The status and prospect of ultrasound and microbubble-mediated gene delivery in cardiovascular disease gene therapy_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

QIN Xionghai , KANG Kai , SUN Lu ,  TIAN Hai ,  JIANG Shulin

Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, P.R.China;

Corresponding author：

TIAN Hai, Email: doctor_tianhai@163.com; JIANG Shulin, Email: sljiang36@163.com

Keywords：

Cardiovascular disease; gene therapy; delivery; targeted ultrasound microbubble destruction; ultrasound-mediated gene delivery

DOI：

10.7507/1007-4848.201612044

Video：

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Abstract Full text Figures/Tables Video References Cited by

With the development of molecular and cellar cardiology, gene therapy to cardiovascular disease has become the hot spot and the direction of study. Now, preclinical studies on ultrasound-mediated gene delivery (UMGD) in cardiovascular disease have achieved some success, but it is still hindered by a series of practical challenges for clinical translation. Even so, UMGD still holds the promise to cardiovascular disease in gene therapy for its non-invasiveness, accuracy, safety and ability to deliver multiple genes with repeated deliveries. In this review, we will focus on the basic principle, the current development, the future prospect and drawbacks of UMGD in the therapeutic applications of cardiovascular disease.

Citation： QIN Xionghai, KANG Kai, SUN Lu, TIAN Hai, JIANG Shulin. The status and prospect of ultrasound and microbubble-mediated gene delivery in cardiovascular disease gene therapy. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2018, 25(3): 256-261. doi: 10.7507/1007-4848.201612044 Copy

