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1
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Tao W, Lai Y, Zhou X, Yang G, Wu P, Yuan L. A narrative review: Ultrasound-Assisted drug delivery: Improving treatments via multiple mechanisms. ULTRASONICS 2025; 151:107611. [PMID: 40068411 DOI: 10.1016/j.ultras.2025.107611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 02/21/2025] [Accepted: 02/21/2025] [Indexed: 04/02/2025]
Abstract
Safe and efficient drug delivery is as important as drug development. Biological barriers, such as cell membranes, present significant challenges in drug delivery, especially for newly developed protein-, nucleic acid-, and cell-based drugs. Ultrasound-mediated drug delivery systems offer a promising strategy to overcome these challenges. Ultrasound, a mechanical wave with energy, produces thermal effects, cavitation, acoustic radiation, and other biophysical effects. Used alone or in combination with microbubbles or sonosensitizers, it breaks biological barriers, enhances targeted drug delivery, reduces adverse reactions, controls drug release, switches on/off drug functions, and ultimately improves therapeutic efficiency. Various ultrasound-mediated drug delivery methods, including transdermal drug delivery, nebulization, targeted microbubble destruction, and sonodynamic therapy, are being actively explored for the treatment of various diseases. This review article introduces the principles, advantages, and applications of ultrasound-mediated drug delivery methods for improved therapeutic outcomes and discusses future prospects in this field.
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Affiliation(s)
- Wenxin Tao
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Yubo Lai
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Xueying Zhou
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Guodong Yang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University Xi'an, Shaanxi 710032, China
| | - Pengying Wu
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
| | - Lijun Yuan
- Department of Ultrasound Medicine, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China.
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2
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Moonen CT, Kilroy JP, Klibanov AL. Focused Ultrasound: Noninvasive Image-Guided Therapy. Invest Radiol 2025; 60:205-219. [PMID: 39163359 PMCID: PMC11801465 DOI: 10.1097/rli.0000000000001116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 06/27/2024] [Indexed: 08/22/2024]
Abstract
ABSTRACT Invasive open surgery used to be compulsory to access tumor mass to perform excision or resection. Development of minimally invasive laparoscopic procedures followed, as well as catheter-based approaches, such as stenting, endovascular surgery, chemoembolization, brachytherapy, which minimize side effects and reduce the risks to patients. Completely noninvasive procedures bring further benefits in terms of reducing risk, procedure time, recovery time, potential of infection, or other side effects. Focusing ultrasound waves from the outside of the body specifically at the disease site has proven to be a safe noninvasive approach to localized ablative hyperthermia, mechanical ablation, and targeted drug delivery. Focused ultrasound as a medical intervention was proposed decades ago, but it only became feasible to plan, guide, monitor, and control the treatment procedures with advanced radiological imaging capabilities. The purpose of this review is to describe the imaging capabilities and approaches to perform these tasks, with the emphasis on magnetic resonance imaging and ultrasound. Some procedures already are in clinical practice, with more at the clinical trial stage. Imaging is fully integrated in the workflow and includes the following: (1) planning, with definition of the target regions and adjacent organs at risk; (2) real-time treatment monitoring via thermometry imaging, cavitation feedback, and motion control, to assure targeting and safety to adjacent normal tissues; and (3) evaluation of treatment efficacy, via assessment of ablation and physiological parameters, such as blood supply. This review also focuses on sonosensitive microparticles and nanoparticles, such as microbubbles injected in the bloodstream. They enable ultrasound energy deposition down to the microvascular level, induce vascular inflammation and shutdown, accelerate clot dissolution, and perform targeted drug delivery interventions, including focal gene delivery. Especially exciting is the ability to perform noninvasive drug delivery via opening of the blood-brain barrier at the desired areas within the brain. Overall, focused ultrasound under image guidance is rapidly developing, to become a choice noninvasive interventional radiology tool to treat disease and cure patients.
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3
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Bezer JH, Prentice P, Lim Kee Chang W, Morse SV, Christensen-Jeffries K, Rowlands CJ, Kozlov AS, Choi JJ. Microbubble dynamics in brain microvessels. PLoS One 2025; 20:e0310425. [PMID: 39908294 PMCID: PMC11798480 DOI: 10.1371/journal.pone.0310425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 08/31/2024] [Indexed: 02/07/2025] Open
Abstract
Focused ultrasound stimulation of microbubbles is being tested in clinical trials for its ability to deliver drugs across the blood-brain barrier (BBB). This technique has the potential to treat neurological diseases by preferentially delivering drugs to targeted regions. Yet despite its potential, the physical mechanisms by which microbubbles alter the BBB permeability remain unclear, as direct observations of microbubbles oscillating in brain microvessels have never been previously recorded. The purpose of this study was to reveal how microbubbles respond to ultrasound when within the microvessels of living brain tissue. Microbubbles in acute brain slices acquired from juvenile rats perfused with a concentrated solution of SonoVue® and dye were exposed to ultrasound pulses typically used in BBB disruption (center frequency: 1 MHz, peak-negative pressure: 0.2-1 MPa, pulse length: up to 10 ms) and observed using high-speed microscopy at up to 10 million frames per second. We observed that microbubbles can exert mechanical stresses on a wide region of tissue beyond their initial location and immediate surroundings. A single microbubble can apply mechanical stress to parenchymal tissues several micrometers away from the vessel. Microbubbles can travel at high velocities within the microvessels, extending their influence across tens of micrometers during a single pulse. With longer pulses and higher pressures, microbubbles could penetrate the vessel wall and move through the parenchyma. The probability of extravasation scales approximately with mechanical index, being rare at low pressures, but much more common at a mechanical index ≥ 0.6. These results present the first direct observations of ultrasound-driven microbubbles within brain tissue, and illustrate a range of microbubble behaviors that have the potential to lead to safe drug delivery or tissue damage.
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Affiliation(s)
- James H. Bezer
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Paul Prentice
- School of Engineering, University of Glasgow, Glasgow, United Kingdom
| | | | - Sophie V. Morse
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | | | | | - Andriy S. Kozlov
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - James J. Choi
- Department of Bioengineering, Imperial College London, London, United Kingdom
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Singh D, Memari E, He S, Yusefi H, Helfield B. Cardiac gene delivery using ultrasound: State of the field. Mol Ther Methods Clin Dev 2024; 32:101277. [PMID: 38983873 PMCID: PMC11231612 DOI: 10.1016/j.omtm.2024.101277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2024]
Abstract
Over the past two decades, there has been tremendous and exciting progress toward extending the use of medical ultrasound beyond a traditional imaging tool. Ultrasound contrast agents, typically used for improved visualization of blood flow, have been explored as novel non-viral gene delivery vectors for cardiovascular therapy. Given this adaptation to ultrasound contrast-enhancing agents, this presents as an image-guided and site-specific gene delivery technique with potential for multi-gene and repeatable delivery protocols-overcoming some of the limitations of alternative gene therapy approaches. In this review, we provide an overview of the studies to date that employ this technique toward cardiac gene therapy using cardiovascular disease animal models and summarize their key findings.
