超声靶向微泡破坏与载药/载基因纳米粒联合应用的生物物理学机制及应用研究进展
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摘要
超声靶向微泡破坏(ultrasound-targeted microbubble destruction, UTMD)能够安全、高效、简便地递送药物与基因,是当前超声医学领域的研究热点,其机制主要涉及超声辐照微泡引起的空化效应及其二级效应、内吞作用与声辐射力。近年来,随着生物医学材料科学迅猛发展,纳米载药系统取材更加广泛,制备方法愈发精良,载药量日益提高。将纳米载药系统与UTMD进行联合,可以扬长避短,为肿瘤等多种疾病的治疗带来新的思路与希望。本文旨在对UTMD与载药/载基因纳米粒联合应用的生物物理学机制及应用研究进行综述并提出展望。
Ultrasound-targeted microbubble destruction(UTMD) can deliver drugs and genes safely, efficiently and conveniently,which has already become present research focuses. Its mechanism is mainly related to cavitation effect and its secondary effects, endocytosis and acoustic radiation. In recent years, with the rapid development of biomedical materials science, the nanocarrier drug delivery system has become more extensive, the preparation methods have become more sophisticated, and the drug loading has increased. The combination of nanocarrier drug delivery system and UTMD can help circumvent weaknesses and bring new ideas and hopes for the treatment of tumors and other diseases. The purpose of this paper is to review the biophysical mechanisms and applications of UTMD combined with drug-and gene-loaded nanoparticles and to provide a perspective.
Ultrasound-targeted microbubble destruction(UTMD) can deliver drugs and genes safely, efficiently and conveniently,which has already become present research focuses. Its mechanism is mainly related to cavitation effect and its secondary effects, endocytosis and acoustic radiation. In recent years, with the rapid development of biomedical materials science, the nanocarrier drug delivery system has become more extensive, the preparation methods have become more sophisticated, and the drug loading has increased. The combination of nanocarrier drug delivery system and UTMD can help circumvent weaknesses and bring new ideas and hopes for the treatment of tumors and other diseases. The purpose of this paper is to review the biophysical mechanisms and applications of UTMD combined with drug-and gene-loaded nanoparticles and to provide a perspective.
引文
[1] Mullick CS, Lee T, Willmann JK. Ultrasound-guided drug delivery in cancer[J]. Ultrasonography, 2017, 36(3):171-184
[2] Tay LM, Xu C. Coating microbubbles with nanoparticles for medical imaging and drug delivery[J]. Nanomedicine, 2017, 12(2):91-94
[3] Danhier F, Feron O, Préat V. To exploit the tumor microenvironment:Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery[J]. Journal of Controlled Release, 2010, 148(2):135-146
[4] Collis J, Manasseh R, Liovic P, et al. Cavitation microstreaming and stress fields created by microbubbles[J]. Ultrasonics, 2010, 50(2):273-279
[5] Fan Z, Chen D, Deng CX. Characterization of the Dynamic Activities of a Population of Microbubbles Driven by Pulsed Ultrasound Exposure in Sonoporation[J]. Ultrasound in Medicine&Biology, 2014, 40(6):1260-1272
[6]赵应征.超声介导药物靶向递送系统[M].北京:化学工业出版社,2010
[7] Ferrara KW, Borden MA, Zhang H. Lipid-shelled vehicles:engineering for ultrasound molecular imaging and drug delivery[J]. Cheminform,2009, 40(47):881
[8] Chomas JE, Dayton PA, May D, et al. Optical observation of contrast agent destruction[J]. Applied Physics Letters, 2000, 77(7):1056-1058