1.	Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation, 2015, 131(4): e29-322.
2.	O’Neill BJ, Rana SN, Bowman V. An integrated approach for vascular health: a call to action. Can J Cardiol, 2015, 31(1): 99-102.
3.	Rincon MY, VandenDriessche T, Chuah MK. Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation. Cardiovasc Res, 2015, 108(1): 4-20.
4.	Tilemann L, Ishikawa K, Weber T, et al. Gene therapy for heart failure. Circ Res, 2012, 110(5): 777-793.
5.	Rapti K, Chaanine AH, Hajjar RJ. Targeted gene therapy for the treatment of heart failure. Can J Cardiol, 2011, 27(3): 265-283.
6.	Shohet RV, Chen S, Zhou YT, et al. Echocardiographic destruction of albumin microbubbles directs gene delivery to the myocardium. Circulation, 2000, 101(22): 2554-2556.
7.	Panje CM, Wang DS, Willmann JK. Ultrasound and microbubblemediated gene delivery in cancer: progress and perspectives. Invest Radiol, 2013, 48(11): 755-769.
8.	Unger E, Porter T, Lindner J, et al. Cardiovascular drug delivery with ultrasound and microbubbles. Adv Drug Deliv Rev, 2014, 72: 110-126.
9.	Carson AR, McTiernan CF, Lavery L, et al. Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Res, 2012, 72(23): 6191-6199.
10.	Castle J, Butts M, Healey A, et al. Ultrasound-mediated targeted drug delivery: recent success and remaining challenges. Am J Physiol Heart Circ Physiol, 2013, 304(3): H350-H357.
11.	Cao WJ, Matkar PN, Chen HH, et al. Microbubbles and ultrasound: therapeutic applications in diabetic nephropathy. Adv Exp Med Biol, 2016, 880: 309-330.
12.	Bazan-Peregrino M, Arvanitis CD, Rifai B, et al. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. J Control Release, 2012, 157(2): 235-242.
13.	冯若. 超声空化与超声医学. 中华超声影像学杂志, 2004, 13(1): 63-65.
14.	钟渝, 刘政. 超声空化效应在治疗领域中的研究进展. 临床超声医学杂志, 2016, 18(4): 256-258.
15.	Prentice P, Cuschieri A, Dholakia K, et al. Membrane disruption byoptically controlled microbubble Cavitation. Nature Physics, 2005, 1(2): 107-110.
16.	李立华, 曹军英, 王占江. 医学超声微泡造影剂空化效应的研究进展.临床超声医学杂志, 2014, 16(1): 41-44．.
17.	牟芸, 姚磊, 郑哲岚, 等. 2006 年浙江省超声医学学术年会论文汇编. 2006．.
18.	刘珊, 伍烽, 邹建中, 等. 连续和脉冲高强度聚焦超声辐照离体牛晶状体致凝固性坏死的变化过程. 中国介入影像与治疗学, 2015, 12(6): 361-365.
19.	刘珊. 空化效应和血流对脉冲 HIFU 消融治疗的影响. 重庆医科大学, 2015. 1-20.
20.	Deshpande N, Needles A, Willmann JK. Molecular ultrasound imaging: current status and future directions. Clin Radiol, 2010, 65(7): 567-581.
21.	Stride E. Physical principles of microbubbles for ultrasound imaging and therapy. Front Neurol Neurosci, 2015, 36: 11-22.
22.	Gramiak R, Shah PM. Echocardiography of the aortic root. Invest Radiol, 1968, 3(5): 356-366.
23.	香丽萍, 穆玉明. 靶向超声造影剂在干细胞移植中的研究进展. 海南医学, 2015, 26(6): 843-846.
24.	王梦, 穆玉明. 靶向超声造影剂在冠心病中的应用. 医学研究杂志, 2015, 44(7): 4-6.
25.	唐红. 靶向超声造影剂在心血管领域的研究现状与展望. 西部医学, 2013, 25(4): 481-483.
26.	Shohet RV, Grayburn PA. Potential bioeffects of ultrasonic destruction of microbubble contrast agents. J Am Coll Cardiol, 2006, 47(7): 1469-a1470.
27.	Gaspar V, De Melo-Diogo D, Costa E, et al. Minicircle DNA vectors for gene therapy: advances and applications. Expert Opin Biol Ther, 2015, 15(3): 353-379.
28.	Bekeredjian R, Chen S, Frenkel PA, et al. Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart. Circulation, 2003, 108(8): 1022-1026.
