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Bouakaz A, Michel Escoffre J. From concept to early clinical trials: 30 years of microbubble-based ultrasound-mediated drug delivery research. Adv Drug Deliv Rev 2024; 206:115199. [PMID: 38325561 DOI: 10.1016/j.addr.2024.115199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/03/2024] [Accepted: 02/02/2024] [Indexed: 02/09/2024]
Abstract
Ultrasound mediated drug delivery, a promising therapeutic modality, has evolved remarkably over the past three decades. Initially designed to enhance contrast in ultrasound imaging, microbubbles have emerged as a main vector for drug delivery, offering targeted therapy with minimized side effects. This review addresses the historical progression of this technology, emphasizing the pivotal role microbubbles play in augmenting drug extravasation and targeted delivery. We explore the complex mechanisms behind this technology, from stable and inertial cavitation to diverse acoustic phenomena, and their applications in medical fields. While the potential of ultrasound mediated drug delivery is undeniable, there are still challenges to overcome. Balancing therapeutic efficacy and safety and establishing standardized procedures are essential areas requiring attention. A multidisciplinary approach, gathering collaborations between researchers, engineers, and clinicians, is important for exploiting the full potential of this technology. In summary, this review highlights the potential of using ultrasound mediated drug delivery in improving patient care across various medical conditions.
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Affiliation(s)
- Ayache Bouakaz
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.
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Choromańska A, Chwiłkowska A, Kulbacka J, Baczyńska D, Rembiałkowska N, Szewczyk A, Michel O, Gajewska-Naryniecka A, Przystupski D, Saczko J. Modifications of Plasma Membrane Organization in Cancer Cells for Targeted Therapy. Molecules 2021; 26:1850. [PMID: 33806009 PMCID: PMC8037978 DOI: 10.3390/molecules26071850] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 12/11/2022] Open
Abstract
Modifications of the composition or organization of the cancer cell membrane seem to be a promising targeted therapy. This approach can significantly enhance drug uptake or intensify the response of cancer cells to chemotherapeutics. There are several methods enabling lipid bilayer modifications, e.g., pharmacological, physical, and mechanical. It is crucial to keep in mind the significance of drug resistance phenomenon, ion channel and specific receptor impact, and lipid bilayer organization in planning the cell membrane-targeted treatment. In this review, strategies based on cell membrane modulation or reorganization are presented as an alternative tool for future therapeutic protocols.
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Affiliation(s)
- Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Agnieszka Chwiłkowska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Dagmara Baczyńska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Nina Rembiałkowska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Anna Szewczyk
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Olga Michel
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Agnieszka Gajewska-Naryniecka
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Dawid Przystupski
- Department of Paediatric Bone Marrow Transplantation, Oncology and Haematology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
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Gouarderes S, Mingotaud AF, Vicendo P, Gibot L. Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site. Expert Opin Drug Deliv 2020; 17:1703-1726. [PMID: 32838565 DOI: 10.1080/17425247.2020.1814735] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Modern comprehensive studies of tumor microenvironment changes allowed scientists to develop new and more efficient strategies that will improve anticancer drug delivery on site. The tumor microenvironment, especially the dense extracellular matrix, has a recognized capability to hamper the penetration of conventional drugs. Development and co-applications of strategies aiming at remodeling the tumor microenvironment are highly demanded to improve drug delivery at the tumor site in a therapeutic prospect. AREAS COVERED Increasing indications suggest that classical physical approaches such as exposure to ionizing radiations, hyperthermia or light irradiation, and emerging ones as sonoporation, electric field or cold plasma technology can be applied as standalone or associated strategies to remodel the tumor microenvironment. The impacts on vasculature and extracellular matrix remodeling of these physical approaches will be discussed with the goal to improve nanotherapeutics delivery at the tumor site. EXPERT OPINION Physical approaches to modulate vascular properties and remodel the extracellular matrix are of particular interest to locally control and improve drug delivery and thus increase its therapeutic index. They are particularly powerful as adjuvant to nanomedicine delivery; the development of these technologies could have extremely widespread implications for cancer treatment.[Figure: see text].
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Affiliation(s)
- Sara Gouarderes
- Laboratoire des IMRCP, Université de Toulouse, CNRS UMR 5623, Université Toulouse III - Paul Sabatier , Toulouse, France
| | - Anne-Françoise Mingotaud
- Laboratoire des IMRCP, Université de Toulouse, CNRS UMR 5623, Université Toulouse III - Paul Sabatier , Toulouse, France
| | - Patricia Vicendo
- Laboratoire des IMRCP, Université de Toulouse, CNRS UMR 5623, Université Toulouse III - Paul Sabatier , Toulouse, France
| | - Laure Gibot
- Laboratoire des IMRCP, Université de Toulouse, CNRS UMR 5623, Université Toulouse III - Paul Sabatier , Toulouse, France
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A review of ultrasound-mediated microbubbles technology for cancer therapy: a vehicle for chemotherapeutic drug delivery. JOURNAL OF RADIOTHERAPY IN PRACTICE 2020. [DOI: 10.1017/s1460396919000633] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
AbstractBackground:The unique behaviour of microbubbles under ultrasound acoustic pressure makes them useful agents for drug and gene delivery. Several studies have demonstrated the potential application of microbubbles as a non-invasive, safe and effective technique for targeted delivery of drugs and genes. The drugs can be incorporated into the microbubbles in several different approaches and then carried to the site of interest where it can be released by destruction of the microbubbles using ultrasound to achieve the required therapeutic effect.Methods:The objective of this article is to report on a review of the recent advances of ultrasound-mediated microbubbles as a vehicle for delivering drugs and genes and its potential application for the treatment of cancer.Conclusion:Ultrasound-mediated microbubble technology has the potential to significantly improve chemotherapy drug delivery to treatment sites with minimal side effects. Moreover, the technology can induce temporary and reversible changes in the permeability of cells and vessels, thereby allowing for drug delivery in a spatially localised region which can improve the efficiency of drugs with poor bioavailability due to their poor absorption, rapid metabolism and rapid systemic elimination.
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Applications of Ultrasound to Stimulate Therapeutic Revascularization. Int J Mol Sci 2019; 20:ijms20123081. [PMID: 31238531 PMCID: PMC6627741 DOI: 10.3390/ijms20123081] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 06/20/2019] [Accepted: 06/21/2019] [Indexed: 12/13/2022] Open
Abstract
Many pathological conditions are characterized or caused by the presence of an insufficient or aberrant local vasculature. Thus, therapeutic approaches aimed at modulating the caliber and/or density of the vasculature by controlling angiogenesis and arteriogenesis have been under development for many years. As our understanding of the underlying cellular and molecular mechanisms of these vascular growth processes continues to grow, so too do the available targets for therapeutic intervention. Nonetheless, the tools needed to implement such therapies have often had inherent weaknesses (i.e., invasiveness, expense, poor targeting, and control) that preclude successful outcomes. Approximately 20 years ago, the potential for using ultrasound as a new tool for therapeutically manipulating angiogenesis and arteriogenesis began to emerge. Indeed, the ability of ultrasound, especially when used in combination with contrast agent microbubbles, to mechanically manipulate the microvasculature has opened several doors for exploration. In turn, multiple studies on the influence of ultrasound-mediated bioeffects on vascular growth and the use of ultrasound for the targeted stimulation of blood vessel growth via drug and gene delivery have been performed and published over the years. In this review article, we first discuss the basic principles of therapeutic ultrasound for stimulating angiogenesis and arteriogenesis. We then follow this with a comprehensive cataloging of studies that have used ultrasound for stimulating revascularization to date. Finally, we offer a brief perspective on the future of such approaches, in the context of both further research development and possible clinical translation.
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Skachkov I, Luan Y, van Tiel ST, van der Steen AFW, de Jong N, Bernsen MR, Kooiman K. SPIO labeling of endothelial cells using ultrasound and targeted microbubbles at diagnostic pressures. PLoS One 2018; 13:e0204354. [PMID: 30235336 PMCID: PMC6147550 DOI: 10.1371/journal.pone.0204354] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 09/06/2018] [Indexed: 02/07/2023] Open
Abstract
In vivo cell tracking of therapeutic, tumor, and endothelial cells is an emerging field and a promising technique for imaging cardiovascular disease and cancer development. Site-specific labeling of endothelial cells with the MRI contrast agent superparamagnetic iron oxide (SPIO) in the absence of toxic agents is challenging. Therefore, the aim of this in vitro study was to find optimal parameters for efficient and safe SPIO-labeling of endothelial cells using ultrasound-activated CD31-targeted microbubbles for future MRI tracking. Ultrasound at a frequency of 1 MHz (10,000 cycles, repetition rate of 20 Hz) was used for varying applied peak negative pressures (10–160 kPa, i.e. low mechanical index (MI) of 0.01–0.16), treatment durations (0–30 s), time of SPIO addition (-5 min– 15 min with respect to the start of the ultrasound), and incubation time after SPIO addition (5 min– 3 h). Iron specific Prussian Blue staining in combination with calcein-AM based cell viability assays were applied to define the most efficient and safe conditions for SPIO-labeling. Optimal SPIO labeling was observed when the ultrasound parameters were 40 kPa peak negative pressure (MI 0.04), applied for 30 s just before SPIO addition (0 min). Compared to the control, this resulted in an approximate 12 times increase of SPIO uptake in endothelial cells in vitro with 85% cell viability. Therefore, ultrasound-activated targeted ultrasound contrast agents show great potential for effective and safe labeling of endothelial cells with SPIO.
