Abstract
Although gene therapy has great potential as a treatment for diseases, clinical trials are slowed down by the development of a safe and efficient gene delivery system. In this review, we will give an overview of the viral and nonviral vehicles used for drug and gene delivery, and the different nonviral delivery techniques, thereby focusing on delivery through ultrasound contrast agents.
The development of ultrasound contrast agents containing encapsulated microbubbles has increased the possibilities not only for diagnostic imaging, but for therapy as well. Microbubbles have been shown to be able to carry drugs and genes, and destruction of the bubbles by ultrasound will result in local release of their contents. Furthermore, ligands can be attached so that they can be targeted to a specific target tissue. The recent advances of microbubbles as vehicles for delivery of drugs and genes will be highlighted.
Keywords: drug delivery, gene therapy, microbubbles, nonviral, ultrasound, viral
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- Basta Giuseppina, Venneri Lucia, Lazzerini Guido, Pasanisi Emilio, Pianelli Mascia, Vesentini Nicoletta, Del Turco Serena, Kusmic Claudia, Picano Eugenio. In vitro modulation of intracellular oxidative stress of endothelial cells by diagnostic cardiac ultrasound. Cardiovasc Res. 2003 Apr 1;58(1):156–161. doi: 10.1016/s0008-6363(02)00665-x. [DOI] [PubMed] [Google Scholar]
- Bekeredjian Raffi, Chen Shuyuan, Frenkel Peter A., Grayburn Paul A., Shohet Ralph V. Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart. Circulation. 2003 Aug 11;108(8):1022–1026. doi: 10.1161/01.CIR.0000084535.35435.AE. [DOI] [PubMed] [Google Scholar]
- Bouakaz A., de Jong N., Cachard C., Jouini K. On the effect of lung filtering and cardiac pressure on the standard properties of ultrasound contrast agent. Ultrasonics. 1998 Feb;36(1-5):703–708. doi: 10.1016/s0041-624x(97)00137-6. [DOI] [PubMed] [Google Scholar]
- Chen Shuyuan, Shohet Ralph V., Bekeredjian Raffi, Frenkel Peter, Grayburn Paul A. Optimization of ultrasound parameters for cardiac gene delivery of adenoviral or plasmid deoxyribonucleic acid by ultrasound-targeted microbubble destruction. J Am Coll Cardiol. 2003 Jul 16;42(2):301–308. doi: 10.1016/s0735-1097(03)00627-2. [DOI] [PubMed] [Google Scholar]
- Fredericksen Brenda L., Wei Bangdong L., Yao Jian, Luo Tianci, Garcia J. Victor. Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus. J Virol. 2002 Nov;76(22):11440–11446. doi: 10.1128/JVI.76.22.11440-11446.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gramiak R., Shah P. M. Echocardiography of the aortic root. Invest Radiol. 1968 Sep-Oct;3(5):356–366. doi: 10.1097/00004424-196809000-00011. [DOI] [PubMed] [Google Scholar]
- Leong-Poi Howard, Christiansen Jonathan, Klibanov Alexander L., Kaul Sanjiv, Lindner Jonathan R. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation. 2003 Jan 28;107(3):455–460. doi: 10.1161/01.cir.0000044916.05919.8b. [DOI] [PubMed] [Google Scholar]
- Lindner J. R., Song J., Xu F., Klibanov A. L., Singbartl K., Ley K., Kaul S. Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes. Circulation. 2000 Nov 28;102(22):2745–2750. doi: 10.1161/01.cir.102.22.2745. [DOI] [PubMed] [Google Scholar]
- Luo D., Saltzman W. M. Synthetic DNA delivery systems. Nat Biotechnol. 2000 Jan;18(1):33–37. doi: 10.1038/71889. [DOI] [PubMed] [Google Scholar]
- Machan L, Burt HM, Hunter WL. Local delivery of chemotherapy: a supplement to existing cancer treatments. A case for surgical pastes and coated stents. Adv Drug Deliv Rev. 1997 Jul 7;26(2-3):199–207. doi: 10.1016/s0169-409x(97)00035-5. [DOI] [PubMed] [Google Scholar]
