© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 3605 www.advmat.de www.MaterialsViews.com wileyonlinelibrary.com COMMUNICATION Hung-Wei Yang, Mu-Yi Hua, Tsong-Long Hwang, Kun-Ju Lin, Chiung-Yin Huang, Rung-Ywan Tsai, Chen-Chi M. Ma, Po-Hung Hsu, Shiaw-Pyng Wey, Peng-Wei Hsu, Pin-Yuan Chen, Yin-Cheng Huang, Yu-Jen Lu, Tzu-Chen Yen, Li-Ying Feng, Chih-Wen Lin, Hao-Li Liu,* and Kuo-Chen Wei* Non-Invasive Synergistic Treatment of Brain Tumors by Targeted Chemotherapeutic Delivery and Amplified Focused Ultrasound-Hyperthermia Using Magnetic Nanographene Oxide Dr. H.-W. Yang, [+] Prof. M.-Y. Hua [+] Department of Chemical and Materials Engineering Chang Gung University Kuei-Shan, Tao-Yuan 33302, Taiwan, ROC Dr. H.-W. Yang, Prof. C.-C. M. Ma, C.-W. Lin Department of Chemical Engineering National Tsing Hua University Hsin-chu 30013, Taiwan, ROC Prof. T.-L. Hwang Graduate Institute of Natural Products Chang Gung University Kuei-Shan, Tao-Yuan 33302, Taiwan ROC Dr. K.-J. Lin, Dr. T.-C. Yen Animal Molecular Imaging Center and Department of Nuclear Medicine Chang Gung Memorial Hospital Kuei-Shan, Tao-Yuan 33305, Taiwan, ROC Dr. C.-Y. Huang, Dr. P.-W. Hsu, Dr. P.-Y. Chen, Dr. Y.-C. Huang, Dr. Y.-J. Lu, L.-Y. Feng, Dr. K.-C. Wei Department of Neurosurgery Chang Gung Memorial Hospital Kuei-Shan, Tao-Yuan 33305, Taiwan, ROC E-mail: kuochenwei@cgmh.org.tw Dr. R.-Y. Tsai Electronics and Optoelectronics Research Laboratories Industrial Technology Research Institute Hsin-chu 31040, Taiwan, ROC P.-H. Hsu, Prof. H.-L. Liu Department of Electrical Engineering Chang Gung University Kuei-Shan, Tao-Yuan 33302, Taiwan, ROC E-mail: haoliliu@mail.cgu.edu.tw Prof. S.-P. Wey Department of Medical Imaging and Radiological Sciences Chang Gung University Kuei-Shan, Tao-Yuan 33302, Taiwan, ROC [+] H.-W.Y. and M.-Y.H. contributed equally to this work. DOI: 10.1002/adma.201301046 Brain tumors have a low incidence but high lethality compared to other cancers. Glioblastoma multiforme (GBM) is the most common primary brain tumor and is highly malignant, [1,2] and most tumors recur locally within 2 cm of the original lesion. [3] The blood–brain barrier (BBB) prevents diffusion of toxic foreign substances into the brain parenchyma but also presents an almost impenetrable barrier to most chemotherapeutics. [4] Although ≈10–20% of an administered chemotherapeutic agent such as Carmustine (BCNU) and temozolomide can cross the BBB, progression-free survival is typically less than six months. Numerous innovative techniques have been used to overcome poor drug delivery, such as injection of hyperosmotic solution, [5] receptor-mediated transcytosis, [6] increased lipid solubility, and BBB opening. [7,8] When delivered non-specifically, chemothera- peutic agents cannot be administered at a dose sufficient to kill cancer cells without leading to undesired side effects in normal tissues. Thus targeted drug delivery (TDD) systems [9–11] and combined treatments [12,13] have been developed, that show great promise for improving cancer therapy outcomes. The intensive recent research on graphene for TDD is due to its many fascinating properties including high specific sur- face area (2630 m 2 g -1 ; loading capacity reaching 200%), [14] enriched oxygen-containing groups, high thermal conductivity ( ≈5000 W m -1 K -1 ), intrinsic biocompatibility, low cost, scal- able production, and facile biological/chemical functionaliza- tion. [15] Graphene oxide (GO) functionalized with polyethylene glycol (PEG), is highly soluble and stable in physiological solutions. [16] GO-based TDD systems capable of co-delivery of chemotherapeutic and photothermal agents to selected tumor regions to improve cancer cell termination have therefore been developed. [17,18] However, current GO-based TDD remains limited by: 1) the mainly surface-distribution of hyperthermia by near-infrared (NIR) photo-energy, with light penetration of only several millimeters; [19] 2) the reliance on passive dif- fusion or enhanced permeability and retention (EPR) in can- cerous tissue, limiting the effective drug dose; and 3) the lack of in vivo imaging of drug distribution. High-intensity focused- ultrasound (FUS) thermal ablation or alternating current (AC) magnetic-field-induced thermal therapy has been combined with chemotherapy. High-intensity FUS is a promising heat source for penetrating soft tissues, but ultrasonic energy is easily obstructed by bone structures, hindering accumulation of sufficient energy in brain or liver tumors; instead, high-inten- sity FUS also produces significant energy decay and reduces heating efficiency, and the surrounding bone tissues (skull or Adv. Mater. 2013, 25, 3605–3611