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Affiliation(s)
- Ilya Skachkov
- Department of Biomedical Engineering, Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands
| | - Ying Luan
- Department of Biomedical Engineering, Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands
| | - Sandra T. van Tiel
- Department of Radiology & Nucleair Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Antonius F. W. van der Steen
- Department of Biomedical Engineering, Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands
- Laboratory of Acoustical Wavefield Imaging, Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands
| | - Nico de Jong
- Department of Biomedical Engineering, Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands
- Laboratory of Acoustical Wavefield Imaging, Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands
| | - Monique R. Bernsen
- Department of Radiology & Nucleair Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Klazina Kooiman
- Department of Biomedical Engineering, Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands
- * E-mail:
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Erikson JM, Valente AJ, Mummidi S, Kandikattu HK, DeMarco VG, Bender SB, Fay WP, Siebenlist U, Chandrasekar B. Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling. J Biol Chem 2017; 292:2345-2358. [PMID: 28053087 DOI: 10.1074/jbc.m116.764522] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 12/07/2016] [Indexed: 11/06/2022] Open
Abstract
Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-κB and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.
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Affiliation(s)
- John M Erikson
- From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Anthony J Valente
- From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Srinivas Mummidi
- From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229
| | - Hemanth Kumar Kandikattu
- the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211.,the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201
| | - Vincent G DeMarco
- the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211.,the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.,the Departments of Medical Pharmacology and Physiology and
| | - Shawn B Bender
- the Departments of Medical Pharmacology and Physiology and.,the Dalton Cardiovascular Research Center, Columbia, Missouri 65201, and.,Biomedical Sciences, University of Missouri School of Medicine, Columbia, Missouri 65211
| | - William P Fay
- the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211.,the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.,the Departments of Medical Pharmacology and Physiology and
| | - Ulrich Siebenlist
- Biomedical Sciences, University of Missouri School of Medicine, Columbia, Missouri 65211.,the Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892
| | - Bysani Chandrasekar
- the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211, .,the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201.,the Departments of Medical Pharmacology and Physiology and.,the Dalton Cardiovascular Research Center, Columbia, Missouri 65201, and
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8
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Seda R, Li DS, Fowlkes JB, Bull JL. Characterization of Bioeffects on Endothelial Cells under Acoustic Droplet Vaporization. ULTRASOUND IN MEDICINE & BIOLOGY 2015; 41:3241-52. [PMID: 26403698 PMCID: PMC4794981 DOI: 10.1016/j.ultrasmedbio.2015.07.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 06/19/2015] [Accepted: 07/16/2015] [Indexed: 05/11/2023]
Abstract
Gas embolotherapy is achieved by locally vaporizing microdroplets through acoustic droplet vaporization, which results in bubbles that are large enough to occlude blood flow directed to tumors. Endothelial cells, lining blood vessels, can be affected by these vaporization events, resulting in cell injury and cell death. An idealized monolayer of endothelial cells was subjected to acoustic droplet vaporization using a 3.5-MHz transducer and dodecafluoropentane droplets. Treatments included insonation pressures that varied from 2 to 8 MPa (rarefactional) and pulse lengths that varied from 4 to 16 input cycles. The bubble cloud generated was directly dependent on pressure, but not on pulse length. Cellular damage increased with increasing bubble cloud size, but was limited to the bubble cloud area. These results suggest that vaporization near the endothelium may impact the vessel wall, an effect that could be either deleterious or beneficial depending on the intended overall therapeutic application.
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Affiliation(s)
- Robinson Seda
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - David S Li
- Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA
| | - J Brian Fowlkes
- Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Joseph L Bull
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
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Sutton JT, Raymond JL, Verleye MC, Pyne-Geithman GJ, Holland CK. Pulsed ultrasound enhances the delivery of nitric oxide from bubble liposomes to ex vivo porcine carotid tissue. Int J Nanomedicine 2014; 9:4671-83. [PMID: 25336947 PMCID: PMC4200074 DOI: 10.2147/ijn.s63850] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Ultrasound-mediated drug delivery is a novel technique for enhancing the penetration of drugs into diseased tissue beds noninvasively. By encapsulating drugs into microsized and nanosized liposomes, the therapeutic can be shielded from degradation within the vasculature until delivery to a target site by ultrasound exposure. Traditional in vitro or ex vivo techniques to quantify this delivery profile include optical approaches, cell culture, and electrophysiology. Here, we demonstrate an approach to characterize the degree of nitric oxide (NO) delivery to porcine carotid tissue by direct measurement of ex vivo vascular tone. An ex vivo perfusion model was adapted to assess ultrasound-mediated delivery of NO. This potent vasodilator was coencapsulated with inert octafluoropropane gas to produce acoustically active bubble liposomes. Porcine carotid arteries were excised post mortem and mounted in a physiologic buffer solution. Vascular tone was assessed in real time by coupling the artery to an isometric force transducer. NO-loaded bubble liposomes were infused into the lumen of the artery, which was exposed to 1 MHz pulsed ultrasound at a peak-to-peak acoustic pressure amplitude of 0.34 MPa. Acoustic cavitation emissions were monitored passively. Changes in vascular tone were measured and compared with control and sham NO bubble liposome exposures. Our results demonstrate that ultrasound-triggered NO release from bubble liposomes induces potent vasorelaxation within porcine carotid arteries (maximal relaxation 31%±8%), which was significantly stronger than vasorelaxation due to NO release from bubble liposomes in the absence of ultrasound (maximal relaxation 7%±3%), and comparable with relaxation due to 12 μM sodium nitroprusside infusions (maximal relaxation 32%±3%). This approach is a valuable mechanistic tool for assessing the extent of drug release and delivery to the vasculature caused by ultrasound.
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Affiliation(s)
- J T Sutton
- University of Cincinnati, Biomedical Engineering Program, Cincinnati, OH, USA
| | - J L Raymond
- University of Cincinnati, Biomedical Engineering Program, Cincinnati, OH, USA
| | - M C Verleye
- University of Notre Dame Department of Chemical Engineering, Notre Dame, IN, USA
| | - G J Pyne-Geithman
- University of Cincinnati, College of Medicine, Department of Neurosurgery and the University of Cincinnati Neuroscience Institute, and Mayfield Clinic, Cincinnati, OH, USA
| | - C K Holland
- University of Cincinnati, College of Medicine, Internal Medicine, Division of Cardiovascular Diseases, Cincinnati, OH, USA
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Rychak JJ, Klibanov AL. Nucleic acid delivery with microbubbles and ultrasound. Adv Drug Deliv Rev 2014; 72:82-93. [PMID: 24486388 PMCID: PMC4204336 DOI: 10.1016/j.addr.2014.01.009] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 01/20/2014] [Accepted: 01/23/2014] [Indexed: 02/02/2023]
Abstract
Nucleic acid-based therapy is a growing field of drug delivery research. Although ultrasound has been suggested to enhance transfection decades ago, it took a combination of ultrasound with nucleic acid carrier systems (microbubbles, liposomes, polyplexes, and viral carriers) to achieve reasonable nucleic acid delivery efficacy. Microbubbles serve as foci for local deposition of ultrasound energy near the target cell, and greatly enhance sonoporation. The major advantage of this approach is in the minimal transfection in the non-insonated non-target tissues. Microbubbles can be simply co-administered with the nucleic acid carrier or can be modified to carry nucleic acid themselves. Liposomes with embedded gas or gas precursor particles can also be used to carry nucleic acid, release and deliver it by the ultrasound trigger. Successful testing in a wide variety of animal models (myocardium, solid tumors, skeletal muscle, and pancreas) proves the potential usefulness of this technique for nucleic acid drug delivery.
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Affiliation(s)
| | - Alexander L Klibanov
- Cardiovascular Division, University of Virginia, Charlottesville, VA 22908-1394, USA.
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11
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Lentacker I, De Cock I, Deckers R, De Smedt SC, Moonen CTW. Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. Adv Drug Deliv Rev 2014; 72:49-64. [PMID: 24270006 DOI: 10.1016/j.addr.2013.11.008] [Citation(s) in RCA: 518] [Impact Index Per Article: 47.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 11/13/2013] [Indexed: 01/01/2023]
Abstract
In the past two decades, research has underlined the potential of ultrasound and microbubbles to enhance drug delivery. However, there is less consensus on the biophysical and biological mechanisms leading to this enhanced delivery. Sonoporation, i.e. the formation of temporary pores in the cell membrane, as well as enhanced endocytosis is reported. Because of the variety of ultrasound settings used and corresponding microbubble behavior, a clear overview is missing. Therefore, in this review, the mechanisms contributing to sonoporation are categorized according to three ultrasound settings: i) low intensity ultrasound leading to stable cavitation of microbubbles, ii) high intensity ultrasound leading to inertial cavitation with microbubble collapse, and iii) ultrasound application in the absence of microbubbles. Using low intensity ultrasound, the endocytotic uptake of several drugs could be stimulated, while short but intense ultrasound pulses can be applied to induce pore formation and the direct cytoplasmic uptake of drugs. Ultrasound intensities may be adapted to create pore sizes correlating with drug size. Small molecules are able to diffuse passively through small pores created by low intensity ultrasound treatment. However, delivery of larger drugs such as nanoparticles and gene complexes, will require higher ultrasound intensities in order to allow direct cytoplasmic entry.