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Affiliation(s)
- Davindra Singh
- Department of Biology, Concordia University, Montreal, QC, Canada
| | - Elahe Memari
- Department of Physics, Concordia University, Montreal, QC, Canada
| | - Stephanie He
- Department of Biology, Concordia University, Montreal, QC, Canada
| | - Hossein Yusefi
- Department of Physics, Concordia University, Montreal, QC, Canada
| | - Brandon Helfield
- Department of Biology, Concordia University, Montreal, QC, Canada
- Department of Physics, Concordia University, Montreal, QC, Canada
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Owen J, Negussie AH, Burks SR, Delgado J, Mikhail AS, Rivera J, Pritchard WF, Karanian JW, Stride E, Frank JA, Wood BJ. Microbubbles bound to drug-eluting beads enable ultrasound imaging and enhanced delivery of therapeutics. Sci Rep 2024; 14:20929. [PMID: 39251665 PMCID: PMC11383944 DOI: 10.1038/s41598-024-71831-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/30/2024] [Indexed: 09/11/2024] Open
Abstract
Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0-37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70-150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.
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Affiliation(s)
- Joshua Owen
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Ayele H Negussie
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Scott R Burks
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA
| | - Jose Delgado
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Andrew S Mikhail
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Jocelyne Rivera
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
- Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK
| | - William F Pritchard
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - John W Karanian
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Eleanor Stride
- Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK
| | - Joseph A Frank
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA
| | - Bradford J Wood
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
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Xin J, Lu X, Cao J, Wu W, Liu Q, Wang D, Zhou X, Ding D. Fluorinated Organic Polymers for Cancer Drug Delivery. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2404645. [PMID: 38678386 DOI: 10.1002/adma.202404645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/22/2024] [Indexed: 04/30/2024]
Abstract
In the realm of cancer therapy, the spotlight is on nanoscale pharmaceutical delivery systems, especially polymer-based nanoparticles, for their enhanced drug dissolution, extended presence in the bloodstream, and precision targeting achieved via surface engineering. Leveraging the amplified permeation and retention phenomenon, these systems concentrate therapeutic agents within tumor tissues. Nonetheless, the hurdles of systemic toxicity, biological barriers, and compatibility with living systems persist. Fluorinated polymers, distinguished by their chemical idiosyncrasies, are poised for extensive biomedical applications, notably in stabilizing drug metabolism, augmenting lipophilicity, and optimizing bioavailability. Material science heralds the advent of fluorinated polymers that, by integrating fluorine atoms, unveil a suite of drug delivery merits: the hydrophobic traits of fluorinated alkyl chains ward off lipid or protein disruption, the carbon-fluorine bond's stability extends the drug's lifecycle in the system, and a lower alkalinity coupled with a diminished ionic charge bolsters the drug's ability to traverse cellular membranes. This comprehensive review delves into the utilization of fluorinated polymers for oncological pharmacotherapy, elucidating their molecular architecture, synthetic pathways, and functional attributes, alongside an exploration of their empirical strengths and the quandaries they encounter in both experimental and clinical settings.
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Affiliation(s)
- Jingrui Xin
- College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Xue Lu
- Frontiers Science Center for New Organic Matter, Nankai International Advanced Research Institute (Shenzhen, Futian), and College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jimin Cao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and First Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, China
| | - Weihui Wu
- Frontiers Science Center for New Organic Matter, Nankai International Advanced Research Institute (Shenzhen, Futian), and College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qian Liu
- Department of Urology, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Deping Wang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and First Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, China
| | - Xin Zhou
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and First Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, China
| | - Dan Ding
- Frontiers Science Center for New Organic Matter, Nankai International Advanced Research Institute (Shenzhen, Futian), and College of Life Sciences, Nankai University, Tianjin, 300071, China
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AIUM Practice Parameter for the Performance of Contrast-Enhanced Ultrasound. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2024; 43:E8-E19. [PMID: 37873725 DOI: 10.1002/jum.16360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/25/2023]
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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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9
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Yin X, Harmancey R, Frierson B, Wu JG, Moody MR, McPherson DD, Huang SL. Efficient Gene Editing for Heart Disease via ELIP-Based CRISPR Delivery System. Pharmaceutics 2024; 16:343. [PMID: 38543237 PMCID: PMC10974117 DOI: 10.3390/pharmaceutics16030343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/09/2024] [Accepted: 02/26/2024] [Indexed: 04/01/2024] Open
Abstract
Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa B (ELIP-NF-κB-FITC) were used both in vitro on mouse neonatal ventricular myocytes and in vivo on rat hearts to assess gene delivery efficacy with or without ultrasound. In vitro analysis was then repeated with ELIP containing Cas9-sg-IL1RL1 (interleukin 1 receptor-like 1) RNA to determine the efficiency of gene knockdown. ELIP-NF-κB-FITC without ultrasound showed limited gene delivery in vitro and in vivo, but ultrasound combined with ELIP notably improved penetration into heart cells and tissues. When ELIP was used to deliver Cas9-sg-IL1RL1 RNA, gene editing was successful and enhanced by ultrasound. This innovative approach shows promise for heart disease gene therapy using CRISPR technology.
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Affiliation(s)
- Xing Yin
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (R.H.); (B.F.); (M.R.M.); (D.D.M.)
| | - Romain Harmancey
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (R.H.); (B.F.); (M.R.M.); (D.D.M.)
| | - Brion Frierson
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (R.H.); (B.F.); (M.R.M.); (D.D.M.)
| | - Jean G. Wu
- Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA;
| | - Melanie R. Moody
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (R.H.); (B.F.); (M.R.M.); (D.D.M.)
| | - David D. McPherson
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (R.H.); (B.F.); (M.R.M.); (D.D.M.)
| | - Shao-Ling Huang
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (R.H.); (B.F.); (M.R.M.); (D.D.M.)