[9] Prentice P, Cuschieri A, Dholakia K, et al. Membrane disruption by optically controlled microbubble cavitation[J]. Nature Physics, 2005,1(2):107
[10] Suslick KS. Sonochemistry[J]. Science, 2004, 35(23):1439-1445
[11] Mehierhumbert S, Bettinger T, Yan F, et al. Plasma membrane poration induced by ultrasound exposure:implication for drug delivery[J].Journal of Controlled Release, 2005, 104(1):213-222
[12] Wu J, Ross JP, Chiu JF. Reparable sonoporation generated by microstreaming[J]. Journal of the Acoustical Society of America, 2002,111(3):1460-1464
[13] Li F, Jin L, Wang H, et al. The dual effect of ultrasound-targeted microbubble destruction in mediating recombinant adeno-associated virus delivery in renal cell carcinoma:transfection enhancement and tumor inhibition[J]. Journal of Gene Medicine, 2014, 16(1-2):28-39
[14] Dalecki D, Raeman CH, Child SZ, et al. Hemolysis in vivo from exposure to pulsed ultrasound[J]. Ultrasound in Medicine&Biology,1997, 23(2):307-313
[15] Kobayashi N, Yasu T, Yamada S, et al. Endothelial cell injury in venule and capillary induced by contrast ultrasonography[J]. Ultrasound in Medicine&Biology, 2002, 28(7):949-956
[16] Juffermans LJM, Kamp O, Dijkmans PA, et al. Low-Intensity Ultrasound-Exposed Microbubbles Provoke Local Hyperpolarization of the Cell Membrane Via Activation of BK Ca, Channels[J]. Ultrasound in Medicine&Biology, 2008, 34(3):502-508
[17] Zupancic G, Ogden D, Magnus CJ, et al. Differential exocytosis from human endothelial cells evoked by high intracellular Ca2+, concentration[J]. Journal of Physiology, 2002, 544(Pt 3):741
[18] Lentacker I, Wang N, Vandenbroucke RE, et al. Ultrasound exposure of lipoplex loaded microbubbles facilitates direct cytoplasmic entry of the lipoplexes[J]. Molecular Pharmaceutics, 2009, 6(2):457
[19] Meijering B, Juffermans LWA, Henning R, et al. Ultrasound and Microbubble-Targeted Delivery of Macromolecules Is Regulated by Induction of Endocytosis and Pore Formation[J]. Circulation Research,2009, 104(5):679-687
[20] Dayton P, Klibanov A, Brandenburger G, et al. Acoustic radiation force in vivo:a mechanism to assist targeting of microbubbles[J]. Ultrasound in Medicine&Biology, 1999, 25(8):1195-1201
[21]杨阳,乔璐,严飞,等.超声辐射力推移靶向微泡的参数设置研究[J].中国超声医学杂志, 2015, 31(2):170-173
[22]平其能.纳米药物和纳米载体系统[J].中国新药杂志, 2002, 11(1):42-46
[23] Mullin LB, Phillips LC, Dayton PA. Nanoparticle delivery enhancement with acoustically activated microbubbles[J]. IEEE Transactions on Ultrasonics Ferroelectrics&Frequency Control, 2013, 60(1):65-77
[24]张明,赵应征,马卫成,等. FGF1纳米脂质体结合超声靶向微泡爆破技术治疗糖尿病心肌病的实验研究[J].中华心血管病杂志,2017, 45(5):427-433
[25] Lin L, Fan Y, Gao F, et al. UTMD-Promoted Co-Delivery of Gemcitabine and miR-21 Inhibitor by Dendrimer-Entrapped Gold Nanoparticles for Pancreatic Cancer Therapy[J]. Theranostics, 2018, 8(7):1923-1939
[26] Shi Q, Liu P, Sun Y, et al. siRNA delivery mediated by copolymer nanoparticles, phospholipid stabilized sulphur hexafluoride microbubbles and ultrasound[J]. Journal of Biomedical Nanotechnology,2014, 10(3):436-444
[27] Pérezherrero E, Fernándezmedarde A. Advanced targeted therapies in cancer:Drug nanocarriers, the future of chemotherapy[J]. European Journal of Pharmaceutics&Biopharmaceutics, 2015, 93:52-79