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Affiliation(s)
- I Lentacker
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium
| | - I De Cock
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium
| | - R Deckers
- Imaging Division, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
| | - S C De Smedt
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
| | - C T W Moonen
- Imaging Division, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
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Shimamura M, Nakagami H, Taniyama Y, Morishita R. Gene therapy for peripheral arterial disease. Expert Opin Biol Ther 2014; 14:1175-84. [PMID: 24766232 DOI: 10.1517/14712598.2014.912272] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. Researchers working in this area have focused on pro-angiogenic factors, such as VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Based on the elaborate studies and favorable results of basic research using naked plasmid DNA (pDNA) encoding these growth factors, some clinical Phase I and Phase II trials have been performed. The results of these studies demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI patients. However, the Phase III clinical trials have so far been limited to HGF gene therapy. Because one pitfall of the Phase III trials has been the limited transgene expression achieved using naked pDNA alone, the development of more efficient gene transfer systems, such as ultrasound microbubbles and the needleless injector, as well as the addition of other genes will make these novel therapies more effective and ease the symptoms of CLI. AREAS COVERED This study reviews the previously published basic research and clinical trials that have studied VEGF, FGF and HGF gene therapies for the treatment of CLI. Adjunctive therapies, such as the addition of prostacyclin synthase genes and the development of more efficient gene transfer techniques for pDNA, are also reviewed. EXPERT OPINION To date, clinical studies have demonstrated the safety of gene therapy in limb ischemia but the effectiveness of this treatment has not been determined. Larger clinical studies, as well as the development of more effective gene therapy, are needed to achieve and confirm beneficial effects.
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Affiliation(s)
- Munehisa Shimamura
- Osaka University, Kanazawa University and Hamamatsu University School of Medicine, United Graduate School of Child Development, Division of Vascular Medicine and Epigenetics, Department of Child Development , Suita , Japan
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Chuang YH, Wang YH, Chang TK, Lin CJ, Li PC. Albumin acts like transforming growth factor β1 in microbubble-based drug delivery. ULTRASOUND IN MEDICINE & BIOLOGY 2014; 40:765-774. [PMID: 24433746 DOI: 10.1016/j.ultrasmedbio.2013.10.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 07/24/2013] [Accepted: 10/22/2013] [Indexed: 06/03/2023]
Abstract
Unlike lipid-shelled microbubbles (MBs), albumin-shelled microbubbles (MBs) have not been reported to be actively targeted to cells without the assistance of antibodies. Recent studies indicate that the albumin molecule is similar to transforming growth factor β (TGF-β) both structurally and functionally. The TGF-β superfamily is important during early tumor outgrowth, with an elevated TGF-β being tumor suppressive; at later stages, this switches to malignant conversion and progression, including breast cancer. TGF-β receptors I and II play crucial roles in both the binding and endocytosis of albumin. However, until now, no specific albumin receptor has been found. On the basis of the above-mentioned information, we hypothesized that non-antibody-conjugated albumin-shelled MBs can be used to deliver drugs to breast cancer cells. We also studied the possible roles of TGF-β1 and radiation force in the behavior of cells and albumin-shelled MBs. The results indicate that albumin-shelled MBs loaded with paclitaxel (PTX) induce breast cancer cell apoptosis without the specific targeting produced by an antibody. Applying either an acoustic radiation force or cavitation alone to cells with PTX-loaded albumin MBs increased the apoptosis rate to 23.2% and 26.3% (p < 0.05), respectively. We also found that albumin-shelled MBs can enter MDA-MB-231 breast cancer cells and remain there for at least 24 h, even in the presence of PTX loading. Confocal micrographs revealed that 70.5% of the breast cancer cells took up albumin-shelled MBs spontaneously after 1 d of incubation. Applying an acoustic radiation force further increased the percentage to 91.9% in our experiments. However, this process could be blocked by TGF-β1, even with subsequent exposure to the radiation force. From these results, we conclude that TGF-β1 receptors are involved in the endocytotic process by which albumin-shelled MBs enter breast cancer cells. The acoustic radiation force increases the contact rate between albumin-shelled MBs and tumor cells. Combining a radiation force and cavitation yields an apoptosis rate of 31.3%. This in vitro study found that non-antibody-conjugated albumin-shelled MBs provide a useful method of drug delivery. Further in vivo studies of the roles of albumin MBs and TGF-β in different stages of cancer are necessary.
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Affiliation(s)
- Yueh-Hsun Chuang
- Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan; Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Hsin Wang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Tien-Kuei Chang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Ching-Jung Lin
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Pai-Chi Li
- Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
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Shah SS, Denham LV, Elison JR, Bhattacharjee PS, Clement C, Huq T, Hill JM. Drug delivery to the posterior segment of the eye for pharmacologic therapy. EXPERT REVIEW OF OPHTHALMOLOGY 2014; 5:75-93. [PMID: 20305803 DOI: 10.1586/eop.09.70] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Treatment of diseases of the posterior segment of the eye, such as age-related macular degeneration, cytomegalovirus retinitis, diabetic retinopathy, posterior uveitis and retinitis pigmentosa, requires novel drug delivery systems that can overcome the many barriers for efficacious delivery of therapeutic drug concentrations. This challenge has prompted the development of biodegradable and nonbiodegradable sustained-release systems for injection or transplantation into the vitreous as well as drug-loaded nanoparticles, microspheres and liposomes. These drug delivery systems utilize topical, systemic, subconjunctival, intravitreal, transscleral and iontophoretic routes of administration. The focus of research has been the development of methods that will increase the efficacy of spatiotemporal drug application, resulting in more successful therapy for patients with posterior segment diseases. This article summarizes recent advances in the research and development of drug delivery methods of the posterior chamber of the eye, with an emphasis on the use of implantable devices as well as micro- and nanoparticles.
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Affiliation(s)
- Shalin S Shah
- Department of Ophthalmology, Louisiana State University Health Sciences Center (LSUHSC), 2020 Gravier St. Suite B, Room 3E6, New Orleans, LA 70112-2234, USA, Tel.: +1 678 296 2334, ,
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15
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Delalande A, Kotopoulis S, Postema M, Midoux P, Pichon C. Sonoporation: mechanistic insights and ongoing challenges for gene transfer. Gene 2013; 525:191-9. [PMID: 23566843 DOI: 10.1016/j.gene.2013.03.095] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 02/27/2013] [Accepted: 03/07/2013] [Indexed: 11/29/2022]
Abstract
Microbubbles first developed as ultrasound contrast agents have been used to assist ultrasound for cellular drug and gene delivery. Their oscillation behavior during ultrasound exposure leads to transient membrane permeability of surrounding cells, facilitating targeted local delivery. The increased cell uptake of extracellular compounds by ultrasound in the presence of microbubbles is attributed to a phenomenon called sonoporation. In this review, we summarize current state of the art concerning microbubble-cell interactions and cellular effects leading to sonoporation and its application for gene delivery. Optimization of sonoporation protocol and composition of microbubbles for gene delivery are discussed.
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Sutton JT, Haworth KJ, Pyne-Geithman G, Holland CK. Ultrasound-mediated drug delivery for cardiovascular disease. Expert Opin Drug Deliv 2013; 10:573-92. [PMID: 23448121 DOI: 10.1517/17425247.2013.772578] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery. AREAS COVERED The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies. EXPERT OPINION These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments.
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Affiliation(s)
- Jonathan T Sutton
- University of Cincinnati, College of Medicine, Internal Medicine, Division of Cardiovascular Diseases, and Biomedical Engineering Program, Cincinnati, OH, USA
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Paclitaxel-liposome–microbubble complexes as ultrasound-triggered therapeutic drug delivery carriers. J Control Release 2013; 166:246-55. [DOI: 10.1016/j.jconrel.2012.12.025] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 11/14/2012] [Accepted: 12/18/2012] [Indexed: 11/19/2022]
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Sorace AG, Saini R, Rosenthal E, Warram JM, Zinn KR, Hoyt K. Optical fluorescent imaging to monitor temporal effects of microbubble-mediated ultrasound therapy. IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL 2013; 60:281-9. [PMID: 23357902 PMCID: PMC3628607 DOI: 10.1109/tuffc.2013.2564] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p <0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors.
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Affiliation(s)
- Anna G. Sorace
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL
| | - Reshu Saini
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL
| | - Eben Rosenthal
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jason M. Warram
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL
| | - Kurt R. Zinn
- Department of Radiology, University of Alabama at Birmingham, Birmingham, AL. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| | - Kenneth Hoyt
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL. Department of Radiology, University of Alabama at Birmingham, Birmingham, AL. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
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Raju BI, Leyvi E, Seip R, Sethuraman S, Luo X, Bird A, Li S, Koeberl D. Enhanced gene expression of systemically administered plasmid DNA in the liver with therapeutic ultrasound and microbubbles. IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL 2013; 60:88-96. [PMID: 23405433 DOI: 10.1109/tuffc.2013.2540] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Ultrasound-mediated delivery (USMD) of novel therapeutic agents in the presence of microbubbles is a potentially safe and effective method for gene therapy offering many desired characteristics, such as low toxicity, potential for repeated treatment, and organ specificity. In this study, we tested the capability of USMD to improve gene expression in mice livers using glycogen storage disease Type Ia as a model disease under systemic administration of naked plasmid DNA. Image-guided therapeutic ultrasound was used in two studies to provide therapeutic ultrasound to mice livers. In the first study, involving wild-type mice, control animals received naked plasmid DNA (pG6Pase 150 μg) via the tail vein, followed by an infusion of microbubbles; the treated animals additionally received therapeutic ultrasound (1 MHz). Following the procedure, the animals were left to recover and were subsequently euthanized after 2 d and liver samples were extracted. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed on the samples to quantify mRNA expression. In addition, Western blot assays of FLAG-tagged glucose-6-phosphatase (G6Pase) were performed to evaluate protein expression. Ultrasound-exposed animals showed a 4-fold increase in G6Pase RNA in the liver, in comparison with control animals. Furthermore, results from Western blot analysis demonstrated a 2-fold increased protein expression in ultrasound-exposed animals after two days ( p < 0.05). A second pilot study was performed with G6Pase knockout mice, and the animals were monitored for correction of hypoglycemia over a period of 3 weeks before tissue analysis. The RT-PCR assays of samples from these animals demonstrated increased G6Pase RNA in the liver following ultrasound treatment. These results demonstrate that USMD can increase gene expression of systemically injected naked pDNA in the liver and also provide insight into the development of realistic approaches that can be translated into clinical practice.