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10
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Li H, Lv W, Zhang Y, Feng Q, Wu H, Su C, Shu H, Nie F. PLGA-PEI nanobubbles carrying PDLIM5 siRNA inhibit EGFR-TKI-resistant NSCLC cell migration and invasion ability using UTND technology. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
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11
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Moradi Kashkooli F, Jakhmola A, Hornsby TK, Tavakkoli JJ, Kolios MC. Ultrasound-mediated nano drug delivery for treating cancer: Fundamental physics to future directions. J Control Release 2023; 355:552-578. [PMID: 36773959 DOI: 10.1016/j.jconrel.2023.02.009] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/13/2023]
Abstract
The application of biocompatible nanocarriers in medicine has provided several benefits over conventional treatment methods. However, achieving high treatment efficacy and deep penetration of nanocarriers in tumor tissue is still challenging. To address this, stimuli-responsive nano-sized drug delivery systems (DDSs) are an active area of investigation in delivering anticancer drugs. While ultrasound is mainly used for diagnostic purposes, it can also be applied to affect cellular function and the delivery/release of anticancer drugs. Therapeutic ultrasound (TUS) has shown potential as both a stand-alone anticancer treatment and a method to induce targeted drug release from nanocarrier systems. TUS approaches have been used to overcome various physiological obstacles, including endothelial barriers, the tumor microenvironment (TME), and immunological hurdles. Combining nanomedicine and ultrasound as a smart DDS can increase in situ drug delivery and improve access to impermeable tissues. Furthermore, smart DDSs can perform targeted drug release in response to distinctive TMEs, external triggers, or dual/multi-stimulus. This results in enhanced treatment efficacy and reduced damage to surrounding healthy tissue or organs at risk. Integrating DDSs and ultrasound is still in its early stages. More research and clinical trials are required to fully understand ultrasound's underlying physical mechanisms and interactions with various types of nanocarriers and different types of cells and tissues. In the present review, ultrasound-mediated nano-sized DDS, specifically focused on cancer treatment, is presented and discussed. Ultrasound interaction with nanoparticles (NPs), drug release mechanisms, and various types of ultrasound-sensitive NPs are examined. Additionally, in vitro, in vivo, and clinical applications of TUS are reviewed in light of the critical challenges that need to be considered to advance TUS toward an efficient, secure, straightforward, and accessible cancer treatment. This study also presents effective TUS parameters and safety considerations for this treatment modality and gives recommendations about system design and operation. Finally, future perspectives are considered, and different TUS approaches are examined and discussed in detail. This review investigates drug release and delivery through ultrasound-mediated nano-sized cancer treatment, both pre-clinically and clinically.
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Affiliation(s)
| | - Anshuman Jakhmola
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario, Canada
| | - Tyler K Hornsby
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario, Canada
| | - Jahangir Jahan Tavakkoli
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Michael C Kolios
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario, Canada; Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
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12
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Yu FTH, Amjad MW, Mohammed SA, Yu GZ, Chen X, Pacella JJ. Effect of Ultrasound Pulse Length on Sonoreperfusion Therapy. ULTRASOUND IN MEDICINE & BIOLOGY 2023; 49:152-164. [PMID: 36253230 PMCID: PMC9712163 DOI: 10.1016/j.ultrasmedbio.2022.08.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 06/16/2023]
Abstract
In recent years, long- and short-pulse ultrasound (US)-targeted microbubble cavitation (UTMC) has been found to increase perfusion in healthy and ischemic skeletal muscle, in pre-clinical animal models of microvascular obstruction and in the myocardium of patients presenting with acute myocardial infarction. There is evidence that the observed microvascular vasodilation is driven by the nitric oxide pathway and purinergic signaling, but the time course of the response and the dependency on US pulse length are not well elucidated. Because our prior data supported that sonoreperfusion efficacy is enhanced by long-pulse US versus short-pulse US, in this study, we sought to compare long-pulse (5000 cycles) and short-pulse (500 × 10 cycles) US at a pressure of 1.5 MPa with an equivalent total number of acoustical cycles, hence constant acoustic energy, and at the same frequency (1 MHz), in a rodent hind limb model with and without microvascular obstruction (MVO). In quantifying perfusion using burst replenishment contrast-enhanced US imaging, we made three findings: (i) Long and short pulses result in different vasodilation kinetics in an intact hind limb model. The long pulse causes an initial spasmic reduction in flow that spontaneously resolved at 4 min, followed by sustained higher flow rates (approximately twofold) compared with baseline, starting 10 min after therapy (p < 0.05). The short pulse caused a short-lived approximately twofold increase in flow rate that peaked at 4 min (p < 0.05), but without the initial spasm. (ii) The sustained increased response with the long pulse is not simply reactive hyperemia. (iii) Both pulses are effective in reperfusion of MVO in our hindlimb model by restoring blood volume, but only the long pulse caused an increase in flow rate after treatment ii, compared with MVO (p < 0.05). Histological analysis of hind limb muscle post-UTMC with either pulse configuration indicates no evidence of tissue damage or hemorrhage. Our findings indicate that the microbubble oscillation induces vasodilation, and therapeutic efficacy for the treatment of MVO can be tuned by varying pulse length; relative to short-pulse US, longer pulses drive greater microbubble cavitation and more rapid microvascular flow rate restoration after MVO, warranting further optimization of the pulse length for sonoreperfusion therapy.
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Affiliation(s)
- François T H Yu
- Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de Radiologie, Radio-Oncologie et Médecine Nucléaire, Université de Montréal, Montréal, Québec, Canada
| | - Muhammad Wahab Amjad
- Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Soheb Anwar Mohammed
- Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Gary Z Yu
- Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Xucai Chen
- Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - John J Pacella
- Center for Ultrasound Molecular Imaging and Therapeutics, Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Stable Cavitation-Mediated Delivery of miR-126 to Endothelial Cells. Pharmaceutics 2022; 14:pharmaceutics14122656. [PMID: 36559150 PMCID: PMC9784098 DOI: 10.3390/pharmaceutics14122656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
In endothelial cells, microRNA-126 (miR-126) promotes angiogenesis, and modulating the intracellular levels of this gene could suggest a method to treat cardiovascular diseases such as ischemia. Novel ultrasound-stimulated microbubbles offer a means to deliver therapeutic payloads to target cells and sites of disease. The purpose of this study was to investigate the feasibility of gene delivery by stimulating miR-126-decorated microbubbles using gentle acoustic conditions (stable cavitation). A cationic DSTAP microbubble was formulated and characterized to carry 6 µg of a miR-126 payload per 109 microbubbles. Human umbilical vein endothelial cells (HUVECs) were treated at 20−40% duty cycle with miR-126-conjugated microbubbles in a custom ultrasound setup coupled with a passive cavitation detection system. Transfection efficiency was assessed by RT-qPCR, Western blotting, and endothelial tube formation assay, while HUVEC viability was monitored by MTT assay. With increasing duty cycle, the trend observed was an increase in intracellular miR-126 levels, up to a 2.3-fold increase, as well as a decrease in SPRED1 (by 33%) and PIK3R2 (by 46%) expression, two salient miR-126 targets. Under these ultrasound parameters, HUVECs maintained >95% viability after 96 h. The present work describes the delivery of a proangiogenic miR-126 using an ultrasound-responsive cationic microbubble with potential to stimulate therapeutic angiogenesis while minimizing endothelial damage.