[28] Szebeni J, Baranyi L, Savay S, et al. Liposome-induced pulmonary hypertension:properties and mechanism of a complement-mediated pseudoallergic reaction[J]. Ajp Heart&Circulatory Physiology, 2000,279(3):H1319-28
[29]沈楠,朱宏.药物载体PAMAM树状大分子的毒理[J].材料导报,2012, 26(19):72-77
[30] Du J, Sun Y, Li FH, et al. Enhanced delivery of biodegradable mPEG-PLGA-PLL nanoparticles loading Cy3-labelled PDGF-BB siRNA by UTMD to rat retina[J]. Journal of Biosciences, 2017, 42(2):299
[31] Song W, Luo Y, Zhao Y, et al. Magnetic nanobubbles with potential for targeted drug delivery and trimodal imaging in breast cancer:an in vitro study[J]. Nanomedicine, 2017, 12(9):991-1009
[32]张桐民,曹兵生,王志媛,等.高强度聚焦超声协同紫杉醇热敏脂质体治疗小鼠Lewis肺癌[J].中华临床医师杂志(电子版), 2012,06(4):852-856
[33] Hobbs SK, Monsky WL, Yuan F, et al. Regulation of transport pathways in tumor vessels:role of tumor type and microenvironment[J].Proceedings of the National Academy of Sciences of the United States of America, 1998, 95(8):4607-4612
[34] Luo W, Wen G, Yang L, et al. Dual-targeted and pH-sensitive Doxorubicin Prodrug-Microbubble Complex with Ultrasound for Tumor Treatment[J]. Theranostics, 2017, 7(2):452-465
[35] Mayer CR, Geis NA, Katus HA, et al. Ultrasound targeted microbubble destruction for drug and gene delivery[J]. Expert Opinion on Drug Delivery, 2008, 5(10):1121-1138
[36] Heun Y, Hildebrand S, Heidsieck A, et al. Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery in vivo[J]. Theranostics, 2017,7(2):295
[37]史秋生,孙颖,张会萍,等.超声靶向微泡破碎和生物可降解纳米粒双靶向递送siRNAs的实验研究[J].中华超声影像学杂志, 2011,20(5):445-450
[38] Lin CY, Huang YL, Li JR, et al. Effects of Focused Ultrasound and Microbubbles on the Vascular Permeability of Nanoparticles Delivered into Mouse Tumors[J]. Ultrasound in Medicine&Biology, 2010,36(9):1460-1469
[39] Geers B, Lentacker I, Sanders NN, et al. Self-assembled liposomeloaded microbubbles:The missing link for safe and efficient ultrasound triggered drug-delivery[J]. Journal of Controlled Release, 2011,152(2):249-256
[40] Seo M, Gorelikov I, Williams R, et al. Microfluidic assembly of monodisperse, nanoparticle-incorporated perfluorocarbon microbubbles for medical imaging and therapy[J]. Langmuir the Acs Journal of Surfaces&Colloids, 2010, 26(17):13855
[41] Price RJ, Skyba DM, Kaul S, et al. Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound[J]. Circulation, 1998,98(13):1264-1267
[42] Chappell JC, Song J, Burke CW, et al. Targeted delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis[J]. Small, 2008, 4(10):1769-1777
[43] Lentacker I, Vandenbroucke RE, Lucas B, et al. New strategies for nucleic acid delivery to conquer cellular and nuclear membranes[J].Journal of Controlled Release, 2008, 132(3):279
[44] Ma J, Xing LX, Shen M, et al. Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel-poly(lactic-co-glycolic acid)-monomethoxypoly(ethylene glycol)nanocapsules with ultrasound-targeted microbubble destruction[J]. Molecular Medicine Reports, 2015, 11(4):2413-2420
[45] Xing L, Shi Q, Zheng K, et al. Ultrasound-Mediated Microbubble Destruction(UMMD)Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer[J]. Theranostics, 2016, 6(10):1573-1587
[46] Gong Y, Wang Z, Dong G, et al. Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits[J]. Drug Delivery, 2016, 23(7):2280-2289