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Van Ruijssevelt L, Smirnov P, Yudina A, Bouchaud V, Voisin P, Moonen C. Observations on the viability of C6-glioma cells after sonoporation with low-intensity ultrasound and microbubbles. IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL 2013; 60:34-45. [PMID: 23287911 DOI: 10.1109/tuffc.2013.2535] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Ultrasound (US) and microbubbles can be used to facilitate cellular uptake of drugs through a cavitationinduced enhancement of cell membrane permeability. The mechanism is, however, still incompletely understood. A direct contact between microbubbles and cell membrane is thought to be essential to create membrane perturbations lasting from seconds to minutes after US exposure of the cells. A recent study showed that the effect may even last up to 8 h after cavitation (with residual permeability up to 24 h after cavitation). In view of possible membrane damage, the purpose of this study was to further investigate the evolution of cell viability in the range of the 24-h temporal window. Furthermore, a description of the functional changes in tumor cells after US exposure was initiated to obtain a better understanding of the mechanism of membrane perturbation after sonication with microbubbles. Our results suggest that US does not reduce cell viability up to 24 h post-exposure. However, a perturbation of the entire cell population exposed to US was observed in terms of enzymatic activity and characteristics of the mitochondrial membrane. Furthermore, we demonstrated that US cavitation induces a transient loss of cell membrane asymmetry, resulting in phosphatidylserine exposure in the outer leaflet of the cell membrane.
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Affiliation(s)
- Lisbeth Van Ruijssevelt
- Laboratory for Molecular and Functional Imaging: from Physiology to Therapy, FRE 3313 CNRS /Universite Bordeaux S egalen, Bordeaux, France
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Ultrasound and microbubble-assisted gene delivery: recent advances and ongoing challenges. Ther Deliv 2012; 3:1199-215. [PMID: 23116012 DOI: 10.4155/tde.12.100] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Having first been developed for ultrasound imaging, nowadays, microbubbles are proposed as tools for ultrasound-assisted gene delivery, too. Their behavior during ultrasound exposure causes transient membrane permeability of surrounding cells, facilitating targeted local delivery. The increased cell uptake of extracellular compounds by ultrasound in the presence of microbubbles is attributed to a phenomenon called sonoporation. Sonoporation has been successfully applied to deliver nucleic acids in vitro and in vivo in a variety of therapeutic applications. However, the biological and physical mechanisms of sonoporation are still not fully understood. In this review, we discuss recent data concerning microbubble--cell interactions leading to sonoporation and we report on the progress in ultrasound-assisted therapeutic gene delivery in different organs. In addition, we outline ongoing challenges of this novel delivery method for its clinical use.
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Zheng X, Du L, Wang H, Gu Q. A novel approach to attenuate proliferative vitreoretinopathy using ultrasound-targeted microbubble destruction and recombinant adeno-associated virus-mediated RNA interference targeting transforming growth factor-β2 and platelet-derived growth factor-B. J Gene Med 2012; 14:339-47. [PMID: 22499528 DOI: 10.1002/jgm.2629] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND To date, with the exception of surgery, there are no satisfactory treatments available for proliferative vitreoretinopathy (PVR). Ultrasound-targeted microbubble destruction (UTMD) represents a new approach for the gene therapy of eye diseases. The present study aimed to investigate the feasibility of the attenuation of PVR by a combinatorial use of UTMD and recombinant adeno-associated virus (rAAV)-mediated RNA interference (RNAi) targeting transforming growth factor (TGF)-β2 and platelet-derived growth factor (PDGF)-B. METHODS One hundred and eighty rats of the PVR model were averagely divided into six groups (G). The left eyes, respectively, received an intravitreal injection as follows: normal saline (G1), rAAV2-control small interfering RNA (siRNA) (G2), rAAV2-TGF-β2-siRNA (G3), rAAV2-PDGF-B-siRNA (G4), rAAV2-TGF-β2-siRNA and rAAV2-PDGF-B-siRNA (G5, G6) on day 3 after PVR induction. In G6, a condition of UTMD was used additionally. On days 14 and 28, pathological changes of eye fundus were assessed by ophthalmoscopic and histopathologic examination, and the protein and mRNA levels of TGF-β2 and PDGF-B expression were tested using enzyme-linked immunosorbent assay and a reverse transcriptase-polymerase chain reaction, respectively. RESULTS The average grade scales of proliferation and the protein and mRNA expression levels of TGF-β2 and PDGF-B in G6 were all lower than that in G5 on day 28 (p<0.05, unpaired t-test). They were all lower in G5 and G6 than in G1, G2, G3 and G4 on day 28 (p<0.05, one-way analysis of variance), although the protein and mRNA expression levels of PDGF-B in G6 did not differ from that in G1, G2, G3, G4 and G5 on day 14. CONCLUSIONS The combinatorial use of UTMD and rAAV2-mediated RNAi targeting TGF-β2 and PDGF-B can serve as a novel approach to attenuate PVR.
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Affiliation(s)
- Xiaozhi Zheng
- Department of Ultrasound, The Fourth Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, People's Republic of China
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Hoffmann A, Gill H. Diastolic timed Vibro-Percussion at 50 Hz delivered across a chest wall sized meat barrier enhances clot dissolution and remotely administered Streptokinase effectiveness in an in-vitro model of acute coronary thrombosis. Thromb J 2012; 10:23. [PMID: 23146079 PMCID: PMC3534480 DOI: 10.1186/1477-9560-10-23] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Accepted: 10/31/2012] [Indexed: 11/28/2022] Open
Abstract
Background Low Frequency Vibro-Percussion (LFVP) assists clearance of thrombi in catheter systems and when applied to the heart and timed to diastole is known to enhance coronary flow. However LFVP on a clotted coronary like vessel given engagement over a chest wall sized barrier (to resemble non-invasive heart attack therapy) requires study. Methods One hour old clots (n=16) were dispensed within a flexible segment of Soft-Flo catheter (4 mm lumen), weighted, interfaced with Heparinized Saline (HS), secured atop a curved dampening base, and photographed. A ~4 cm meat slab was placed over the segment and randomized to receive intermittent LFVP (engaged, - disengaged at 1 second intervals), or no LFVP for 20 minutes. HS was pulsed (~120/80 mmHg), with the diastolic phase coordinated to match LFVP delivery. The segment was then re-photographed and aspirated of fluid to determine post clot weight. The trial was then repeated with 0.5 mls of Streptokinase (15,000 IU/100 microlitre) delivered ~ 2 cm upstream from the clot. Results LFVP - HS only samples (vs. controls) showed; a) development of clot length fluid channels absent in the control group (p < 0.0002); b) enhanced dissolved clot mixing scores ( 5.0 vs. 0.8, p < 2.8 E – 6); and c) increased percent clot dissolution (23.0% vs. 1.8% respectively, p < 8.5 E-6). LFVP - SK samples had a similar comparative clot disruptive profile, however fluid channels developed faster and percent clot dissolution more than doubled (51.0% vs. 3.0%, p< 9.8 E- 6). Conclusion Diastolic timed LFVP (50 Hz) engaged across a chest wall sized barrier enhances clot disruptive effects to an underlying coronary like system.
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Affiliation(s)
- Andrew Hoffmann
- Ahof Biophysical Systems Inc, 3858 Regent St, Burnaby, BC, Canada , V5C4G8.
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Zheng X, Ji P, Hu J. Sonoporation using microbubbles promotes lipofectamine-mediated siRNA transduction to rat retina. Bosn J Basic Med Sci 2012; 11:147-52. [PMID: 21875415 DOI: 10.17305/bjbms.2011.2565] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Ultrasound-targeted microbubble destruction(UTMD) has been utilized to deliver naked siRNA into cells in in vitro settings. But whether UTMD can safely deliver naked siRNA into in vivo cells have remained unknown. This work was performed to investigate the feasibility of UTMD-enhanced naked siRNA transduction (or combined with Lipofectamine 2000) in vivo retinal cells and compare the performance between UTMD and ultrasonic irradiation alone in this enhancing effect. A dose of Cy3-labeled siRNA was injected into the vitreous cavity of rat eyes under the different conditions of Lipofectamine 2000 or/and UTMD. Transduction efficiency was assessed by fluorescence microscopy and flow cytometry. Cell and tissue damage was assessed by trypan blue exclusion test and hematoxylineosin staining, respectively. The quantity and the density of transducted cells in the group received Lipofectamine 2000 and UTMD was far more than that in other groups. The number of transducted cells in the group received Lipofectamine 2000 and ultrasonic irradiation alone was slightly more than that in the group received Lipofectamine 2000. Cy3-siRNA-positive cells can also seen in the group received UTMD alone, although the transduction efficiency is extremely low. Cell viability in each group was more than 90%, and retinal architecture in each group was well preserved. These results indicated that UTMD, with a significantly higher performance than ultrasonic irradiation alone, can effectively enhance the Lipofectamine 2000-mediated naked siRNA transduction in vivo reinal cells without any cell or tissue damage. This method can serve as a novel approach to treat the diseases of eye ground.
