title: Ultrasound/Magnetic Targeting with SPIO-DOX-Microbubble Complex for Image-Guided Drug Delivery in Brain Tumors.
abstract: One of the greatest challenges in the deployment of chemotherapeutic drugs against brain tumors is ensuring that sufficient drug concentrations reach the tumor, while minimizing drug accumulation at undesired sites. Recently, injection of therapeutic agents following blood-brain barrier (BBB) opening by focused ultrasound (FUS) with microbubbles (MBs) has been shown to enhance drug delivery in targeted brain regions. Nevertheless, the distribution and quantitative deposition of agents delivered to the brain are still hard to estimate. Based on our previous work on superparamagnetic iron oxide (SPIO)-loaded MBs, we present a novel theranostic complex of SPIO-Doxorubicin (DOX)-conjugated MB (SD-MB) for drug delivery to the brain. Magnetic labeling of the drug enables direct visualization via magnetic resonance imaging, and also facilitates magnetic targeting (MT) to actively enhance targeted deposition of the drug. In a rat glioma model, we demonstrated that FUS sonication can be used with SD-MBs to simultaneously facilitate BBB opening and allow dual ultrasound/magnetic targeting of chemotherapeutic agent (DOX) delivery. The accumulation of SD complex within brain tumors can be significantly enhanced by MT (25.7 fold of DOX, 7.6 fold of SPIO). The change in relaxation rate R2 (1/T2) within tumors was highly correlated with SD deposition as quantified by high performance liquid chromatography (R(2) = 0.93) and inductively coupled plasma-atomic emission spectroscopy (R(2) = 0.94), demonstrating real-time monitoring of DOX distribution. Our results suggest that SD-MBs can serve as multifunction agents to achieve advanced molecular theranostics.
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Ching-Hsiang
authors.initials: CH
authors.lastname: Fan
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Yu-Hang
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Ting
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Ho
authors.affiliation: 2. Department of Electrical Engineering, Chang-Gung University, 259 Wen-Hwa 1st Road, Kuei-Shan, Tao-Yuan 33302, Taiwan.
authors.forename: Po-Hung
authors.initials: PH
authors.lastname: Hsu
authors.affiliation: 2. Department of Electrical Engineering, Chang-Gung University, 259 Wen-Hwa 1st Road, Kuei-Shan, Tao-Yuan 33302, Taiwan.; 3. Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, 259 Wen-Hwa 1st Road, Kuei-Shan, Tao-Yuan 33302, Taiwan.
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Liu
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Yeh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005290:Ferric Compounds / Q000008:administration & dosage*; D005910:Glioma / Q000000981:diagnostic imaging / Q000188:drug therapy; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics; D045423:Microbubbles; D051381:Rats; D014463:Ultrasonography
chemical_list: D000970:Antineoplastic Agents; D005290:Ferric Compounds; C000499:ferric oxide; D004317:Doxorubicin
keywords: blood-brain barrier; brain tumor.; focused ultrasound; microbubbles; superparamagnetic iron oxide