[47] Huang WC, Shen MY, Chen HH, et al. Monocytic delivery of therapeutic oxygen bubbles for dual-modality treatment of tumor hypoxia[J]. Journal of Controlled Release, 2015, 220(Pt B):738-750
[48] Wang TY, Choe JW, Pu K, et al. Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer[J]. Journal of Controlled Release, 2015, 203:99
[49] Zhao YZ, Lin Q, Wong HL, et al. Glioma-targeted therapy using Cilengitide nanoparticles combined with UTMD enhanced delivery[J]. Journal of Controlled Release, 2016, 224:112-125
[50] Lin CY, Tseng HC, Shiu HR, et al. Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug[J]. International Journal of Nanomedicine, 2012,7(2):2143-2152
[51] Tian XQ, Ni XW, Xu HL, et al. Prevention of doxorubicin-induced cardiomyopathy using targeted Ma FGF mediated by nanoparticles combined with ultrasound-targeted MB destruction[J]. International Journal of Nanomedicine, 2017, 12:7103-7119
[52] Mead BP, Mastorakos P, Suk JS, et al. Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound[J]. Journal of Controlled Release, 2016, 223:109-117
[2] Tay LM, Xu C. Coating microbubbles with nanoparticles for medical imaging and drug delivery[J]. Nanomedicine, 2017, 12(2):91-94
[3] Danhier F, Feron O, Préat V. To exploit the tumor microenvironment:Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery[J]. Journal of Controlled Release, 2010, 148(2):135-146
[4] Collis J, Manasseh R, Liovic P, et al. Cavitation microstreaming and stress fields created by microbubbles[J]. Ultrasonics, 2010, 50(2):273-279
[5] Fan Z, Chen D, Deng CX. Characterization of the Dynamic Activities of a Population of Microbubbles Driven by Pulsed Ultrasound Exposure in Sonoporation[J]. Ultrasound in Medicine&Biology, 2014, 40(6):1260-1272
[6]赵应征.超声介导药物靶向递送系统[M].北京:化学工业出版社,2010
[7] Ferrara KW, Borden MA, Zhang H. Lipid-shelled vehicles:engineering for ultrasound molecular imaging and drug delivery[J]. Cheminform,2009, 40(47):881
[8] Chomas JE, Dayton PA, May D, et al. Optical observation of contrast agent destruction[J]. Applied Physics Letters, 2000, 77(7):1056-1058
[9] Prentice P, Cuschieri A, Dholakia K, et al. Membrane disruption by optically controlled microbubble cavitation[J]. Nature Physics, 2005,1(2):107
[10] Suslick KS. Sonochemistry[J]. Science, 2004, 35(23):1439-1445
[11] Mehierhumbert S, Bettinger T, Yan F, et al. Plasma membrane poration induced by ultrasound exposure:implication for drug delivery[J].Journal of Controlled Release, 2005, 104(1):213-222
[12] Wu J, Ross JP, Chiu JF. Reparable sonoporation generated by microstreaming[J]. Journal of the Acoustical Society of America, 2002,111(3):1460-1464
[13] Li F, Jin L, Wang H, et al. The dual effect of ultrasound-targeted microbubble destruction in mediating recombinant adeno-associated virus delivery in renal cell carcinoma:transfection enhancement and tumor inhibition[J]. Journal of Gene Medicine, 2014, 16(1-2):28-39
[14] Dalecki D, Raeman CH, Child SZ, et al. Hemolysis in vivo from exposure to pulsed ultrasound[J]. Ultrasound in Medicine&Biology,1997, 23(2):307-313
[15] Kobayashi N, Yasu T, Yamada S, et al. Endothelial cell injury in venule and capillary induced by contrast ultrasonography[J]. Ultrasound in Medicine&Biology, 2002, 28(7):949-956