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Affiliation(s)
- Xiaozhi Zheng
- Department of Ultrasound, The Fourth Affiliated Hospital of Nantong University (The First People's Hospital of Yancheng), Jiangsu Province, China
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Sorace AG, Warram JM, Umphrey H, Hoyt K. Microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer. J Drug Target 2011; 20:43-54. [PMID: 21981609 DOI: 10.3109/1061186x.2011.622397] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Ultrasound (US) exposed microbubble (MB) contrast agents have the capability to transiently enhance cell membrane permeability. Using this technique in cancer treatment to increase the efficiency of chemotherapy through passive, localized delivery has been an emerging area of research. PURPOSE Investigation of the influence of US parameters on MB-mediated drug delivery in cancer. METHODS The 2LMP breast cancer cells were used for in vitro experiments and 2LMP tumor-bearing mice were used during in vivo experiments. Changes in membrane permeability were investigated after the influence of MB-mediated US therapy parameters (i.e. frequency, mechanical index, pulse repetition period, US duration, and MB dosing and characteristics) on cancer cells. Calcein, a non-permeable fluorescent molecule, and Taxol, chemotherapeutic, were used to evaluate membrane permeability. Tumor response was also assessed histologically. RESULTS Combination chemotherapy and MB-mediated US therapy with optimized parameters increased cancer cell death by 50% over chemotherapy alone. DISCUSSION Increased cellular uptake of chemotherapeutic was dependent upon US system parameters. CONCLUSION Optimized MB-mediated US therapy has the potential to improve cancer patient response to therapy via increased localized drug uptake, which may lead to a lowering of chemotherapeutic drug dosages and systemic toxicity.
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Affiliation(s)
- Anna G Sorace
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA
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Yan F, Li X, Jin Q, Jiang C, Zhang Z, Ling T, Qiu B, Zheng H. Therapeutic ultrasonic microbubbles carrying paclitaxel and LyP-1 peptide: preparation, characterization and application to ultrasound-assisted chemotherapy in breast cancer cells. ULTRASOUND IN MEDICINE & BIOLOGY 2011; 37:768-779. [PMID: 21458148 DOI: 10.1016/j.ultrasmedbio.2011.02.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Revised: 02/16/2011] [Accepted: 02/17/2011] [Indexed: 05/30/2023]
Abstract
The aim of this work was to develop a novel targeted drug-loaded microbubble (MB) and to investigate its chemotherapy effect in vitro. Paclitaxel (PTX)-loaded lipid MBs were prepared by a mechanical vibration technique. The LyP-1, a breast tumor homing peptide, was coated onto the surface of PTX-loaded MBs through biotin-avidin linkage. The resulting targeted drug-loaded MBs were characterized and applied to ultrasound-assisted chemotherapy in breast cancer cells. Our results showed the ultrasonic MBs were able to achieve 43%-63% of drug encapsulation efficiency, depending on drug loading amount. The binding affinity assay indicated the attachment of targeted MBs to human MDA-MB-231 breast cancer cells was highly efficient and stable even with ultrasonic irradiation on. The cellular uptake efficiency of payload in targeted MBs was 3.71-, 4.95-, 7.43- and 7.66-fold higher than that of non-targeted MBs at the applied ultrasound time of 30, 60, 90 and 120 s, respectively. In addition, the cell proliferation inhibition assay showed the cell viability of targeted PTX-loaded MBs was significantly lower than that of non-targeted PTX-loaded MBs and non-targeted unloaded MBs when ultrasound was utilized. In conclusion, the study indicated the LyP-1-coated PTX-loaded MBs significantly increased the antitumor efficacy and can be used as a potential chemotherapy approach for ultrasound-assisted breast cancer treatment.
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Affiliation(s)
- Fei Yan
- Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Wang XH. Role of constituents of Optison in Optison-mediated gene transfection enhancement in skeletal muscle in vivo. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2011; 30:325-332. [PMID: 21357554 DOI: 10.7863/jum.2011.30.3.325] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
OBJECTIVES The mechanism by which Optison (an albumin-shelled, octafluoropropane gas-filled microbubble contrast agent; Amersham Health, Amersham, England) enhances gene transfection in skeletal muscle in vivo with or without ultrasound (US) is unclear. The possible mechanisms were investigated by experimenting with different constituents, both with and without US. METHODS Plasmid DNA (10 μg) encoding green fluorescent protein was mixed with Optison or its constituents dissolved in saline (in an equivalent concentration as in Optison) and injected into the tibialis anterior muscle of mice with or without adjunct US (1 MHz, 2 W/cm², 30 seconds, and 20% duty cycle). The efficiencies of green fluorescent protein transgene expression were determined under different experimental conditions: (1) plasmid plus saline as a negative control; (2) plasmid plus Optison as a positive control; (3) plasmid plus heat-treated Optison (without microbubbles); (4) plasmid plus human serum albumin; (5) plasmid plus N-acetyltryptophan; and (6) plasmid plus caprylic acid. Transfection efficiency was assessed by counting the maximum number of green fluorescent protein-positive fibers. Tissue damage was assessed by measuring the damaged area on serial sections. RESULTS Heat-treated Optison with or without US and albumin with US showed similarly high levels of transgene expression as Optison in mouse muscle without substantially increased tissue damage. N-Acetyltryptophan and caprylic acid had no effect on the delivery of plasmid green fluorescent protein into mouse muscle but instead showed the potential to increase tissue damage. CONCLUSIONS These data suggest that US and albumin separately potentiate transfection in this model. The combination of albumin and perfluoropropane is highly effective, which probably explains why Optison is so effective.
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Affiliation(s)
- Xing-Hua Wang
- Department of Ultrasound, Second Hospital of Shanxi Medical University, Taiyuan, China.
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Postema M, Gilja OH. Contrast-enhanced and targeted ultrasound. World J Gastroenterol 2011; 17:28-41. [PMID: 21218081 PMCID: PMC3016677 DOI: 10.3748/wjg.v17.i1.28] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Revised: 09/03/2010] [Accepted: 09/10/2010] [Indexed: 02/06/2023] Open
Abstract
Ultrasonic imaging is becoming the most popular medical imaging modality, owing to the low price per examination and its safety. However, blood is a poor scatterer of ultrasound waves at clinical diagnostic transmit frequencies. For perfusion imaging, markers have been designed to enhance the contrast in B-mode imaging. These so-called ultrasound contrast agents consist of microscopically small gas bubbles encapsulated in biodegradable shells. In this review, the physical principles of ultrasound contrast agent microbubble behavior and their adjustment for drug delivery including sonoporation are described. Furthermore, an outline of clinical imaging applications of contrast-enhanced ultrasound is given. It is a challenging task to quantify and predict which bubble phenomenon occurs under which acoustic condition, and how these phenomena may be utilized in ultrasonic imaging. Aided by high-speed photography, our improved understanding of encapsulated microbubble behavior will lead to more sophisticated detection and delivery techniques. More sophisticated methods use quantitative approaches to measure the amount and the time course of bolus or reperfusion curves, and have shown great promise in revealing effective tumor responses to anti-angiogenic drugs in humans before tumor shrinkage occurs. These are beginning to be accepted into clinical practice. In the long term, targeted microbubbles for molecular imaging and eventually for directed anti-tumor therapy are expected to be tested.
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Abstract
Ultrasound is a very effective modality for drug delivery and gene therapy because energy that is non-invasively transmitted through the skin can be focused deeply into the human body in a specific location and employed to release drugs at that site. Ultrasound cavitation, enhanced by injected microbubbles, perturbs cell membrane structures to cause sonoporation and increases the permeability to bioactive materials. Cavitation events also increase the rate of drug transport in general by augmenting the slow diffusion process with convective transport processes. Drugs and genes can be incorporated into microbubbles, which in turn can target a specific disease site using ligands such as the antibody. Drugs can be released ultrasonically from microbubbles that are sufficiently robust to circulate in the blood and retain their cargo of drugs until they enter an insonated volume of tissue. Local drug delivery ensures sufficient drug concentration at the diseased region while limiting toxicity for healthy tissues. Ultrasound-mediated gene delivery has been applied to heart, blood vessel, lung, kidney, muscle, brain, and tumour with enhanced gene transfection efficiency, which depends on the ultrasonic parameters such as acoustic pressure, pulse length, duty cycle, repetition rate, and exposure duration, as well as microbubble properties such as size, gas species, shell material, interfacial tension, and surface rigidity. Microbubble-augmented sonothrombolysis can be enhanced further by using targeting microbubbles.
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Affiliation(s)
- H-D Liang
- School of Engineering, Cardiff University, Cardiff, UK.
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Ren J, Xu C, Zhou Z, Zhang Y, Li X, Zheng Y, Ran H, Wang Z. A novel ultrasound microbubble carrying gene and Tat peptide: preparation and characterization. Acad Radiol 2009; 16:1457-65. [PMID: 19781962 DOI: 10.1016/j.acra.2009.06.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2009] [Revised: 05/14/2009] [Accepted: 06/15/2009] [Indexed: 11/30/2022]
Abstract
RATIONALE AND OBJECTIVES Ultrasound-targeted microbubble destruction is a promising technology for the targeted gene delivery. The purpose of the present study is to prepare a novel lipid ultrasound microbubble-carrying gene and transactivating transcriptional activator (Tat) peptide and to investigate its transfection effect in vivo. METHODS AND MATERIALS Lipid ultrasound microbubbles were prepared using mechanical vibration, and the appearance, distribution, concentration, diameter, and zeta potential of the lipid ultrasound microbubbles were measured. The efficiencies of the microbubble carrying gene and Tat peptide were investigated using the fluorospectrophotometer. Contrast-enhanced ultrasonography was performed on normal rabbits to observe the duration and intensity of enhancement in myocardium. Quantitative analysis was detected using the DFY Ultrasound Image Analyzer. Transfection in vivo was performed using the CGZZ ultrasound gene transfection instrument. The expression of enhanced green fluorescent protein in the organs was observed using confocal laser scanning microscope. RESULTS The diameter of the lipid microbubbles carrying gene and Tat was (2.3 +/- 0.4) mum, the concentration was (3.1 +/- 0.4) x10(9)/mL, and Zeta potential was (2.0 +/- 0.1) mV. The gene encapsulation efficiency of the lipid ultrasound microbubbles was 32%, and the Tat encapsulation efficiency was 35%. In vivo experiment showed that lipid ultrasound microbubbles could enhance the echo intensity and transfection efficiency. CONCLUSION Lipid microbubbles containing gene and Tat peptide can be used as a new vehicle for gene transfection.