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Zhang L, Lin Z, Zeng L, Zhang F, Sun L, Sun S, Wang P, Xu M, Zhang J, Liang X, Ge H. Ultrasound-induced biophysical effects in controlled drug delivery. SCIENCE CHINA. LIFE SCIENCES 2022; 65:896-908. [PMID: 34453275 DOI: 10.1007/s11427-021-1971-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/27/2021] [Indexed: 12/30/2022]
Abstract
Ultrasound is widely used in biomedical engineering and has applications in conventional diagnosis and drug delivery. Recent advances in ultrasound-induced drug delivery have been summarized previously in several reviews that have primarily focused on the fabrication of drug delivery carriers. This review discusses the mechanisms underlying ultrasound-induced drug delivery and factors affecting delivery efficiency, including the characteristics of drug delivery carriers and ultrasound parameters. Firstly, biophysical effects induced by ultrasound, namely thermal effects, cavitation effects, and acoustic radiation forces, are illustrated. Secondly, the use of these biophysical effects to enhance drug delivery by affecting drug carriers and corresponding tissues is clarified in detail. Thirdly, recent advances in ultrasound-triggered drug delivery are detailed. Safety issues and optimization strategies to improve therapeutic outcomes and reduce side effects are summarized. Finally, current progress and future directions are discussed.
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Affiliation(s)
- Lulu Zhang
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Zhuohua Lin
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Lan Zeng
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Fan Zhang
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Lihong Sun
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Suhui Sun
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Ping Wang
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Menghong Xu
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Jinxia Zhang
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Xiaolong Liang
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China.
| | - Huiyu Ge
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China.
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15
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Singh R, Yang X. A 3D finite element model to study the cavitation induced stresses on blood-vessel wall during the ultrasound-only phase of photo-mediated ultrasound therapy. AIP ADVANCES 2022; 12:045020. [PMID: 35465057 PMCID: PMC9020880 DOI: 10.1063/5.0082429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/28/2022] [Indexed: 06/14/2023]
Abstract
Photo-mediated ultrasound therapy (PUT) is a novel technique utilizing synchronized ultrasound and laser to generate enhanced cavitation inside blood vessels. The enhanced cavitation inside blood vessels induces bio-effects, which can result in the removal of micro-vessels and the reduction in local blood perfusion. These bio-effects have the potential to treat neovascularization diseases in the eye, such as age-related macular degeneration and diabetic retinopathy. Currently, PUT is in the preclinical stage, and various PUT studies on in vivo rabbit eye models have shown successful removal of micro-vessels. PUT is completely non-invasive and particle-free as opposed to current clinical treatments such as anti-vascular endothelial growth factor therapy and photodynamic therapy, and it precisely removes micro-vessels without damaging the surrounding tissue, unlike laser photocoagulation therapy. The stresses produced by oscillating bubbles during PUT are responsible for the induced bio-effects in blood vessels. In our previous work, stresses induced during the first phase of PUT due to combined ultrasound and laser irradiation were studied using a 2D model. In this work, stresses induced during the third or last phase of PUT due to ultrasound alone were studied using a 3D finite element method-based numerical model. The results showed that the circumferential and shear stress increased as the bubble moves from the center of the vessel toward the vessel wall with more than a 16 times increase in shear stress from 1.848 to 31.060 kPa as compared to only a 4 times increase in circumferential stress from 211 to 906 kPa for a 2 µm bubble placed inside a 10 µm vessel on the application of 1 MHz ultrasound frequency and 130 kPa amplitude. In addition, the stresses decreased as the bubble was placed in smaller sized vessels with a larger decrease in circumferential stress. The changes in shear stress were found to be more dependent on the bubble-vessel wall distance, and the changes in circumferential stress were more dependent on the bubble oscillation amplitude. Moreover, the bubble shape changed to an ellipsoidal with a higher oscillation amplitude in the vessel's axial direction as it was moved closer to the vessel wall, and the bubble oscillation amplitude decreased drastically as it was placed in vessels of a smaller size.
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Affiliation(s)
| | - Xinmai Yang
- Author to whom correspondence should be addressed:
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16
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Highlights in ultrasound-targeted microbubble destruction-mediated gene/drug delivery strategy for treatment of malignancies. Int J Pharm 2021; 613:121412. [PMID: 34942327 DOI: 10.1016/j.ijpharm.2021.121412] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/06/2021] [Accepted: 12/17/2021] [Indexed: 01/05/2023]
Abstract
Ultrasound is one of the safest and most advanced medical imaging technologies that is widely used in clinical practice. Ultrasound microbubbles, traditionally used for contrast-enhanced imaging, are increasingly applied in Ultrasound-targeted Microbubble Destruction (UTMD) technology which enhances tissue and cell membrane permeability through cavitation and sonoporation, to result in a promising therapeutic gene/drug delivery strategy. Here, we review recent developments in the application of UTMD-mediated gene and drug delivery in the diagnosis and treatment of tumors, including the concept, mechanism of action, clinical application status, and advantages of UTMD. Furthermore, the future perspectives that should be paid more attention to in this field are prospected.
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17
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Resealed erythrocytes: Towards a novel approach for anticancer therapy. J INDIAN CHEM SOC 2021. [DOI: 10.1016/j.jics.2021.100257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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18
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Ultrasound-Enabled Therapeutic Delivery and Regenerative Medicine: Physical and Biological Perspectives. ACS Biomater Sci Eng 2021; 7:4371-4387. [PMID: 34460238 DOI: 10.1021/acsbiomaterials.1c00276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The role of ultrasound in medicine and biological sciences is expanding rapidly beyond its use in conventional diagnostic imaging. Numerous studies have reported the effects of ultrasound on cellular and tissue physiology. Advances in instrumentation and electronics have enabled successful in vivo applications of therapeutic ultrasound. Despite path breaking advances in understanding the biophysical and biological mechanisms at both microscopic and macroscopic scales, there remain substantial gaps. With the progression of research in this area, it is important to take stock of the current understanding of the field and to highlight important areas for future work. We present herein key developments in the biological applications of ultrasound especially in the context of nanoparticle delivery, drug delivery, and regenerative medicine. We conclude with a brief perspective on the current promise, limitations, and future directions for interfacing ultrasound technology with biological systems, which could provide guidance for future investigations in this interdisciplinary area.