[16] Juffermans LJM, Kamp O, Dijkmans PA, et al. Low-Intensity Ultrasound-Exposed Microbubbles Provoke Local Hyperpolarization of the Cell Membrane Via Activation of BK Ca, Channels[J]. Ultrasound in Medicine&Biology, 2008, 34(3):502-508
[17] Zupancic G, Ogden D, Magnus CJ, et al. Differential exocytosis from human endothelial cells evoked by high intracellular Ca2+, concentration[J]. Journal of Physiology, 2002, 544(Pt 3):741
[18] Lentacker I, Wang N, Vandenbroucke RE, et al. Ultrasound exposure of lipoplex loaded microbubbles facilitates direct cytoplasmic entry of the lipoplexes[J]. Molecular Pharmaceutics, 2009, 6(2):457
[19] Meijering B, Juffermans LWA, Henning R, et al. Ultrasound and Microbubble-Targeted Delivery of Macromolecules Is Regulated by Induction of Endocytosis and Pore Formation[J]. Circulation Research,2009, 104(5):679-687
[20] Dayton P, Klibanov A, Brandenburger G, et al. Acoustic radiation force in vivo:a mechanism to assist targeting of microbubbles[J]. Ultrasound in Medicine&Biology, 1999, 25(8):1195-1201
[21]杨阳,乔璐,严飞,等.超声辐射力推移靶向微泡的参数设置研究[J].中国超声医学杂志, 2015, 31(2):170-173
[22]平其能.纳米药物和纳米载体系统[J].中国新药杂志, 2002, 11(1):42-46
[23] Mullin LB, Phillips LC, Dayton PA. Nanoparticle delivery enhancement with acoustically activated microbubbles[J]. IEEE Transactions on Ultrasonics Ferroelectrics&Frequency Control, 2013, 60(1):65-77
[24]张明,赵应征,马卫成,等. FGF1纳米脂质体结合超声靶向微泡爆破技术治疗糖尿病心肌病的实验研究[J].中华心血管病杂志,2017, 45(5):427-433
[25] Lin L, Fan Y, Gao F, et al. UTMD-Promoted Co-Delivery of Gemcitabine and miR-21 Inhibitor by Dendrimer-Entrapped Gold Nanoparticles for Pancreatic Cancer Therapy[J]. Theranostics, 2018, 8(7):1923-1939
[26] Shi Q, Liu P, Sun Y, et al. siRNA delivery mediated by copolymer nanoparticles, phospholipid stabilized sulphur hexafluoride microbubbles and ultrasound[J]. Journal of Biomedical Nanotechnology,2014, 10(3):436-444
[27] Pérezherrero E, Fernándezmedarde A. Advanced targeted therapies in cancer:Drug nanocarriers, the future of chemotherapy[J]. European Journal of Pharmaceutics&Biopharmaceutics, 2015, 93:52-79
[28] Szebeni J, Baranyi L, Savay S, et al. Liposome-induced pulmonary hypertension:properties and mechanism of a complement-mediated pseudoallergic reaction[J]. Ajp Heart&Circulatory Physiology, 2000,279(3):H1319-28
[29]沈楠,朱宏.药物载体PAMAM树状大分子的毒理[J].材料导报,2012, 26(19):72-77
[30] Du J, Sun Y, Li FH, et al. Enhanced delivery of biodegradable mPEG-PLGA-PLL nanoparticles loading Cy3-labelled PDGF-BB siRNA by UTMD to rat retina[J]. Journal of Biosciences, 2017, 42(2):299
[31] Song W, Luo Y, Zhao Y, et al. Magnetic nanobubbles with potential for targeted drug delivery and trimodal imaging in breast cancer:an in vitro study[J]. Nanomedicine, 2017, 12(9):991-1009
[32]张桐民,曹兵生,王志媛,等.高强度聚焦超声协同紫杉醇热敏脂质体治疗小鼠Lewis肺癌[J].中华临床医师杂志(电子版), 2012,06(4):852-856
[33] Hobbs SK, Monsky WL, Yuan F, et al. Regulation of transport pathways in tumor vessels:role of tumor type and microenvironment[J].Proceedings of the National Academy of Sciences of the United States of America, 1998, 95(8):4607-4612
[34] Luo W, Wen G, Yang L, et al. Dual-targeted and pH-sensitive Doxorubicin Prodrug-Microbubble Complex with Ultrasound for Tumor Treatment[J]. Theranostics, 2017, 7(2):452-465