29.	Kondo I, Ohmori K, Oshita A, et al. Treatment of acute myocardial infarction by hepatocyte growth factor gene transfer: the first demonstration of myocardial transfer of a " functional” gene using ultrasonic microbubble destruction. J Am Coll Cardiol, 2004, 44 (3): 644-653.
30.	Fujii H, Sun Z, Li SH, et al. Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice. JACC Cardiovasc Imaging, 2009, 2(7): 869-879.
31.	Fujii H, Li SH, Wu J, et al. Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair. Eur Heart J, 2011, 32(16): 2075-2084.
32.	曹治寰, 曹省, 宋宏宁, 等. 超声靶向破坏阳离子微泡介导 SDF-1α 基因转染提高外源性血管新生效应的研究. 临床超声医学杂志, 2015, 17(5):289-292.
33.	崔晶晶, 曹省陈, 金玲, 等. 核定位信号肽在超声靶向破坏微泡介导基因转染治疗犬心肌梗死中的促进作用. 临床超声医学杂志, 2017, 19(1): 1-6.
34.	邓倾. 超声靶向破坏阳离子微泡联合 NFκB 核定位基序促进 SDF-1α 基因转染治疗心肌梗死. 武汉大学, 2014. 1-20.
35.	Cui K, Yan T, Luo Q, et al. Ultrasound microbubble-mediated delivery of integrin-linked kinase gene improves endothelial progenitor cells dysfunction in pre-eclampsia. DNA Cell Biol, 2014, 33(5): 301-310.
36.	Kokhuis TJ, Skachkov I, Naaijkens BA, et al.Intravital microscopy of localized stem cell delivery using microbubbles and acoustic radiation force. Biotechnol Bioeng, 2015, 112(1): 220-227.
37.	李露. 微泡联合超声上调 SDF-1/CXCR4 促 MSCs 归巢修复缺血心肌的实验研究. 第三军医大学, 2015.1-20.
38.	Sun L, Huang CW, Wu J, et al. The use of cationic microbubbles to improve ultrasound-targeted gene delivery to the ischemic myocardium. Biomaterials, 2013, 34(8): 2107-2116.
39.	Lee PJ, Rudenko D, Kuliszewski MA, et al. Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathyby reducing apoptosis and fibrosis. Cardiovasc Res, 2014, 101(3): 423-433.
40.	Chen S, Chen J, Huang P, et al. Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction. Biochem Biophys Res Commun, 2015, 458(4):823-829.
41.	Liu Y, Li L, Su Q, et al. Ultrasound-targeted microbubble destruction enhances gene expression of microRNA-21 in Swine Heart via Intracoronary Delivery. Echocardiography, 2015, 32(9): 1407-1416.
42.	Su Q, Li L, Wang J, et al. Mechanism of programmed cell death factor 4/nuclear factor-κB signaling pathway in porcine coronary micro-embolization-induced cardiac dysfunction. Exp Biol Med (Maywood), 2015, 240(11): 1426-1433.
43.	Wang Y, Zhou J, Zhang Y, et al. Delivery of TFPI-2 using SonoVue and adenovirus results in the suppression of thrombosis and arterial re-stenosis. Exp Biol Med (Maywood), 2010, 235(9): 1072-1081.
44.	苏强. 超声微泡靶向介导 microRNA-21 调控 PDCD4/NF-κB/TNF-α 通路防治冠状动脉微栓塞致心肌损伤机制的研究. 广西医科大学, 2015.1-20.
45.	Chen S, Ding J, Yu C, et al. Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1. Gene Ther, 2007, 14(14): 1102-1110.
46.	Chen S, Shimoda M, Wang MY, et al. Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Ther, 2010, 17(11): 1411-1420.
47.	Chen S, Shimoda M, Chen J, et al. Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle, 2012, 11(4): 695-705.
48.	Chen S, Shimoda M, Chen J, et al. Ectopic transgenic expression of NKX2.2 induces differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle, 2012, 11(8): 1544-1553.
49.	Chen S, Bastarrachea RA, Roberts BJ, et al. Successful beta cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1. Cell Cycle, 2014, 13(7): 1145-1151.
50.	Castle JW, Kent KP, Fan Y, et al. Therapeutic ultrasound: increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids. Atherosclerosis, 2015, 241(1): 92-99.