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Grygorczyk R, Boudreault F, Ponomarchuk O, Tan JJ, Furuya K, Goldgewicht J, Kenfack FD, Yu F. Lytic Release of Cellular ATP: Physiological Relevance and Therapeutic Applications. Life (Basel) 2021; 11:life11070700. [PMID: 34357072 PMCID: PMC8307140 DOI: 10.3390/life11070700] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 05/28/2021] [Accepted: 07/13/2021] [Indexed: 01/01/2023] Open
Abstract
The lytic release of ATP due to cell and tissue injury constitutes an important source of extracellular nucleotides and may have physiological and pathophysiological roles by triggering purinergic signalling pathways. In the lungs, extracellular ATP can have protective effects by stimulating surfactant and mucus secretion. However, excessive extracellular ATP levels, such as observed in ventilator-induced lung injury, act as a danger-associated signal that activates NLRP3 inflammasome contributing to lung damage. Here, we discuss examples of lytic release that we have identified in our studies using real-time luciferin-luciferase luminescence imaging of extracellular ATP. In alveolar A549 cells, hypotonic shock-induced ATP release shows rapid lytic and slow-rising non-lytic components. Lytic release originates from the lysis of single fragile cells that could be seen as distinct spikes of ATP-dependent luminescence, but under physiological conditions, its contribution is minimal <1% of total release. By contrast, ATP release from red blood cells results primarily from hemolysis, a physiological mechanism contributing to the regulation of local blood flow in response to tissue hypoxia, mechanical stimulation and temperature changes. Lytic release of cellular ATP may have therapeutic applications, as exemplified by the use of ultrasound and microbubble-stimulated release for enhancing cancer immunotherapy in vivo.
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Affiliation(s)
- Ryszard Grygorczyk
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
- Département de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada
- Correspondence: (R.G.); (F.Y.)
| | - Francis Boudreault
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
| | - Olga Ponomarchuk
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
| | - Ju Jing Tan
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
| | - Kishio Furuya
- Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan;
| | - Joseph Goldgewicht
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
| | - Falonne Démèze Kenfack
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
| | - François Yu
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; (F.B.); (O.P.); (J.J.T.); (J.G.); (F.D.K.)
- Département de Radiologie, Radio-Oncologie et Médecine Nucléaire, Université de Montréal, Montréal, QC H2X 0A9, Canada
- Institut de Génie Biomédical, Université de Montréal, Montréal, QC H2X 0A9, Canada
- Correspondence: (R.G.); (F.Y.)
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20
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Ruan JL, Browning RJ, Yildiz YO, Bau L, Kamila S, Gray MD, Folkes L, Hampson A, McHale AP, Callan JF, Vojnovic B, Kiltie AE, Stride E. Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles. ULTRASOUND IN MEDICINE & BIOLOGY 2021; 47:1596-1615. [PMID: 33707089 DOI: 10.1016/j.ultrasmedbio.2021.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 06/12/2023]
Abstract
In this study we compared three different microbubble-based approaches to the delivery of a widely used chemotherapy drug, gemcitabine: (i) co-administration of gemcitabine and microbubbles (Gem+MB); (ii) conjugates of microbubbles and gemcitabine-loaded liposomes (GemlipoMB); and (iii) microbubbles with gemcitabine directly bound to their surfaces (GembioMB). Both in vitro and in vivo investigations were carried out, respectively, in the RT112 bladder cancer cell line and in a murine orthotopic muscle-invasive bladder cancer model. The in vitro (in vivo) ultrasound exposure conditions were a 1 (1.1) MHz centre frequency, 0.07 (1.0) MPa peak negative pressure, 3000 (20,000) cycles and 100 (0.5) Hz pulse repetition frequency. Ultrasound exposure produced no significant increase in drug uptake either in vitro or in vivo compared with the drug-only control for co-administered gemcitabine and microbubbles. In vivo, GemlipoMB prolonged the plasma circulation time of gemcitabine, but only GembioMB produced a statistically significant increase in cleaved caspase 3 expression in the tumor, indicative of gemcitabine-induced apoptosis.
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Affiliation(s)
- Jia-Ling Ruan
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Richard J Browning
- Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom
| | - Yesna O Yildiz
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Luca Bau
- Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom
| | - Sukanta Kamila
- Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Michael D Gray
- Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom
| | - Lisa Folkes
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Alix Hampson
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Anthony P McHale
- Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - John F Callan
- Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Borivoj Vojnovic
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Anne E Kiltie
- MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Eleanor Stride
- Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.
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21
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Wang F, Chen J, Liu J, Zeng H. Cancer theranostic platforms based on injectable polymer hydrogels. Biomater Sci 2021; 9:3543-3575. [PMID: 33634800 DOI: 10.1039/d0bm02149k] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Theranostic platforms that combine therapy with diagnosis not only prevent the undesirable biological responses that may occur when these processes are conducted separately, but also allow individualized therapies for patients. Polymer hydrogels have been employed to provide well-controlled drug release and targeted therapy in theranostics, where injectable hydrogels enable non-invasive treatment and monitoring with a single injection, offering greater patient comfort and efficient therapy. Efforts have been focused on applying injectable polymer hydrogels in theranostic research and clinical use. This review highlights recent progress in the design of injectable polymer hydrogels for cancer theranostics, particularly focusing on the elements/components of theranostic hydrogels, and their cross-linking strategies, structures, and performance with regard to drug delivery/tracking. Therapeutic agents and tracking modalities that are essential components of the theranostic platforms are introduced, and the design strategies, properties and applications of the injectable hydrogels developed via two approaches, namely chemical bonds and physical interactions, are described. The theranostic functions of the platforms are highly dependent on the architecture and components employed for the construction of hydrogels. Challenges currently presented by theranostic platforms based on injectable hydrogels are identified, and prospects of acquiring more comfortable and personalized therapies are proposed.
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Affiliation(s)
- Feifei Wang
- The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510700, China. and Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada.
| | - Jingsi Chen
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada.
| | - Jifang Liu
- The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510700, China.
| | - Hongbo Zeng
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada.
