Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model.
Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood-brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.
['Sun|Tao|T|', 'Zhang|Yongzhi|Y|', 'Power|Chanikarn|C|', 'Alexander|Phillip M|PM|', 'Sutton|Jonathan T|JT|', 'Aryal|Muna|M|', 'Vykhodtseva|Natalia|N|', 'Miller|Eric L|EL|', 'McDannold|Nathan J|NJ|']
D000162:Acoustics D000818:Animals D000903:Antibiotics, Antineoplastic D001812:Blood-Brain Barrier D001932:Brain Neoplasms D002232:Carbocyanines D003342:Corpus Striatum D004195:Disease Models, Animal D004317:Doxorubicin D016503:Drug Delivery Systems D005456:Fluorescent Dyes D005910:Glioma D006624:Hippocampus D008164:Luminescent Proteins D008279:Magnetic Resonance Imaging D008297:Male D045423:Microbubbles D058990:Molecular Targeted Therapy D011092:Polyethylene Glycols D051381:Rats D017207:Rats, Sprague-Dawley D014159:Transducers D014464:Ultrasonic Therapy D000069453:Ultrasonic Waves
drug delivery focused ultrasound treatment control acoustic cavitation blood–brain barrier