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Affiliation(s)
- JianLi Ren
- Institute of Ultrasound Imaging, Department of Ultrasonography, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Lin Jiang Road, YuZhong District, ChongQing City, 400010, China
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Juffermans LJM, van Dijk A, Jongenelen CAM, Drukarch B, Reijerkerk A, de Vries HE, Kamp O, Musters RJP. Ultrasound and microbubble-induced intra- and intercellular bioeffects in primary endothelial cells. ULTRASOUND IN MEDICINE & BIOLOGY 2009; 35:1917-27. [PMID: 19766381 DOI: 10.1016/j.ultrasmedbio.2009.06.1091] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2008] [Revised: 05/27/2009] [Accepted: 06/08/2009] [Indexed: 05/05/2023]
Abstract
Recent developments in the field of ultrasound (US) contrast agents have demonstrated that these encapsulated microbubbles can not only be used for diagnostic imaging but may also be employed as therapeutic carriers for localized, targeted drug or gene delivery. The exact mechanisms behind increased uptake of therapeutic compounds by US-exposed microbubbles are still not fully understood. Therefore, we studied the effects of stably oscillating SonoVue microbubbles on relevant parameters of cellular and intercellular permeability, i.e., reactive oxygen species (ROS) homeostasis, calcium permeability, F-actin cytoskeleton, monolayer integrity and cell viability using live-cell fluorescence microscopy. US was applied at 1-MHz, 0.1MPa peak-negative pressure, 0.2% duty cycle and 20Hz pulse repetition frequency to primary endothelial cells. We demonstrated increased membrane permeability for calcium ions, with an important role for H(2)O(2). Catalase, an extracellular H(2)O(2) scavenger, significantly blocked the influx of calcium ions. Further changes in ROS homeostasis involved an increase in intracellular H(2)O(2) levels, protein nitrosylation and a decrease in total endogenous glutathione levels. In addition, an increase in the number of F-actin stress fibers and F-actin cytoskeletal rearrangement were observed. Furthermore, US-exposed microbubbles significantly affected endothelial monolayer integrity, but importantly, disrupted cell-cell interactions were restored within 30min. Finally, cell viability was not affected. In conclusion, these data provide more insight in the interactions between US, microbubbles and endothelial cells, which is important for understanding the mechanisms behind US and microbubble-enhanced uptake of drugs or genes.
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Affiliation(s)
- Lynda J M Juffermans
- Department of Physiology, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.
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Cardiovascular cavitation. Med Eng Phys 2009; 31:742-51. [DOI: 10.1016/j.medengphy.2009.03.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 03/12/2009] [Accepted: 03/15/2009] [Indexed: 12/22/2022]
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Tinkov S, Bekeredjian R, Winter G, Coester C. Microbubbles as ultrasound triggered drug carriers. J Pharm Sci 2009; 98:1935-61. [PMID: 18979536 DOI: 10.1002/jps.21571] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Originally developed as contrast agents for ultrasound imaging and diagnostics, in the past years, microbubbles have made their way back from the patients' bedside to the researcher's laboratory. Microbubbles are currently believed to have great potential as carriers for drugs, small molecules, nucleic acids, and proteins. This review provides insight into this intriguing new frontier from the perspective of the pharmaceutical scientist. First, basic aspects on the application of ultrasound-targeted microbubble destruction for drug delivery will be presented. Next, we will review the recently applied approaches for manufacturing and drug-loading microbubbles. Important quality issues and characterization techniques for advanced microbubble formulation will be discussed. Finally, we will provide an assessment of the prospects for microbubbles in drug and gene therapy, illustrating the problems and requirements for their future development.
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Affiliation(s)
- Steliyan Tinkov
- Department of Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians University-Munich, Butenandtstr. 5-13, D-81377 Munich, Germany
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Expression of endostatin mediated by a novel non-viral delivery system inhibits human umbilical vein endothelial cells in vitro. Mol Biol Rep 2009; 37:1755-62. [DOI: 10.1007/s11033-009-9600-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2008] [Accepted: 06/24/2009] [Indexed: 10/20/2022]
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Laing ST, McPherson DD. Cardiovascular therapeutic uses of targeted ultrasound contrast agents. Cardiovasc Res 2009; 83:626-35. [PMID: 19581314 DOI: 10.1093/cvr/cvp192] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The therapeutic use of ultrasound contrast agents (UCAs) is an emerging methodology with high potential for enhanced directed therapeutic gene, bioactive gas, drug, and stem cell delivery. Ultrasound-targeted microbubble destruction has already demonstrated feasibility for plasmid DNA delivery. Similarly, therapeutic ultrasound for thrombolysis treatment has been taken into the clinical setting, and the addition of UCAs for therapeutic delivery or enhanced effect through cavitation is a natural progression to this investigation. However, as with any new technique, safety needs to be first demonstrated before translation into clinical practice. This review article will focus on the development of UCAs for cardiac and vascular therapeutics as well as the limitations/concerns for the use of therapeutic ultrasound in clinical medicine in order to lay a foundation for investigators planning to enter this exciting field or for those who want to broaden their understanding.
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Affiliation(s)
- Susan T Laing
- Division of Cardiology, Department of Internal Medicine, University of Texas Health Sciences Center-Houston, 6431 Fannin Street, MSB 1.246, Houston, TX 77030, USA.
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Wang H, Chen X. Applications for site-directed molecular imaging agents coupled with drug delivery potential. Expert Opin Drug Deliv 2009; 6:745-68. [DOI: 10.1517/17425240902889751] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Alter J, Sennoga CA, Lopes DM, Eckersley RJ, Wells DJ. Microbubble stability is a major determinant of the efficiency of ultrasound and microbubble mediated in vivo gene transfer. ULTRASOUND IN MEDICINE & BIOLOGY 2009; 35:976-84. [PMID: 19285783 DOI: 10.1016/j.ultrasmedbio.2008.12.015] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2008] [Revised: 12/04/2008] [Accepted: 12/10/2008] [Indexed: 05/12/2023]
Abstract
In the search for an efficient nonviral gene therapy approach for the treatment of genetic disorders of cardiac and skeletal muscle such as Duchenne muscular dystrophy, ultrasound in combination with contrast enhancing microbubbles has emerged as a promising tool for safe and site-specific enhancement of gene delivery. Indeed, microbubble-enhanced gene transfer (MBGT) has been investigated for a wide variety of target sites using both reporter and therapeutic genes. Although a range of different microbubbles have been used for MBGT studies, comparison of their efficiencies is difficult because microbubble concentration and the ultrasound settings used for the application vary considerably. Only two studies to date have attempted a direct comparison of commercially available microbubbles, and both concluded that not all microbubbles show the same efficiencies with MBGT. Thus far, the reason for this is unclear. Here, the efficiency of three commercially available microbubbles--Optison, SonoVue and Sonazoid--was analyzed to understand the microbubble properties that are important for their function as an effective enhancer for gene transfer in vivo. In this study, plasmid DNA or antisense oligonucleotides were delivered by systemic injection with MBGT, focused on the heart. Gene delivery to the heart with equalized concentrations of the three microbubbles showed that Optison and Sonazoid are more efficient in MBGT compared with SonoVue, which showed the weakest gene transfer to the myocardium. Investigations into the properties of these microbubbles showed that size and shell composition did not directly influence MBGT, whereas the microbubbles with increased stability in an ultrasound field showed better MBGT results than those degrading faster. Moreover, the microbubble concentration used for MBGT was also found to be an important factor influencing the efficiency of MBGT. In conclusion, the stability of a microbubble was shown to be a major influential factor for its performance in MBGT, as is the concentration of the microbubbles used. These findings emphasize the importance of detailed investigations into the properties of microbubbles to allow the production of a microbubble specifically designed for optimum performance with MBGT.
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Affiliation(s)
- Julia Alter
- Imaging Sciences Department, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, UK
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Xu YL, Gao YH, Liu Z, Tan KB, Hua X, Fang ZQ, Wang YL, Wang YJ, Xia HM, Zhuo ZX. Myocardium-targeted transplantation of mesenchymal stem cells by diagnostic ultrasound-mediated microbubble destruction improves cardiac function in myocardial infarction of New Zealand rabbits. Int J Cardiol 2009; 138:182-95. [PMID: 19383567 DOI: 10.1016/j.ijcard.2009.03.071] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2008] [Revised: 12/31/2008] [Accepted: 03/10/2009] [Indexed: 11/17/2022]
Abstract
BACKGROUND Therapeutic ultrasound-mediated microbubble destruction has been applied in the targeted delivery of genes, drugs and stem cells. We intended to study whether diagnostic US irradiating lipid-coated microbubble destruction combined with bone-marrow derived MSC infusion could enable the targeted delivery of MSCs into the myocardium and improve cardiac function of the myocardial infarction of New Zealand rabbits. METHODS Diagnostic ultrasound was applied to the anterior chest for 10 min after intravenous injection of lipid-coated microbubble followed by infusion of BM-MSCs. Echocardiography, histological examination, and western blotting were performed 4 weeks after cell transplantation. RESULTS The cardiac function (assessed by fractional shortening and ejection fraction) was markedly improved by US+Microbubble+MSC treatment. The number of capillaries stained by HE in US+Microbubble+MSC group (47+/-23) was much greater than that of the MSCs infusion group (26+/-7), US+Microbubble group(22+/-5) and PBS infusion group (19+/-10), P<0.01. US+Microbubble stimulation induced the expression of adhesion molecule (VCAM-1) in capillaries and enhanced the myocardial permeability of microvessels. US+Microbubble-mediated supply of MSCs increased the level of VEGF in ischemic myocardium. Area of cardiac fibrosis in the US+Microbubble+MSC group was significantly decreased by 25.6%,40.1% and 46.8% when compared with MSC infusion group, US+Microbubble group and PBS infusion group, respectively. CONCLUSIONS This non-invasive cell delivery system may be useful as a novel and efficient approach for angiogenic cell therapy to the infarcted myocardium.