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22
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Abstract
Gas-filled microbubbles are currently in clinical use as blood pool contrast agents for ultrasound imaging. The goal of this review is to discuss the trends and issues related to these relatively unusual intravascular materials, which are not small molecules per se, not polymers, not even nanoparticles, but larger micrometer size structures, compressible, flexible, elastic, and deformable. The intent is to connect current research and initial studies from 2 to 3 decades ago, tied to gas exchange between the bubbles and surrounding biological medium, in the following areas of focus: (1) parameters of microbubble movement in relation to vasculature specifics; (2) gas uptake and loss from the bubbles in the vasculature; (3) adhesion of microbubbles to target receptors in the vasculature; and (4) microbubble interaction with the surrounding vessels and tissues during insonation.Microbubbles are generally safe and require orders of magnitude lower material doses than x-ray and magnetic resonance imaging contrast agents. Application of microbubbles will soon extend beyond blood pool contrast and tissue perfusion imaging. Microbubbles can probe molecular and cellular biomarkers of disease by targeted contrast ultrasound imaging. This approach is now in clinical trials, for example, with the aim to detect and delineate tumor nodes in prostate, breast, and ovarian cancer. Imaging of inflammation, ischemia-reperfusion injury, and ischemic memory is also feasible. More importantly, intravascular microbubbles can be used for local deposition of focused ultrasound energy to enhance drug and gene delivery to cells and tissues, across endothelial barrier, especially blood-brain barrier.Overall, microbubble behavior, stability and in vivo lifetime, bioeffects upon the action of ultrasound and resulting enhancement of drug and gene delivery, as well as targeted imaging are critically dependent on the events of gas exchange between the bubbles and surrounding media, as outlined in this review.
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Affiliation(s)
- Alexander L Klibanov
- From the Cardiovascular Division, Department of Medicine and Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine; and Departments of Biomedical Engineering, and Radiology, University of Virginia, Charlottesville, VA
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23
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Zhang Z, Chen Z, Fan L, Landry T, Brown J, Yu Z, Yin S, Wang J. Ultrasound-microbubble cavitation facilitates adeno-associated virus mediated cochlear gene transfection across the round-window membrane. Bioeng Transl Med 2021; 6:e10189. [PMID: 33532589 PMCID: PMC7823126 DOI: 10.1002/btm2.10189] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/12/2020] [Accepted: 09/14/2020] [Indexed: 11/09/2022] Open
Abstract
The round window of the cochlea provides an ideal route for delivering medicines and gene therapy reagents that can cross the round window membrane (RWM) into the inner ear. Recombinant adeno-associated viruses (rAAVs) have several advantages and are recommended as viral vectors for gene transfection. However, rAAVs cannot cross an intact RWM. Consequently, ultrasound-mediated microbubble (USMB) cavitation is potentially useful, because it can sonoporate the cell membranes, and increase their permeability to large molecules. The use of USMB cavitation for drug delivery across the RWM has been tested in a few animal studies but has not been used in the context of AAV-mediated gene transfection. The currently available large size of the ultrasound probe appears to be a limiting factor in the application of this method to the RWM. In this study, we used home-made ultrasound probe with a decreased diameter to 1.5 mm, which enabled the easy positioning of the probe close to the RWM. In guinea pigs, we used this probe to determine that (1) USMB cavitation caused limited damage to the outer surface layer or the RWM, (2) an eGFP-gene carrying rAAV could effectively pass the USMB-treated RWM and reliably transfect cochlear cells, and (3) the hearing function of the cochlea remained unchanged. Our results suggest that USMB cavitation of the RWM is a good method for rAAV-mediated cochlear gene transfection with clear potential for clinical translation. We additionally discuss several advantages of the small probe size.
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Affiliation(s)
- Zhen Zhang
- Otolaryngology Research Institute, 6th Affiliated HospitalJiao Tong UniversityShanghaiChina
- Shanghai Key Laboratory of Sleep Disordered Breathing, 6th Affiliated Hospital, Jiao Tong UniversityShanghaiChina
| | - Zhengnong Chen
- Otolaryngology Research Institute, 6th Affiliated HospitalJiao Tong UniversityShanghaiChina
- Shanghai Key Laboratory of Sleep Disordered Breathing, 6th Affiliated Hospital, Jiao Tong UniversityShanghaiChina
| | - Liqiang Fan
- Otolaryngology Research Institute, 6th Affiliated HospitalJiao Tong UniversityShanghaiChina
- Shanghai Key Laboratory of Sleep Disordered Breathing, 6th Affiliated Hospital, Jiao Tong UniversityShanghaiChina
| | - Thomas Landry
- School of Biomedical EngineeringDalhousie UniversityHalifaxCanada
| | - Jeremy Brown
- School of Biomedical EngineeringDalhousie UniversityHalifaxCanada
| | - Zhiping Yu
- School of Communication Science and DisordersDalhousie UniversityHalifaxCanada
| | - Shankai Yin
- Otolaryngology Research Institute, 6th Affiliated HospitalJiao Tong UniversityShanghaiChina
- Shanghai Key Laboratory of Sleep Disordered Breathing, 6th Affiliated Hospital, Jiao Tong UniversityShanghaiChina
| | - Jian Wang
- School of Communication Science and DisordersDalhousie UniversityHalifaxCanada
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Amate M, Goldgewicht J, Sellamuthu B, Stagg J, Yu FTH. The effect of ultrasound pulse length on microbubble cavitation induced antibody accumulation and distribution in a mouse model of breast cancer. Nanotheranostics 2020; 4:256-269. [PMID: 33033688 PMCID: PMC7532643 DOI: 10.7150/ntno.46892] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/21/2020] [Indexed: 12/14/2022] Open
Abstract
In solid tumors, the limited diffusion of therapeutic molecules in the perivascular space is a known limitation impacting treatment efficacy. Ultrasound Targeted Microbubble Cavitation (UTMC) has been shown to increase vascular permeability and improve the delivery of therapeutic compounds including small molecules, antibodies (mAb), nanoparticles and even cells, notably across the blood-brain-barrier (BBB). In this study, we hypothesized that UTMC could improve the accumulation and biodistribution of mAb targeting the adenosinergic pathway (i.e. CD73) in mice bearing bilateral subcutaneous 4T1 mammary carcinoma. METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc "long", 125x40cyc "mid" and 500x10cyc "short"), and leaving the left tumor as a paired control. Longitudinal accumulation at 0 h, 4 h and 24 h was measured using whole-body biofluorescence and confocal microscopy. RESULTS: Our data support an increase in antibody accumulation and extravasation (# extravasated vessels and extravasated signal intensity) at 0 h for all pulses and at 4 h for the mid and short pulses when compared to the control non treated side. However, this difference was not found at 24 h post UTMC, indicative of the transient nature of UTMC. Interestingly, confocal data supported that the highest extravasation range was obtained at 0 h with the long pulse and that the short pulse caused no increase in the extravasation range. Overall, the mid pulse was the only pulse to increase all our metrics (biofluorescence, fraction of extravasated vessels, amount of extravasated Ab, and extravasation range) at 0 h and 4 h time points. CONCLUSIONS: Our results support that UTMC can enhance antibody accumulation in solid tumors at the macroscopic and microscopic levels. This preferential accumulation was evident at early time points (0 h and 4 h) but had started to fade by 24 h, a time dependence that is consistent with the ultrasound blood brain barrier opening literature. Further development and optimization of this theranostic platform, such as repeated UTMC, could help improve antibody based therapies against solid cancer.
