Drug-carrying microbubbles as a theranostic tool in convection-enhanced delivery for brain tumor therapy

// Pin-Yuan Chen 1, 5 , Chih-Kuang Yeh 2 , Po-Hung Hsu 3 , Chung-Yin Lin 4 , Chiung-Yin Huang 1 , Kuo-Chen Wei 1 and Hao-Li Liu 1, 3, 4 1 Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou Medical Center and School of Medicine, Chang Gung University, Taoyuan 333, Taiwan 2 Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan 3 Department of Electrical Engineering, Chang Gung University, Taoyuan 333, Taiwan 4 Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan 5 Department of Neurosurgery, Chang Gung Memorial Hospital, Keelung 204, Taiwan Correspondence to: Hao-Li Liu, email: haoliliu@mail.cgu.edu.tw Kuo-Chen Wei, email: kuochenwei@cgmh.org.tw Keywords: convection-enhanced delivery, microbubbles, magnetic resonance imaging, R2 relaxometry Received: September 14, 2016     Accepted: February 22, 2017     Published: March 15, 2017 ABSTRACT Convection-enhanced delivery (CED) is a promising technique for infusing a therapeutic agent through a catheter with a pressure gradient to create bulk flow for improving drug spread into the brain. So far, gadopentetate dimeglumine (Gd-DTPA) is the most commonly applied surrogate agent for predicting drug distribution through magnetic resonance imaging (MRI). However, Gd-DTPA provides only a short observation duration, and concurrent infusion provides an indirect measure of the exact drug distribution. In this study, we propose using microbubbles as a contrast agent for MRI monitoring, and evaluate their use as a drug-carrying vehicle to directly monitor the infused drug. Results show that microbubbles can provide excellent detectability through MRI relaxometry and accurately represent drug distribution during CED infusion. Compared with the short half-life of Gd-DTPA (1-2 hours), microbubbles allow an extended observation period of up to 12 hours. Moreover, microbubbles provide a sufficiently high drug payload, and glioma mice that underwent a CED infusion of microbubbles carrying doxorubicin presented considerable tumor growth suppression and a significantly improved survival rate. This study recommends microbubbles as a new theranostic tool for CED procedures.