Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain.
OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 μl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 μl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd-DTPA in the nonhuman primate used in this study was 1209.8 ± 193.6 mm(3). This volume was much larger than that achieved by conventional CED (568.6 ± 141.0 mm(3)). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd-DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders.
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Yui
Y
Mano
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Ryuta
R
Saito
Department of Biomedical Engineering, Tohoku University Graduate School of Biomedical Engineering;
Yoichi
Y
Haga
Tohoku University Micro System Integration Center (μSIC); and.
Tadao
T
Matsunaga
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Rong
R
Zhang
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Masashi
M
Chonan
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Shinya
S
Haryu
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Takuhiro
T
Shoji
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Aya
A
Sato
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Yukihiko
Y
Sonoda
Department of Biomedical Engineering, Tohoku University Graduate School of Biomedical Engineering;
Noriko
N
Tsuruoka
Department of Biomedical Engineering, Tohoku University Graduate School of Biomedical Engineering;
Keisuke
K
Nishiyachi
Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
Akira
A
Sumiyoshi
Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
Hiroi
H
Nonaka
Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
Ryuta
R
Kawashima
Department of Neurosurgery, Tohoku University Graduate School of Medicine;
Teiji
T
Tominaga
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018481:Convection; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005070:Evans Blue / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007260:Infusion Pumps; D008252:Macaca fascicularis; D008297:Male; D000072356:Parenchymal Tissue / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018084:Ultrasonography, Interventional / Q000295:instrumentation*
D005070:Evans Blue
CED = convection-enhanced delivery; EBD = Evans blue dye; FUS = focused ultrasound; Gd-DTPA = gadopentetate dimeglumine; Macaca fascicularis; PBS = phosphate-buffered saline; PZT = lead zirconate titanate; RARE = rapid acquisition with relaxation enhancement; UFD = ultrasound-facilitated delivery; Vd = volume of distribution; blood-brain barrier; central nervous system; convection-enhanced delivery; diagnostic and operative techniques; drug delivery; rat; ultrasound