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Affiliation(s)
- Marie Amate
- Microbubble Theranostic Laboratory, CHUM Research Center, Montreal, Canada
| | - Joseph Goldgewicht
- Microbubble Theranostic Laboratory, CHUM Research Center, Montreal, Canada.,Department of Radiology, Radiation Oncology and Nuclear Medicine, Faculty of Medicine, Université de Montréal
| | | | - John Stagg
- Faculty of Pharmacy, Université de Montréal
| | - Francois T H Yu
- Microbubble Theranostic Laboratory, CHUM Research Center, Montreal, Canada.,Department of Radiology, Radiation Oncology and Nuclear Medicine, Faculty of Medicine, Université de Montréal
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25
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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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26
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Wang S, Hossack JA, Klibanov AL. From Anatomy to Functional and Molecular Biomarker Imaging and Therapy: Ultrasound Is Safe, Ultrafast, Portable, and Inexpensive. Invest Radiol 2020; 55:559-572. [PMID: 32776766 PMCID: PMC10290890 DOI: 10.1097/rli.0000000000000675] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ultrasound is the most widely used medical imaging modality worldwide. It is abundant, extremely safe, portable, and inexpensive. In this review, we consider some of the current development trends for ultrasound imaging, which build upon its current strength and the popularity it experiences among medical imaging professional users.Ultrasound has rapidly expanded beyond traditional radiology departments and cardiology practices. Computing power and data processing capabilities of commonly available electronics put ultrasound systems in a lab coat pocket or on a user's mobile phone. Taking advantage of new contributions and discoveries in ultrasound physics, signal processing algorithms, and electronics, the performance of ultrasound systems and transducers have progressed in terms of them becoming smaller, with higher imaging performance, and having lower cost. Ultrasound operates in real time, now at ultrafast speeds; kilohertz frame rates are already achieved by many systems.Ultrasound has progressed beyond anatomical imaging and monitoring blood flow in large vessels. With clinical approval of ultrasound contrast agents (gas-filled microbubbles) that are administered in the bloodstream, tissue perfusion studies are now routine. Through the use of modern ultrasound pulse sequences, individual microbubbles, with subpicogram mass, can be detected and observed in real time, many centimeters deep in the body. Ultrasound imaging has broken the wavelength barrier; by tracking positions of microbubbles within the vasculature, superresolution imaging has been made possible. Ultrasound can now trace the smallest vessels and capillaries, and obtain blood velocity data in those vessels.Molecular ultrasound imaging has now moved closer to clinic; the use of microbubbles with a specific affinity to endothelial biomarkers allows selective accumulation and retention of ultrasound contrast in the areas of ischemic injury, inflammation, or neoangiogenesis. This will aid in noninvasive molecular imaging and may provide additional help with real-time guidance of biopsy, surgery, and ablation procedures.The ultrasound field can be tightly focused inside the body, many centimeters deep, with millimeter precision, and ablate lesions by energy deposition, with thermal or mechanical bioeffects. Some of such treatments are already in clinical use, with more indications progressing through the clinical trial stage. In conjunction with intravascular microbubbles, focused ultrasound can be used for tissue-specific drug delivery; localized triggered release of sequestered drugs from particles in the bloodstream may take time to get to clinic. A combination of intravascular microbubbles with circulating drug and low-power ultrasound allows transient opening of vascular endothelial barriers, including blood-brain barrier; this approach has reached clinical trial stage. Therefore, the drugs that normally would not be getting to the target tissue in the brain will now have an opportunity to produce therapeutic efficacy.Overall, medical ultrasound is developing at a brisk rate, even in an environment where other imaging modalities are also advancing rapidly and may be considered more lucrative. With all the current advances that we discuss, and many more to come, ultrasound may help solve many problems that modern medicine is facing.
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Liu DD, Ullah M, Concepcion W, Dahl JJ, Thakor AS. The role of ultrasound in enhancing mesenchymal stromal cell-based therapies. Stem Cells Transl Med 2020; 9:850-866. [PMID: 32157802 PMCID: PMC7381806 DOI: 10.1002/sctm.19-0391] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 02/17/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been a popular platform for cell-based therapy in regenerative medicine due to their propensity to home to damaged tissue and act as a repository of regenerative molecules that can promote tissue repair and exert immunomodulatory effects. Accordingly, a great deal of research has gone into optimizing MSC homing and increasing their secretion of therapeutic molecules. A variety of methods have been used to these ends, but one emerging technique gaining significant interest is the use of ultrasound. Sound waves exert mechanical pressure on cells, activating mechano-transduction pathways and altering gene expression. Ultrasound has been applied both to cultured MSCs to modulate self-renewal and differentiation, and to tissues-of-interest to make them a more attractive target for MSC homing. Here, we review the various applications of ultrasound to MSC-based therapies, including low-intensity pulsed ultrasound, pulsed focused ultrasound, and extracorporeal shockwave therapy, as well as the use of adjunctive therapies such as microbubbles. At a molecular level, it seems that ultrasound transiently generates a local gradient of cytokines, growth factors, and adhesion molecules that facilitate MSC homing. However, the molecular mechanisms underlying these methods are far from fully elucidated and may differ depending on the ultrasound parameters. We thus put forth minimal criteria for ultrasound parameter reporting, in order to ensure reproducibility of studies in the field. A deeper understanding of these mechanisms will enhance our ability to optimize this promising therapy to assist MSC-based approaches in regenerative medicine.
