Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier opening and local gene delivery.


Author: Fan CH1, Chang EL1, Ting CY1, Lin YC2, Liao EC3, Huang CY4, Chang YC5, Chan HL3, Wei KC4, Yeh CK6

Affiliation: <sup>1</sup>Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.

<sup>2</sup>Institute of Molecular Medicine, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.

<sup>3</sup>Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.

<sup>4</sup>Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang Gung University, 5 Fu-shing Road, Kuei-Shan, Tao-Yuan 33305, Taiwan.

<sup>5</sup>Institute of Cellular and Organismic Biology, Academia Sinica, No. 128, Section 2, Academia Road, Nankang, Taipei 11529, Taiwan.

<sup>6</sup>Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan. Electronic address: ckyeh@mx.nthu.edu.tw.
Conference/Journal: Biomaterials.
Date published: 2016 Nov
Other:
 Volume ID: 106   ,  Pages: 46-57   ,  Special Notes: doi: 10.1016/j.biomaterials.2016.08.017. Epub  2016 Aug 12.   ,  Word Count: 215  
    Previous studies have demonstrated that circulating DNA-encapsulated microbubbles (MBs) combined with focused ultrasound (FUS) can be used for local blood-brain barrier (BBB) opening and gene delivery. However, few studies focused on how to increase the efficiency of gene delivery to brain tumors after the released gene penetrating the BBB. Here, we proposed the use of folate-conjugated DNA-loaded cationic MBs (FCMBs). When combined with FUS as a trigger for BBB opening, FCMBs were converted into nanometer-sized vesicles that were transported to the brain parenchyma. The FCMBs can selectively aggregate around tumor cells that overexpressed the folate receptor, thus enhancing gene delivery via folate-stimulated endocytosis. Our results confirmed that FCMBs can carry DNA on the surface of the MB shell and have good targeting ability on C6 glioma cells. In addition, the optimized FUS parameters for FCMBs-enhanced gene delivery were confirmed by cell experiments (center frequency = 1 MHz; acoustic pressure = 700 kPa; pulse repetition frequency = 5 Hz; cycle number = 10000; exposure time = 1 min; FCMBs concentration = 4 × 10(7) MB/mL). In vivo data also indicated that FCMBs show better gene transfection efficiency than MBs without folate conjugation and the traditional approach of directly injecting the gene. This study described our novel development of multifunctional MBs for FUS-triggered gene delivery/therapy.



KEYWORDS: Folate receptor targeting; Glioblastoma multiforme; Microbubble; Targeted gene therapy



PMID: 27544926  DOI: 10.1016/j.biomaterials.2016.08.017