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation, 2015, 131(4): e29-322.
2. O’Neill BJ, Rana SN, Bowman V. An integrated approach for vascular health: a call to action. Can J Cardiol, 2015, 31(1): 99-102.
3. Rincon MY, VandenDriessche T, Chuah MK. Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation. Cardiovasc Res, 2015, 108(1): 4-20.
4. Tilemann L, Ishikawa K, Weber T, et al. Gene therapy for heart failure. Circ Res, 2012, 110(5): 777-793.
5. Rapti K, Chaanine AH, Hajjar RJ. Targeted gene therapy for the treatment of heart failure. Can J Cardiol, 2011, 27(3): 265-283.
6. Shohet RV, Chen S, Zhou YT, et al. Echocardiographic destruction of albumin microbubbles directs gene delivery to the myocardium. Circulation, 2000, 101(22): 2554-2556.
7. Panje CM, Wang DS, Willmann JK. Ultrasound and microbubblemediated gene delivery in cancer: progress and perspectives. Invest Radiol, 2013, 48(11): 755-769.
8. Unger E, Porter T, Lindner J, et al. Cardiovascular drug delivery with ultrasound and microbubbles. Adv Drug Deliv Rev, 2014, 72: 110-126.
9. Carson AR, McTiernan CF, Lavery L, et al. Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Res, 2012, 72(23): 6191-6199.
10. Castle J, Butts M, Healey A, et al. Ultrasound-mediated targeted drug delivery: recent success and remaining challenges. Am J Physiol Heart Circ Physiol, 2013, 304(3): H350-H357.
11. Cao WJ, Matkar PN, Chen HH, et al. Microbubbles and ultrasound: therapeutic applications in diabetic nephropathy. Adv Exp Med Biol, 2016, 880: 309-330.
12. Bazan-Peregrino M, Arvanitis CD, Rifai B, et al. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. J Control Release, 2012, 157(2): 235-242.
13. 冯若. 超声空化与超声医学. 中华超声影像学杂志, 2004, 13(1): 63-65.
14. 钟渝, 刘政. 超声空化效应在治疗领域中的研究进展. 临床超声医学杂志, 2016, 18(4): 256-258.
15. Prentice P, Cuschieri A, Dholakia K, et al. Membrane disruption byoptically controlled microbubble Cavitation. Nature Physics, 2005, 1(2): 107-110.
16. 李立华, 曹军英, 王占江. 医学超声微泡造影剂空化效应的研究进展.临床超声医学杂志, 2014, 16(1): 41-44．.
17. 牟芸, 姚磊, 郑哲岚, 等. 2006 年浙江省超声医学学术年会论文汇编. 2006．.
18. 刘珊, 伍烽, 邹建中, 等. 连续和脉冲高强度聚焦超声辐照离体牛晶状体致凝固性坏死的变化过程. 中国介入影像与治疗学, 2015, 12(6): 361-365.
19. 刘珊. 空化效应和血流对脉冲 HIFU 消融治疗的影响. 重庆医科大学, 2015. 1-20.
20. Deshpande N, Needles A, Willmann JK. Molecular ultrasound imaging: current status and future directions. Clin Radiol, 2010, 65(7): 567-581.
21. Stride E. Physical principles of microbubbles for ultrasound imaging and therapy. Front Neurol Neurosci, 2015, 36: 11-22.
22. Gramiak R, Shah PM. Echocardiography of the aortic root. Invest Radiol, 1968, 3(5): 356-366.
23. 香丽萍, 穆玉明. 靶向超声造影剂在干细胞移植中的研究进展. 海南医学, 2015, 26(6): 843-846.
24. 王梦, 穆玉明. 靶向超声造影剂在冠心病中的应用. 医学研究杂志, 2015, 44(7): 4-6.
25. 唐红. 靶向超声造影剂在心血管领域的研究现状与展望. 西部医学, 2013, 25(4): 481-483.
26. Shohet RV, Grayburn PA. Potential bioeffects of ultrasonic destruction of microbubble contrast agents. J Am Coll Cardiol, 2006, 47(7): 1469-a1470.
27. Gaspar V, De Melo-Diogo D, Costa E, et al. Minicircle DNA vectors for gene therapy: advances and applications. Expert Opin Biol Ther, 2015, 15(3): 353-379.
28. Bekeredjian R, Chen S, Frenkel PA, et al. Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart. Circulation, 2003, 108(8): 1022-1026.
29. Kondo I, Ohmori K, Oshita A, et al. Treatment of acute myocardial infarction by hepatocyte growth factor gene transfer: the first demonstration of myocardial transfer of a " functional” gene using ultrasonic microbubble destruction. J Am Coll Cardiol, 2004, 44 (3): 644-653.
