboratory, Columbia University, New York, NY, USA.
Cherry
C
Chen
1 Department of Biomedical Engineering, Ultrasound and Elasticity Imaging Laboratory, Columbia University, New York, NY, USA.
Shih-Ying
SY
Wu
1 Department of Biomedical Engineering, Ultrasound and Elasticity Imaging Laboratory, Columbia University, New York, NY, USA.
Maria E
ME
Karakatsani
2 Department of Microbiology and Immunology, Columbia University, New York, NY, USA.
Manuel
M
Bernal
1 Department of Biomedical Engineering, Ultrasound and Elasticity Imaging Laboratory, Columbia University, New York, NY, USA.|3 Department of Radiology, Columbia University, New York, NY, USA.
Elisa E
EE
Konofagou
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005240:Feasibility Studies; D005452:Fluoresceins / Q000008:administration & dosage / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D018613:Microscopy, Confocal; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D013010:Sonication / Q000379:methods*
C503505:5-dodecanoylaminofluorescein; D003287:Contrast Media; D005452:Fluoresceins; D008055:Lipids; D014677:Pharmaceutical Vehicles
Blood–brain barrier; MRI; microscopy; targeted drug delivery; ultrasound