Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier, opening and local gene delivery
Folate-conjugated gene-carrying microbubbles with focused ultrasound for concurrent blood-brain barrier, opening and local gene delivery
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DOI：
10.1016/j.biomaterials.2016.08.017
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发表时间：
2016-11-01
期刊：
影响因子：
14
通讯作者：
Yeh, Chih-Kuang
中科院分区：
文献类型：
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作者：
Fan, Ching-Hsiang;Chang, En-Ling;Yeh, Chih-Kuang
先前的研究表明，循环dna包封微泡（mb）结合聚焦超声（FUS）可用于局部血脑屏障（BBB）打开和基因传递。然而，很少有研究关注释放的基因穿透血脑屏障后如何提高基因传递到脑肿瘤的效率。在这里，我们建议使用叶酸偶联dna负载阳离子mb （FCMBs）。当与FUS结合作为血脑屏障打开的触发器时，FCMBs被转化为纳米大小的囊泡，并被运输到脑实质。FCMBs可以选择性地聚集在过表达叶酸受体的肿瘤细胞周围，从而通过叶酸刺激的内吞作用增强基因传递。我们的研究结果证实FCMBs可以在MB外壳表面携带DNA，对C6胶质瘤细胞具有良好的靶向能力。此外，通过细胞实验确定了FCMBs增强基因传递的优化FUS参数（中心频率= 1 MHz，声压= 700 kPa，脉冲重复频率= 5 Hz，循环次数= 10000，暴露时间= 1 min， FCMBs浓度= 4 × 10(7) MB/mL）。体内实验数据也表明，FCMBs的基因转染效率高于未结合叶酸的MBs和直接注射基因的传统方法。本研究描述了我们用于fus触发基因传递/治疗的多功能MBs的新进展。(C) 2016 Elsevier Ltd.版权所有。
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 x 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. (C) 2016 Elsevier Ltd. All rights reserved.