30. Fujii H, Sun Z, Li SH, et al. Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice. JACC Cardiovasc Imaging, 2009, 2(7): 869-879.
31. Fujii H, Li SH, Wu J, et al. Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair. Eur Heart J, 2011, 32(16): 2075-2084.
32. 曹治寰, 曹省, 宋宏宁, 等. 超声靶向破坏阳离子微泡介导 SDF-1α 基因转染提高外源性血管新生效应的研究. 临床超声医学杂志, 2015, 17(5):289-292.
33. 崔晶晶, 曹省陈, 金玲, 等. 核定位信号肽在超声靶向破坏微泡介导基因转染治疗犬心肌梗死中的促进作用. 临床超声医学杂志, 2017, 19(1): 1-6.
34. 邓倾. 超声靶向破坏阳离子微泡联合 NFκB 核定位基序促进 SDF-1α 基因转染治疗心肌梗死. 武汉大学, 2014. 1-20.
35. Cui K, Yan T, Luo Q, et al. Ultrasound microbubble-mediated delivery of integrin-linked kinase gene improves endothelial progenitor cells dysfunction in pre-eclampsia. DNA Cell Biol, 2014, 33(5): 301-310.
36. Kokhuis TJ, Skachkov I, Naaijkens BA, et al.Intravital microscopy of localized stem cell delivery using microbubbles and acoustic radiation force. Biotechnol Bioeng, 2015, 112(1): 220-227.
37. 李露. 微泡联合超声上调 SDF-1/CXCR4 促 MSCs 归巢修复缺血心肌的实验研究. 第三军医大学, 2015.1-20.
38. Sun L, Huang CW, Wu J, et al. The use of cationic microbubbles to improve ultrasound-targeted gene delivery to the ischemic myocardium. Biomaterials, 2013, 34(8): 2107-2116.
39. Lee PJ, Rudenko D, Kuliszewski MA, et al. Survivin gene therapy attenuates left ventricular systolic dysfunction in doxorubicin cardiomyopathyby reducing apoptosis and fibrosis. Cardiovasc Res, 2014, 101(3): 423-433.
40. Chen S, Chen J, Huang P, et al. Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction. Biochem Biophys Res Commun, 2015, 458(4):823-829.
41. Liu Y, Li L, Su Q, et al. Ultrasound-targeted microbubble destruction enhances gene expression of microRNA-21 in Swine Heart via Intracoronary Delivery. Echocardiography, 2015, 32(9): 1407-1416.
42. Su Q, Li L, Wang J, et al. Mechanism of programmed cell death factor 4/nuclear factor-κB signaling pathway in porcine coronary micro-embolization-induced cardiac dysfunction. Exp Biol Med (Maywood), 2015, 240(11): 1426-1433.
43. Wang Y, Zhou J, Zhang Y, et al. Delivery of TFPI-2 using SonoVue and adenovirus results in the suppression of thrombosis and arterial re-stenosis. Exp Biol Med (Maywood), 2010, 235(9): 1072-1081.
44. 苏强. 超声微泡靶向介导 microRNA-21 调控 PDCD4/NF-κB/TNF-α 通路防治冠状动脉微栓塞致心肌损伤机制的研究. 广西医科大学, 2015.1-20.
45. Chen S, Ding J, Yu C, et al. Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1. Gene Ther, 2007, 14(14): 1102-1110.
46. Chen S, Shimoda M, Wang MY, et al. Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy. Gene Ther, 2010, 17(11): 1411-1420.
47. Chen S, Shimoda M, Chen J, et al. Transient overexpression of cyclin D2/CDK4/GLP1 genes induces proliferation and differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle, 2012, 11(4): 695-705.
48. Chen S, Shimoda M, Chen J, et al. Ectopic transgenic expression of NKX2.2 induces differentiation of adult pancreatic progenitors and mediates islet regeneration. Cell Cycle, 2012, 11(8): 1544-1553.
49. Chen S, Bastarrachea RA, Roberts BJ, et al. Successful beta cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1. Cell Cycle, 2014, 13(7): 1145-1151.
50. Castle JW, Kent KP, Fan Y, et al. Therapeutic ultrasound: increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids. Atherosclerosis, 2015, 241(1): 92-99.

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The status and prospect of ultrasound and microbubble-mediated gene delivery in cardiovascular disease gene therapy

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