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J Med Biol Eng. 2015;35(2):156-164. Epub 2015 Apr 10.

Enhanced Therapeutic Epidermal Growth Factor Receptor (EGFR) Antibody Delivery via Pulsed Ultrasound with Targeting Microbubbles for Glioma Treatment.

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Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, 106 Taiwan.
Department of Electrical Engineering, Chang Gung University, Taoyuan, 333 Taiwan.
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan.
Department of Neurosurgery, Chang Gung University and Memorial Hospital, Linkou, Taoyuan, 333 Taiwan.
Department of Electrical Engineering, Chang Gung University, Taoyuan, 333 Taiwan ; Medical Imaging Research Center, Institute for Radiological Research and Health Aging Research Center, Chang Gung University, Taoyuan, 333 Taiwan.


Pulsed-mode ultrasound (pUS) in combination with intravenously (IV) administered microbubbles (MBs) can enhance local drug delivery by temporarily enhancing capillary permeability. This study evaluates the use of epidermal growth factor receptor (EGFR)-targeting MBs after pUS treatment to enhance the effects of therapeutic-EGFR antibody delivery to glioma tumor cells in mice. Three animal groups were compared: (1) IV-injected non-targeting MBs, (2) IV-injected targeting MBs, and (3) IV-injected targeting MBs combined with pUS treatment. All animals were analyzed using high-frequency small-animal US imaging. The mean halftime of circulating targeting MBs was significantly increased from 3.13 min of targeting bubble alone to 5.86 min by targeting MBs combined with pUS treatment, compared to 2.34 min for non-targeting MBs. Compared to targeting bubble administration alone, pUS exposure prior to injection of targeting MBs was also significantly better at suppressing tumor growth when monitored for up to 35 days (p < 0.05). The final relative tumor volumes were 2664, 700, and 188 mm3 for non-targeting MBs, targeting MBs, and targeting MBs combined with pUS treatment, respectively. pUS treatment prolonged the mean circulatory halftime of targeting MBs and enhanced the anti-tumor effect of EGFR antibodies in a human glioma model in mice. Targeting MBs combined with pUS treatment thus has potential for enhanced therapeutic antibody delivery for facilitating anti-glioma treatment.


Epidermal growth factor receptor; Microbubbles; Pulsed ultrasound

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