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Affiliation(s)
- Ya-Li Xu
- Department of Ultrasound, Second affiliated Hospital, Third Military Medical University, Chongqing 400037, PR China.
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Affiliation(s)
- Eric C Pua
- Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27705, USA
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Mayer CR, Geis NA, Katus HA, Bekeredjian R. Ultrasound targeted microbubble destruction for drug and gene delivery. Expert Opin Drug Deliv 2009; 5:1121-38. [PMID: 18817517 DOI: 10.1517/17425247.5.10.1121] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Gas-filled microbubbles have been used as ultrasound contrast agents for some decades. More recently, such microbubbles have evolved as experimental tools for organ- and tissue-specific drug and gene delivery. When sonified with ultrasound near their resonance frequency, microbubbles oscillate. With higher ultrasound energies, oscillation amplitudes increase, leading to microbubble destruction. This phenomenon can be used to deliver a substance into a target organ, if microbubbles are co-administered loaded with drugs or gene therapy vectors before i.v. injection. OBJECTIVE This review focuses on different experimental applications of microbubbles as tools for drug and gene delivery. Different organ systems and different classes of bioactive substances that have been used in previous studies will be discussed. METHODS All the available literature was reviewed to highlight the potential of this non-invasive, organ-specific delivery system. CONCLUSION Ultrasound targeted microbubble destruction has been used in various organ systems and in tumours to successfully deliver drugs, proteins, gene therapy vectors and gene silencing constructs. Many proof of principle studies have demonstrated its potential as a non-invasive delivery tool. However, too few large animal studies and studies with therapeutic aims have been performed to see a clinical application of this technique in the near future. Nevertheless, there is great hope that preclinical large animal studies will confirm the successful results already obtained in small animals.
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Affiliation(s)
- Christian R Mayer
- University of Heidelberg, Department of Internal Medicine III, Im Neuenheimer Feld 410, 69120 Heidelberg,Germany
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Lionetti V, Fittipaldi A, Agostini S, Giacca M, Recchia FA, Picano E. Enhanced caveolae-mediated endocytosis by diagnostic ultrasound in vitro. ULTRASOUND IN MEDICINE & BIOLOGY 2009; 35:136-43. [PMID: 18950933 DOI: 10.1016/j.ultrasmedbio.2008.07.011] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2008] [Revised: 05/26/2008] [Accepted: 07/16/2008] [Indexed: 05/19/2023]
Abstract
The modulation of cellular endothelial permeability is a desirable goal for targeted delivery of labels and therapeutic macromolecules; the underlying mechanisms, however, remains poorly understood. Here, we hypothesize that a higher endothelial permeability may result as an outcome of selective enhancement of caveolar endocytosis by ultrasound (US), in the frequency and intensity range of current clinical diagnostic use. To assess the role of free radicals in this phenomenon, we exposed confluent human endothelial cells to pulsed diagnostic US for 30 min, with a mechanical index (MI) of 0.5 and 1.2, using a 1.6-MHz cardiac US scan, and endothelial cells not exposed to US were used as control. Here we show that pulsed diagnostic US with a MI of 1.2 (high mechanical index ultrasound [HMIUS]) were able to selectively enhance endothelial caveolar internalization of recombinant glutathione-S-transferase (GST)-Tat11-EGFP fusion protein (26 +/- 1 vs. 11.6 +/- 1 A.U, p < 0.001 vs. control), without disruption of plasma membrane integrity. Moreover, pulsed diagnostic US with a MI of 0.5 (low mechanical index ultrasound) did not increase caveolar endocytosis compared with control (11.4 +/- 1.2 vs. 11.6 +/- 1). Free-radical generation inhibitors, such as catalase and superoxide dismutase, reduced the HMIUS-induced caveolar internalization by a 49.29% factor; finally, HMIUS-induced caveolar endocytosis was found to be associated with a significant increase in the phosphorylation of tyr-14-caveolin1, ser1177-eNOS and Thr202/Tyr204-ERK(1/2) compared with control. These findings show how HMIUS irradiation of human endothelial cells cause a selective enhancement of caveolar-dependent permeability, partially mediated by free radicals generation, inducing a marked increase of phosphorylation of caveolar-related proteins. Thus, the use of diagnostic US could potentially be used as an adjuvant to drive caveolar traffic of extracellular peptides by using a higher level of US energy.
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Forbes MM, Steinberg RL, O'Brien WD. Examination of inertial cavitation of Optison in producing sonoporation of chinese hamster ovary cells. ULTRASOUND IN MEDICINE & BIOLOGY 2008; 34:2009-18. [PMID: 18692296 PMCID: PMC2610271 DOI: 10.1016/j.ultrasmedbio.2008.05.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2007] [Revised: 05/13/2008] [Accepted: 05/14/2008] [Indexed: 05/11/2023]
Abstract
The objective of this project was to elucidate the relationship between ultrasound contrast agents (UCAs) and sonoporation. Sonoporation is an ultrasound-induced, transient cell membrane permeability change that allows for the uptake of normally impermeable macromolecules. Specifically, this study will determine the role that inertial cavitation plays in eliciting sonoporation. The inertial cavitation thresholds of the UCA, Optison, are compared directly with the results of sonoporation to determine the involvement of inertial cavitation in sonoporation. Chinese hamster ovary (CHO) cells were exposed as a monolayer in a solution of Optison, 500,000 Da fluorescein isothiocyanate-dextran (FITC-dextran), and phosphate-buffered saline (PBS) to 30 s of pulsed ultrasound at 3.15-MHz center frequency, 5-cycle pulse duration and 10-Hz pulse repetition frequency. The peak rarefactional pressure (P(r)) was varied over a range from 120 kPa-3.5 MPa, and five independent replicates were performed at each pressure. As the P(r) was increased, from 120 kPa-3.5 MPa, the fraction of sonoporated cells among the total viable population increased from 0.63-10.21%, with the maximum occurring at 2.4 MPa. The inertial cavitation threshold for Optison at these exposure conditions has previously been shown to be in the range 0.77-0.83 MPa, at which sonoporation activity was found to be 50% of its maximum level. Furthermore, significant sonoporation activity was observed at pressure levels below the threshold for inertial cavitation of Optison. Above 2.4 MPa, a significant drop in sonoporation activity occurred, corresponding to pressures where >95% of the Optison was collapsing. These results demonstrate that sonoporation is not directly a result of inertial cavitation of the UCA, rather that the effect is related to linear and/or nonlinear oscillation of the UCA occurring at pressure levels below the inertial cavitation threshold.
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Affiliation(s)
- Monica M Forbes
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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Acoustic attenuation by contrast agent microbubbles in superficial tissue markedly diminishes petechiae bioeffects in deep tissue. Invest Radiol 2008; 43:322-9. [PMID: 18424953 DOI: 10.1097/rli.0b013e318168c715] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To measure how ultrasound attenuation by contrast agent microbubbles (MBs) in superficial tissue affects petechiae creation in underlying deep tissue. MATERIALS AND METHODS Studies using Sprague-Dawley rats were approved by the Animal Care and Use Committee. MBs were injected intravenously, and 12 ultrasound pulses (100 sinusoids of 1 MHz ultrasound per pulse) were applied through the skin overlying the hindlimb adductors at intervals of 10 or 60 seconds. In some groups, the skin was resected and immediately returned without re-establishing vascular connections. Muscle petechiae were counted. RESULTS Applying ultrasound through unperfused skin after bolus and continuous intravenous MB injection yielded, respectively, 30-fold and 3.5-fold more petechiae than for perfused skin. Surprisingly, petechiae/mm2 decreased with a higher MB dosage [0.12 +/- 0.05 (1 x 10 MBs/g) vs. 0.04 +/- 0.02 (3 x 10 MBs/g)] when ultrasound was applied through perfused skin. In contrast, petechiae/mm2 was approximately proportional to MB dosage for unperfused skin [0.17 +/- 0.10(5) (1 x 10 MBs/g) vs. 0.42 + 0.14 (3 x 10(5) MBs/g)]. In comparison to MB-free controls, MB solutions in this concentration range reduced the peak-negative pressure of ultrasound by 65% to 85%. CONCLUSIONS Acoustic attenuation by MBs in skin markedly reduces petechiae creation in deep muscle. Petechiae inhibition is dependent on [MB]2.1 and, therefore, dominates the otherwise proportional relationship between petechiae and [MB] in muscle. The drop of peak-negative pressure below a critical microvessel rupturing threshold is the probable mechanism for petechiae inhibition. These results indicate that high MB doses could, paradoxically, reduce the potential for petechiae creation and may have important bearing on the design of contrast ultrasound-based therapeutics.