[35] Mayer CR, Geis NA, Katus HA, et al. Ultrasound targeted microbubble destruction for drug and gene delivery[J]. Expert Opinion on Drug Delivery, 2008, 5(10):1121-1138
[36] Heun Y, Hildebrand S, Heidsieck A, et al. Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery in vivo[J]. Theranostics, 2017,7(2):295
[37]史秋生,孙颖,张会萍,等.超声靶向微泡破碎和生物可降解纳米粒双靶向递送siRNAs的实验研究[J].中华超声影像学杂志, 2011,20(5):445-450
[38] Lin CY, Huang YL, Li JR, et al. Effects of Focused Ultrasound and Microbubbles on the Vascular Permeability of Nanoparticles Delivered into Mouse Tumors[J]. Ultrasound in Medicine&Biology, 2010,36(9):1460-1469
[39] Geers B, Lentacker I, Sanders NN, et al. Self-assembled liposomeloaded microbubbles:The missing link for safe and efficient ultrasound triggered drug-delivery[J]. Journal of Controlled Release, 2011,152(2):249-256
[40] Seo M, Gorelikov I, Williams R, et al. Microfluidic assembly of monodisperse, nanoparticle-incorporated perfluorocarbon microbubbles for medical imaging and therapy[J]. Langmuir the Acs Journal of Surfaces&Colloids, 2010, 26(17):13855
[41] Price RJ, Skyba DM, Kaul S, et al. Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound[J]. Circulation, 1998,98(13):1264-1267
[42] Chappell JC, Song J, Burke CW, et al. Targeted delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis[J]. Small, 2008, 4(10):1769-1777
[43] Lentacker I, Vandenbroucke RE, Lucas B, et al. New strategies for nucleic acid delivery to conquer cellular and nuclear membranes[J].Journal of Controlled Release, 2008, 132(3):279
[44] Ma J, Xing LX, Shen M, et al. Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel-poly(lactic-co-glycolic acid)-monomethoxypoly(ethylene glycol)nanocapsules with ultrasound-targeted microbubble destruction[J]. Molecular Medicine Reports, 2015, 11(4):2413-2420
[45] Xing L, Shi Q, Zheng K, et al. Ultrasound-Mediated Microbubble Destruction(UMMD)Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer[J]. Theranostics, 2016, 6(10):1573-1587
[46] Gong Y, Wang Z, Dong G, et al. Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits[J]. Drug Delivery, 2016, 23(7):2280-2289
[47] Huang WC, Shen MY, Chen HH, et al. Monocytic delivery of therapeutic oxygen bubbles for dual-modality treatment of tumor hypoxia[J]. Journal of Controlled Release, 2015, 220(Pt B):738-750
[48] Wang TY, Choe JW, Pu K, et al. Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer[J]. Journal of Controlled Release, 2015, 203:99
[49] Zhao YZ, Lin Q, Wong HL, et al. Glioma-targeted therapy using Cilengitide nanoparticles combined with UTMD enhanced delivery[J]. Journal of Controlled Release, 2016, 224:112-125
[50] Lin CY, Tseng HC, Shiu HR, et al. Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug[J]. International Journal of Nanomedicine, 2012,7(2):2143-2152
[51] Tian XQ, Ni XW, Xu HL, et al. Prevention of doxorubicin-induced cardiomyopathy using targeted Ma FGF mediated by nanoparticles combined with ultrasound-targeted MB destruction[J]. International Journal of Nanomedicine, 2017, 12:7103-7119
[52] Mead BP, Mastorakos P, Suk JS, et al. Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound[J]. Journal of Controlled Release, 2016, 223:109-117