d Original Contribution EVALUATION OF DOSE DISTRIBUTION OF MOLECULAR DELIVERYAFTER BLOOD-BRAIN BARRIER DISRUPTION BY FOCUSED ULTRASOUND WITH TREATMENT PLANNING FENG-YI YANG,* CHIEN-CHENG CHEN, y YI-HSUAN KAO,* CHUAN-LIN CHEN,* CHIA-EN KO,* SHIH-CHENG HORNG, z and RAN-CHOU CHEN* x *Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan; y Department of Physical Medicine & Rehabilitation, Cheng Hsin Rehabilitation Medical Center, Taipei, Taiwan; z Department of Computer Science & Information Engineering, Chaoyang University of Technology,Taichung County, Taiwan; and x Department of Radiology, Taipei City Hospital, Taipei, Taiwan (Received 4 July 2012; revised 18 November 2012; in final form 28 November 2012) Abstract—The permeability of the blood-brain barrier (BBB) can be enhanced by focused ultrasound (FUS) in localized regions with applications of ultrasound contrast agent (UCA). The purpose of this study was to evaluate the dose distribution of Evans blue (EB) in the targeted brain by sonication with treatment strategy. FUS exposure was applied with an ultrasound frequency of 1 MHz, a 5% duty cycle and a repetition frequency of 1 Hz. Single sonication with two doses of UCA and two sonications at the same location or an interval of 3 mm to induce BBB disruption for assessing dose distribution. The permeability of the BBB was measured quantitatively based on EB extravasation. Gadolinium deposition was monitored by contrast enhanced MR imaging for dose distribu- tion of the focal plane. Hematoxylin and eosin staining was performed for histologic observation. No significant difference was found for EB in the focal regions between the single sonication with UCA at a dose of 300 mL/kg and repeated sonication with UCA at a lower dose of 150 mL/kg. There was a sharper dose distribution in the brain with repeated sonication at the same location, compared with the brain receiving two sonications at an interval of 3 mm. Compared with a single sonication with UCA at a dose of 150 mL/kg, the histologic evaluation of the sonicated regions indicated that more erythrocytes were seen in the brain treated with single sonication at a higher dose of 300 mL/kg or repeated sonication at a dose of 150 mL/kg. This study demonstrated that the dose distribution of molecular delivery could be regulated by sonication with treatment planning. (E-mail: fyyang@ym.edu. tw) Ó 2013 World Federation for Ultrasound in Medicine & Biology. Key Words: Focused ultrasound, Multiple sonications, Blood-brain barrier disruption, Dose distribution, Treatment planning. INTRODUCTION The blood-brain barrier (BBB) keeps the brain healthy, and its impermeability makes the treatment of brain diseases using chemotherapy difficult. The BBB is a key factor involved in the delivery of drugs to the human brain (Pardridge 2005). Chemical modification of potent agents is able to increase permeability, but the drugs may have undesired dose-limiting side effects due to their spread over a large volume within the brain. The combi- nation of focused ultrasound (FUS) and ultrasound contrast agent (UCA) may provide a non-invasive, tran- sient and localized method for opening the BBB (Hynynen et al. 2001; Hynynen et al. 2005). Passive drug release into tumor tissues following extravasation from leaky tumor vessels allows most drug delivery systems to target tumor tissue (Allen and Cullis 2004). Liposome encapsulated drugs are used to increase drug levels in tumors, in comparison with drugs used to treat normal tissues. Some chemical formulations use specific ligands or antibodies to enhance intracellular uptake of these carriers (Park et al. 2002). Different proto- cols for hyperthermia-mediated drug release from lipo- somes could permit intra-tumoral drug distribution to be controlled in real time. Drug accumulation patterns may influence anti-tumor efficacy (Ponce et al. 2007); hence, uniform temperature regulation in this technology Address correspondence to: Feng-Yi Yang, Department of Biomedical Imaging and Radiological Sciences, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan. E-mail: fyyang@ym.edu.tw 620 Ultrasound in Med. & Biol., Vol. 39, No. 4, pp. 620–627, 2013 Copyright Ó 2013 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter http://dx.doi.org/10.1016/j.ultrasmedbio.2012.11.027