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Ultrasonic gene and drug delivery to the cardiovascular system. Adv Drug Deliv Rev 2008; 60:1177-92. [PMID: 18474407 DOI: 10.1016/j.addr.2008.03.004] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Accepted: 03/04/2008] [Indexed: 11/22/2022]
Abstract
Ultrasound targeted microbubble destruction has evolved as a promising tool for organ specific gene and drug delivery. This technique has initially been developed as a method in myocardial contrast echocardiography, destroying intramyocardial microbubbles to characterize refill kinetics. When loading similar microbubbles with a bioactive substance, ultrasonic destruction of microbubbles may release the transported substance in the targeted organ. Furthermore, high amplitude oscillations of microbubbles lead to increased capillary and cell membrane permeability, thus facilitating tissue and cell penetration of the released substance. While this technique has been successfully used in many organs, its application in the cardiovascular system has dominated so far. Drug delivery using microbubbles has played a minor role in the cardiovascular system. In contrast, gene transfer has been successfully achieved in many studies. Both viral and non-viral vectors were used for loading on microbubbles. This review article will give an overview on studies that have applied ultrasound targeted microbubble destruction to deliver substances in the heart and blood vessels. It will show potential therapeutic targets, especially for gene therapy, describe feasible substances that can be loaded on microbubbles, and critically discuss prospects and limitations of this technique.
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Zhao YZ, Luo YK, Lu CT, Xu JF, Tang J, Zhang M, Zhang Y, Liang HD. Phospholipids-based microbubbles sonoporation pore size and reseal of cell membrane cultured in vitro. J Drug Target 2008; 16:18-25. [PMID: 18172816 DOI: 10.1080/10611860701637792] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To investigate phospholipids-based microbubbles induced sonoporation and cell membrane reseal in vitro under various conditions. METHODS A breast cancer cell line SK-BR-3 was used to investigate ultrasonic sonoporation under various conditions. Atomic force microscopy (AFM) scanning techniques were employed to observe the change of membrane pores. RESULTS Normal SK-BR-3 cells membrane pores were evenly distributed and less than 1 microm. After ultrasound exposure, membrane pores were enlarged at different degree depending on ultrasound exposure durations, filling gas species and microbubble suspension concentration. With microbubble suspension concentration being increased to 5% or ultrasound exposure reached 30 s, membrane pores in fluorocarbon (C(3)F(8) or SF(6))-filled microbubble groups exceeded 1 microm, which were significantly larger than that of air-filled microbubble group. Membrane pores were about 2-3 microm under ultrasound 60 s with 5% fluorocarbon-filled microbubble suspension. After 24 h of incubation, most of the enlarged membrane pores could reseal to normal size, which corresponded to cell viability. CONCLUSIONS Membrane pores can be obviously enlarged by ultrasonic sonoporation of fluorocarbon-filled microbubbles, whose reseal time depended on ultrasound exposure duration and microbubble suspension concentration.
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Affiliation(s)
- Ying-Zheng Zhao
- Department of Clinical Pharmacology, General Hospital of Beijing Military Command of PLA, Dong Si Shi Tiao Road, Dongcheng District, Beijing, People's Republic of China.
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Chappell JC, Song J, Klibanov AL, Price RJ. Ultrasonic microbubble destruction stimulates therapeutic arteriogenesis via the CD18-dependent recruitment of bone marrow-derived cells. Arterioscler Thromb Vasc Biol 2008; 28:1117-22. [PMID: 18403725 DOI: 10.1161/atvbaha.108.165589] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE We have previously shown that, under certain conditions, ultrasonic microbubble destruction creates arteriogenesis and angiogenesis in skeletal muscle. Here, we tested whether this neovascularization response enhances hyperemia in a rat model of arterial insufficiency and is dependent on the recruitment of bone marrow-derived cells (BMDCs) to treated tissues via a beta2 integrin (CD18)-dependent mechanism. METHODS AND RESULTS Sprague-Dawley rats, C57BL/6 wild-type mice, and C57BL/6 chimeric mice engrafted with BMDCs from either GFP+ or CD18-/- mice received bilateral femoral artery ligations. Microbubbles (MBs) were intravenously injected, and one gracilis muscle was exposed to pulsed 1 MHz ultrasound (US). Rat hindlimbs exhibited significant increases in adenosine-induced hyperemia and arteriogenesis compared to contralateral controls at 14 and 28 days posttreatment. US-MB-treated wild-type C57BL/6 mice exhibited significant arteriogenesis, angiogenesis, and CD11b+ monocyte recruitment; however, these responses were all completely blocked in CD18-/- chimeric mice. The number of BMDCs increased in US-MB-treated muscles of GFP+ chimeric mice; however, GFP+ BMDCs did not incorporate into microvessels as vascular cells. CONCLUSIONS In skeletal muscle affected by arterial occlusion, arteriogenesis and hyperemia can be significantly enhanced by ultrasonic MB destruction. This response depends on the recruitment, but not vascular incorporation, of BMDCs via a CD18-dependent mechanism.
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Affiliation(s)
- John C Chappell
- Department of Biomedical Engineering, University of Virginia, UVA Health System, Charlottesville, VA 22908, USA
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Stratmeyer ME, Greenleaf JF, Dalecki D, Salvesen KA. Fetal ultrasound: mechanical effects. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2008; 27:597-609. [PMID: 18359910 DOI: 10.7863/jum.2008.27.4.597] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
In this discussion, any biological effect of ultrasound that is accompanied by temperature increments less than 1 degrees C above normal physiologic levels is called a mechanical effect. However, one should keep in mind that the term mechanical effect also includes processes that are not of a mechanical nature but arise secondary to mechanical interaction between ultrasound and tissues, such as chemical reactions initiated by free oxygen species generated during cavitation and sonoluminescence. Investigations with laboratory animals have documented that pulsed ultrasound can produce damage to biological tissues in vivo through nonthermal mechanisms. The acoustic output used to induce these adverse bio-effects is considerably greater than the output of diagnostic devices when gas bodies are not present. However, low-intensity pulsed ultrasound is used clinically to accelerate the bone fracture repair process and induce healing of nonunions in humans. Low-intensity pulsed ultrasound also has been shown to enhance repair of soft tissue damage and accelerate nerve regeneration in animal models. Although such exposures to low intensity do not appear to cause damage to exposed tissues, they do raise questions about the acoustic threshold that might induce potentially adverse developmental effects in the fetus. To date, bioeffects studies in humans do not substantiate a causal relationship between diagnostic ultrasound exposure during pregnancy and adverse biological effects to the fetus. However, the epidemiologic studies were conducted with commercially available devices predating 1992, having outputs not exceeding a derated spatial-peak temporal-average intensity (ISPTA.3) of 94 mW/cm2. Current limits in the United States allow an ISPTA.3 of 720 mW/cm2 for obstetric modes. At the time of this report, available evidence, experimental or epidemiologic, is insufficient to conclude that there is a causal relationship between obstetric diagnostic ultrasound exposure and adverse nonthermal effects to the fetus. However, low-intensity pulsed ultrasound effects reported in humans and animal models indicate a need for further investigation of potentially adverse developmental effects.
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Affiliation(s)
- Melvin E Stratmeyer
- Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, 9200 Corporate Blvd, HFZ-120, Rockville, MD 20850 USA.
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Deckers R, Rome C, Moonen CT. The role of ultrasound and magnetic resonance in local drug delivery. J Magn Reson Imaging 2008; 27:400-9. [DOI: 10.1002/jmri.21272] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Rome C, Deckers R, Moonen CTW. The use of ultrasound in transfection and transgene expression. Handb Exp Pharmacol 2008:225-243. [PMID: 18626604 DOI: 10.1007/978-3-540-77496-9_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
The interaction of ultrasound with tissue leads to radiation pressure, heat generation, and cavitation. These phenomena have been utilised for local gene delivery, transfection and control of expression. Specially designed nanocarriers or adapted ultrasound contrast agents can further enhance local delivery by: (1) increased permeability of cell membranes; (2) local release of genes. Biological carriers may also be used for local gene delivery. Stem cells and immune cells appear especially promising because of their homing capabilities to lesion sites. Imaging methods can be employed for pharmacodistribution and pharmacokinetics. MRI contrast agents can serve as non-invasive reporters on gene distribution when co-delivered with the gene. They can be used to label nanocarriers and cellular transport systems in gene therapy strategies such as those based on stem cells. Finally, ultrasound heating together with the use of a temperature sensitive promoter allows a local, physical, spatio-temporal control of transgene expression, in particular when combined with MRI temperature mapping for monitoring and even controlling ultrasound heating.
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Affiliation(s)
- Claire Rome
- Laboratory for Molecular and Functional Imaging, UMR5231 CNRS, Université Victor Segalen Bordeaux 2, Bordeaux, France
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Ferrara K, Pollard R, Borden M. Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng 2007; 9:415-47. [PMID: 17651012 DOI: 10.1146/annurev.bioeng.8.061505.095852] [Citation(s) in RCA: 797] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
This review offers a critical analysis of the state of the art of medical microbubbles and their application in therapeutic delivery and monitoring. When driven by an ultrasonic pulse, these small gas bubbles oscillate with a wall velocity on the order of tens to hundreds of meters per second and can be deflected to a vessel wall or fragmented into particles on the order of nanometers. While single-session molecular imaging of multiple targets is difficult with affinity-based strategies employed in some other imaging modalities, microbubble fragmentation facilitates such studies. Similarly, a focused ultrasound beam can be used to disrupt delivery vehicles and blood vessel walls, offering the opportunity to locally deliver a drug or gene. Clinical translation of these vehicles will require that current challenges be overcome, where these challenges include rapid clearance and low payload. The technology, early successes with drug and gene delivery, and potential clinical applications are reviewed.
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Affiliation(s)
- Katherine Ferrara
- Department of Biomedical Engineering, University of California, Davis, California 95616-8686, USA.
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