药学学报, 2015, 50(1): 99-103
引用本文:
陈丽娟, 鲁翠涛, 赵应征, 杜丽娜, 金义光. 超声微泡用于脑胶质瘤靶向药物递送[J]. 药学学报, 2015, 50(1): 99-103.
CHEN Li-juan, LU Cui-tao, ZHAO Ying-zheng, DU Li-na, JIN Yi-guang. Ultrasonic microbubbles for glioma-targeted drug delivery[J]. Acta Pharmaceutica Sinica, 2015, 50(1): 99-103.

超声微泡用于脑胶质瘤靶向药物递送
陈丽娟1, 鲁翠涛1, 赵应征1, 杜丽娜2, 金义光1,2
1. 温州医科大学, 浙江 温州 325035;
2. 军事医学科学院放射与辐射医学研究所, 北京 100850
摘要:
本文用超声微泡可逆地有限开放血脑屏障 (blood-brain barrier, BBB), 为抗肿瘤药物的脑内靶向递送打下基础。建立脑胶质瘤大鼠模型, 探索低频超声 (1 MHz) 结合微泡对脑胶质瘤部位BBB开放的影响, 并与非超声条件下伊文思蓝 (Evans blue, EB) 渗透BBB对比。考察超声的时机和时长对BBB渗透和脑组织的损伤作用。考察脑胶质瘤生长期对BBB渗透性的影响。结果表明, 脑胶质瘤对BBB渗透性影响非常有限; 而超声微泡可短暂有限开放BBB, 并具有可逆性, 可促进EB和核磁增强造影剂渗透BBB。超声时长30 s最合适, 可开放BBB, 并且对脑组织不会造成明显损伤。药物需在超声前注射才能借助BBB开放进入脑。超声微泡可安全有效开放BBB, 控制时机和时长, 能促进药物进入脑胶质瘤和脑组织。
关键词:    超声      微泡      脑胶质瘤      血脑屏障     
Ultrasonic microbubbles for glioma-targeted drug delivery
CHEN Li-juan1, LU Cui-tao1, ZHAO Ying-zheng1, DU Li-na2, JIN Yi-guang1,2
1. Wenzhou Medical University, Wenzhou 325035, China;
2. Beijing Institute of Radiation Medicine, Beijing 100850, China
Abstract:
Ultrasonic microbubbles were used to open blood-brain barriers (BBB) with a reversed and limited behavior feature in the study, which could improve the brain-targeted delivery of anti-tumor drugs. The glioma rat model was prepared. Low-frequency ultrasound was combined with microbubbles to affect the permeability of BBB compared with the permeability of independently administered Evans blue (EB) crossing BBB. Time point and length of ultrasound were investigated whether they affect the permeability of BBB and the damage of brain tissue. The effect of the growth time of glioma on BBB permeability was explored. Only glioma had a very little impact on BBB permeability. However, ultrasonic microbubbles opened the BBB with the features of temporary, limited and reversed behavior and improved EB and magnetic resonance imaging contrast agent penetrating BBB. A length of 30 s ultrasound is appropriate for opening BBB and no damage of brain tissue. Drugs should be injected before ultrasound so that they enter into brain as BBB opening. Ultrasonic microbubbles can open BBB effectively and safely, which improve drugs penetrating BBB under proper time point and length.
Key words:    ultrasound    microbubble    glioma    blood-brain barrier   
收稿日期: 2014-09-15
基金项目: “重大新药创制”科技重大专项资助项目 (2012ZX09301003-001-009); 国家自然科学基金资助项目 (81360195).
通讯作者: 金义光
Email: jinyg@139.com
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参考文献:
[1] Hong Y, Zhou Y, Wang J, et al. Lead compound optimization strategy (4)-improving blood-brain barrier permeability through structural modification [J]. Acta Pharm Sin (药学学报), 2014, 49: 789-799.
[2] Aryal M, Arvanitis CD, Alexander PM, et al. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system [J]. Adv Drug Deliv Rev, 2014, 72: 94-109.
[3] Liu HL, Fan CH, Ting CY, et al. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview [J]. Theranostics, 2014, 4: 432-444.
[4] Konofagou EE. Optimization of the ultrasound-induced blood-brain barrier opening [J]. Theranostics, 2012, 2: 1223-1237.
[5] Fan CH, Ting CY, Lin HJ, et al. Spio-conjugated, doxorubicin-loaded micro-bubbles for concurrent MRI and focused-ultrasoundenhanced brain-tumor drug delivery [J]. Biomaterials, 2013, 34: 3706-3715.
[6] Treat LH, McDannold N, Zhang Y, et al. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma [J]. Ultrasound Med Biol, 2012, 38: 1716-1725.
[7] Sheikov N, McDannold N, Sharma S, et al. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium [J]. Ultrasound Med Biol, 2008, 34: 1093-1104.
[8] Zhao YZ, Liang HD, Mei XG, et al. Preparation, characterization and in vivo observation of phospholipid-based gas-filled microbubbles containing hirudin [J]. Ultrasound Med Biol, 2005, 31: 1237-1243.
[9] Do J, Foster D, Renier C, et al. Ex vivo Evans blue assessment of the blood brain barrier in three breast cancer brain metastasis models [J]. Breast Cancer Res Treat, 2014, 144: 93-101.
[10] Marquet F, Teichert T, Wu SY, et al. Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates [J]. PLoS One, 2014, 9: e84310.
[11] McDannold N, Zhang Y, Vykhodtseva N. Blood-brain barrier disruption and vascular damage induced by ultrasound bursts combined with microbubbles can be influenced by choice of anesthesia protocol [J]. Ultrasound Med Biol, 2011, 37: 1259-1270.
[12] Unger EC, Porter T, Culp W, et al. Therapeutic applications of lipid-coated microbubbles [J]. Adv Drug Deliv Rev, 2004, 56: 1291-1314.
[13] Aryal M, Vykhodtseva N, Zhang YZ, et al. Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model [J]. J Control Release, 2013, 169: 103-111.
[14] Park EJ, Zhang YZ, Vykhodtseva N, et al. Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model [J]. J Control Release, 2012, 163: 277-284.
[15] Hynynen K, McDannold N, Vykhodtseva N, et al. Non-invasive opening of BBB by focused ultrasound [J]. Acta Neurochir Suppl, 2003, 86: 555-558.
[16] Mesiwala AH, Farrell L, Wenzel HJ. High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo [J]. Ultrasound Med Biol, 2002, 28: 389-400.
[17] O'Reilly MA, Waspe AC, Ganguly M, et al. Focused-ultrasound disruption of the blood-brain barrier using closely-timed short pulses: influence of sonication parameters and injection rate [J]. Ultrasound Med Biol, 2011, 37: 587-594.
[18] O'Reilly MA, Hynynen K. Ultrasound enhanced drug delivery to the brain and central nervous system [J]. Int J Hyperthermia, 2012, 28: 386-396.
[19] O'Reilly MA, Waspe AC, Chopra R, et al. MRI-guided disruption of the blood-brain barrier using transcranial focused ultrasound in a rat model [J]. J Vis Exp, 2012, (61): pii: 3555.
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