- Miller D. L., Gies R. A. Enhancement of ultrasonically-induced hemolysis by perfluorocarbon-based compared to air-based echo-contrast agents. Ultrasound Med Biol. 1998 Feb;24(2):285–292. doi: 10.1016/s0301-5629(97)00267-6. [DOI] [PubMed] [Google Scholar]
- Murthy Niren, Campbell Jean, Fausto Nelson, Hoffman Allan S., Stayton Patrick S. Design and synthesis of pH-responsive polymeric carriers that target uptake and enhance the intracellular delivery of oligonucleotides. J Control Release. 2003 May 20;89(3):365–374. doi: 10.1016/s0168-3659(03)00099-3. [DOI] [PubMed] [Google Scholar]
- Plank Christian, Schillinger Ulrike, Scherer Franz, Bergemann Christian, Rémy Jean-Serge, Krötz Florian, Anton Martina, Lausier Jim, Rosenecker Joseph. The magnetofection method: using magnetic force to enhance gene delivery. Biol Chem. 2003 May;384(5):737–747. doi: 10.1515/BC.2003.082. [DOI] [PubMed] [Google Scholar]
- Poliachik S. L., Chandler W. L., Mourad P. D., Bailey M. R., Bloch S., Cleveland R. O., Kaczkowski P., Keilman G., Porter T., Crum L. A. Effect of high-intensity focused ultrasound on whole blood with and without microbubble contrast agent. Ultrasound Med Biol. 1999 Jul;25(6):991–998. doi: 10.1016/s0301-5629(99)00043-5. [DOI] [PubMed] [Google Scholar]
- Porter T. R., Xie F. Therapeutic ultrasound for gene delivery. Echocardiography. 2001 May;18(4):349–353. doi: 10.1046/j.1540-8175.2001.00349.x. [DOI] [PubMed] [Google Scholar]
- Price R. J., Skyba D. M., Kaul S., Skalak T. C. Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation. 1998 Sep 29;98(13):1264–1267. doi: 10.1161/01.cir.98.13.1264. [DOI] [PubMed] [Google Scholar]
- Pulfer S. K., Ciccotto S. L., Gallo J. M. Distribution of small magnetic particles in brain tumor-bearing rats. J Neurooncol. 1999 Jan;41(2):99–105. doi: 10.1023/a:1006137523591. [DOI] [PubMed] [Google Scholar]
- Schmidt-Wolf Gabriele D., Schmidt-Wolf Ingo G. H. Non-viral and hybrid vectors in human gene therapy: an update. Trends Mol Med. 2003 Feb;9(2):67–72. doi: 10.1016/s1471-4914(03)00005-4. [DOI] [PubMed] [Google Scholar]
- Schumann Patricia A., Christiansen Jonathan P., Quigley Rachel M., McCreery Thomas P., Sweitzer Robert H., Unger Evan C., Lindner Jonathan R., Matsunaga Terry O. Targeted-microbubble binding selectively to GPIIb IIIa receptors of platelet thrombi. Invest Radiol. 2002 Nov;37(11):587–593. doi: 10.1097/00004424-200211000-00001. [DOI] [PubMed] [Google Scholar]
- Somia N., Verma I. M. Gene therapy: trials and tribulations. Nat Rev Genet. 2000 Nov;1(2):91–99. doi: 10.1038/35038533. [DOI] [PubMed] [Google Scholar]
- Unger E. C., Hersh E., Vannan M., Matsunaga T. O., McCreery T. Local drug and gene delivery through microbubbles. Prog Cardiovasc Dis. 2001 Jul-Aug;44(1):45–54. doi: 10.1053/pcad.2001.26443. [DOI] [PubMed] [Google Scholar]
- Verma I. M., Somia N. Gene therapy -- promises, problems and prospects. Nature. 1997 Sep 18;389(6648):239–242. doi: 10.1038/38410. [DOI] [PubMed] [Google Scholar]
- Villanueva F. S., Jankowski R. J., Klibanov S., Pina M. L., Alber S. M., Watkins S. C., Brandenburger G. H., Wagner W. R. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation. 1998 Jul 7;98(1):1–5. doi: 10.1161/01.cir.98.1.1. [DOI] [PubMed] [Google Scholar]
- Wu J. Temperature rise generated by ultrasound in the presence of contrast agent. Ultrasound Med Biol. 1998 Feb;24(2):267–274. doi: 10.1016/s0301-5629(97)00246-9. [DOI] [PubMed] [Google Scholar]
- Wu Junru. Theoretical study on shear stress generated by microstreaming surrounding contrast agents attached to living cells. Ultrasound Med Biol. 2002 Jan;28(1):125–129. doi: 10.1016/s0301-5629(01)00497-5. [DOI] [PubMed] [Google Scholar]
- Zhao N., Liu D. P., Liang C. C. Hot topics in adeno-associated virus as a gene transfer vector. Mol Biotechnol. 2001 Nov;19(3):229–237. doi: 10.1385/MB:19:3:229. [DOI] [PubMed] [Google Scholar]