title: Magnetic-resonance imaging for kinetic analysis of permeability changes during focused ultrasound-induced blood-brain barrier opening and brain drug delivery.
abstract: Focused ultrasound (FUS) with the presence of microbubbles has been shown to induce transient and local opening of the blood-brain barrier (BBB) for the delivery of therapeutic molecules which normally cannot penetrate into the brain. The success of FUS brain-drug delivery relies on its integration with in-vivo imaging to monitor kinetic change of therapeutic molecules into the brain. In this study, we developed a dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) technique for kinetic analysis of delivered molecules during FUS-BBB opening. Three kinetic parameters (Ktrans, Ve, Kep) were characterized dynamically to describe BBB-permeability at two FUS exposure conditions (0.4 or 0.8MPa) over 24h. Ktrans, defined as the influx volume transfer constant from plasma to EES, and Ve, the EES volume fraction, were both found to be pressure-dependent. Ktrans and Ve showed a peak increase of 0.0086-0.0131min(-1) (for 0.4-0.8MPa pressure), and 0.0431-0.0692, respectively, immediately after FUS exposure. Both parameters subsequently decreased exponentially as a function of time, with estimated half-lives of decay of 2.89-5.3 and 2.2-4.93h, respectively. The kinetics of Kep, defined as the efflux rate constant from the extracellular extravascular space (EES) to the plasma, were complementary to Ktrans, with an initial decrease from 0.2010 to 0.1901min(-1) followed by a significantly longer recovery time (half-life of 17.39-99.92h). Our observations strongly supported the existence of imbalanced and mismatched kinetics of influx (Ktrans) and efflux (Kep) between the plasma and EES, indicating the existence of directional permeability during FUS-BBB opening. We further showed that kinetic change determined by DCE-MRI correlated well with the concentration of Evans Blue (EB)-albumin (coefficient of 0.74-0.89). These findings suggest that MRI kinetic monitoring may serve as an alternative method for in-vivo monitoring of pharmacokinetics and pharmacodynamics (PK/PD) change of therapeutic agents during drug delivery to the brain, and provide useful information for future optimization of FUS-BBB opening.
authors: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan; Department of Diagnostic Radiology and Intervention, Chang-Gung Memorial Hospital, Linkou, Taiwan.
authors: Wen-Yen
authors: WY
authors: Chai
authors: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan.
authors: Po-Chun
authors: PC
authors: Chu
authors: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan.
authors: Meng-Yen
authors: MY
authors: Tsai
authors: Department of Diagnostic Radiology and Intervention, Chang-Gung Memorial Hospital, Linkou, Taiwan; Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taiwan.
authors: Yu-Chun
authors: YC
authors: Lin
authors: Department of Medical Imaging and Radiological Sciences, Chang-Gung University, Taiwan.
authors: Jiun-Jie
authors: JJ
authors: Wang
authors: Department of Neurosurgery, Chang-Gung University and Memorial Hospital, Taoyuan, Taiwan.
authors: Kuo-Chen
authors: KC
authors: Wei
authors: Department of Diagnostic Radiology and Intervention, Chang-Gung Memorial Hospital, Linkou, Taiwan. Electronic address: yauwaiwu@ms4.hinet.net.
authors: Yau-Yau
authors: YY
authors: Wai
authors: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. Electronic address: haoliliu@mail.cgu.edu.tw.
authors: Hao-Li
authors: HL
authors: Liu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D004396:Coloring Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005070:Evans Blue / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D045423:Microbubbles; D017207:Rats, Sprague-Dawley; D014465:Ultrasonics / Q000379:methods*
chemical_list: D004396:Coloring Agents; D005070:Evans Blue
keywords: Blood–brain barrier; Focused ultrasound; Kinetic analysis; MRI; Microbubble