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Affiliation(s)
- Daniel D. Liu
- Interventional Regenerative Medicine and Imaging Laboratory, Department of RadiologyStanford UniversityPalo AltoCalifornia
| | - Mujib Ullah
- Interventional Regenerative Medicine and Imaging Laboratory, Department of RadiologyStanford UniversityPalo AltoCalifornia
| | | | - Jeremy J. Dahl
- Interventional Regenerative Medicine and Imaging Laboratory, Department of RadiologyStanford UniversityPalo AltoCalifornia
| | - Avnesh S. Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of RadiologyStanford UniversityPalo AltoCalifornia
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Combes F, Meyer E, Sanders NN. Immune cells as tumor drug delivery vehicles. J Control Release 2020; 327:70-87. [PMID: 32735878 DOI: 10.1016/j.jconrel.2020.07.043] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 12/21/2022]
Abstract
This review article describes the use of immune cells as potential candidates to deliver anti-cancer drugs deep within the tumor microenvironment. First, the rationale of using drug carriers to target tumors and potentially decrease drug-related side effects is discussed. We further explain some of the current limitations when using nanoparticles for this purpose. Next, a comprehensive step-by-step description of the migration cascade of immune cells is provided as well as arguments on why immune cells can be used to address some of the limitations associated with nanoparticle-mediated drug delivery. We then describe the benefits and drawbacks of using red blood cells, platelets, granulocytes, monocytes, macrophages, myeloid-derived suppressor cells, T cells and NK cells for tumor-targeted drug delivery. An additional section discusses the versatility of nanoparticles to load anti-cancer drugs into immune cells. Lastly, we propose increasing the circulatory half-life and development of conditional release strategies as the two main future pillars to improve the efficacy of immune cell-mediated drug delivery to tumors.
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Affiliation(s)
- Francis Combes
- Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium
| | - Evelyne Meyer
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Niek N Sanders
- Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium.
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Bellary A, Villarreal A, Eslami R, Undseth QJ, Lec B, Defnet AM, Bagrodia N, Kandel JJ, Borden MA, Shaikh S, Chopra R, Laetsch TW, Delaney LJ, Shaw CM, Eisenbrey JR, Hernandez SL, Sirsi SR. Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake in vivo. Theranostics 2020; 10:8143-8161. [PMID: 32724463 PMCID: PMC7381728 DOI: 10.7150/thno.45903] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/03/2020] [Indexed: 12/31/2022] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.
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Affiliation(s)
- Aditi Bellary
- Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA
| | - Arelly Villarreal
- Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA
| | - Rojin Eslami
- Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA
| | - Quincy J. Undseth
- Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA
| | - Bianca Lec
- Department of Surgery, University of Chicago Medical School, Chicago, IL, USA
| | - Ann M. Defnet
- Department of Surgery, University of Chicago Medical School, Chicago, IL, USA
| | - Naina Bagrodia
- Department of Surgery, University of Chicago Medical School, Chicago, IL, USA
| | - Jessica J. Kandel
- Department of Surgery, University of Chicago Medical School, Chicago, IL, USA
| | - Mark A. Borden
- Biomedical Engineering, Mechanical Engineering, University of Colorado, Boulder, CO, USA
| | - Sumbul Shaikh
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rajiv Chopra
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Theodore W. Laetsch
- Department of Pediatrics and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX, USA
| | - Lauren J. Delaney
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Colette M. Shaw
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA
| | - John R. Eisenbrey
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sonia L. Hernandez
- Department of Surgery, University of Chicago Medical School, Chicago, IL, USA
| | - Shashank R. Sirsi
- Department of Biomedical Engineering, University of Texas at Dallas, Richardson, TX, USA
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Presset A, Bonneau C, Kazuyoshi S, Nadal-Desbarats L, Mitsuyoshi T, Bouakaz A, Kudo N, Escoffre JM, Sasaki N. Endothelial Cells, First Target of Drug Delivery Using Microbubble-Assisted Ultrasound. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:1565-1583. [PMID: 32331799 DOI: 10.1016/j.ultrasmedbio.2020.03.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 03/12/2020] [Accepted: 03/13/2020] [Indexed: 06/11/2023]
Abstract
Microbubble-assisted ultrasound has emerged as a promising method for local drug delivery. Microbubbles are intravenously injected and locally activated by ultrasound, thus increasing the permeability of vascular endothelium for facilitating extravasation and drug uptake into the treated tissue. Thereby, endothelial cells are the first target of the effects of ultrasound-driven microbubbles. In this review, the in vitro and in vivo bioeffects of this method on endothelial cells are described and discussed, including aspects on the permeabilization of biologic barriers (endothelial cell plasma membranes and endothelial barriers), the restoration of their integrity, the molecular and cellular mechanisms involved in both these processes, and the resulting intracellular and intercellular consequences. Finally, the influence of the acoustic settings, microbubble parameters, treatment schedules and flow parameters on these bioeffects are also reviewed.
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Affiliation(s)
- Antoine Presset
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
| | | | - Sasaoka Kazuyoshi
- Laboratory of Veterinary Internal Medicine, Department of Clinical Sciences; Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | | | - Takigucho Mitsuyoshi
- Laboratory of Veterinary Internal Medicine, Department of Clinical Sciences; Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Ayache Bouakaz
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
| | - Nobuki Kudo
- Laboratory of Biological Engineering, Graduate School of Information Science and Technology, Hokkaido University, Sapporo, Japan
| | | | - Noboru Sasaki
- Laboratory of Veterinary Internal Medicine, Department of Clinical Sciences; Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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AIUM Practice Parameter for the Performance of Contrast-Enhanced Ultrasound Examinations. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2020; 39:421-429. [PMID: 31930582 DOI: 10.1002/jum.15204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
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Wang L, Li X, Dong Y, Wang P, Xu M, Zheng C, Jiao Y, Zou C. Effects of Cytotoxic T Lymphocyte-Associated Antigen 4 Immunoglobulin Combined with Microbubble-Mediated Irradiation on Hemodynamics of the Renal Artery in Rats with Diabetic Nephropathy. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:703-711. [PMID: 31864804 DOI: 10.1016/j.ultrasmedbio.2019.11.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 11/18/2019] [Accepted: 11/20/2019] [Indexed: 06/10/2023]
Abstract
Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA-4-Ig) can inhibit the effect of B7-1 and improve renal hemodynamics in rats with diabetic nephropathy (DN). Nevertheless, a strategy that could increase the permeation of CTLA-4-Ig through endothelial cells and basement membrane remains to be discovered. We investigated the effect of CTLA-4-Ig combined with microbubble-mediated irradiation on the hemodynamics of renal arteries in DN rats. Rats were treated with CTLA-4-Ig and/or microbubble exposure. After 8 wk of intervention, color Doppler ultrasonography was used to detect peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), systolic acceleration (SAC), pulsatility index (PI) and resistance index (RI) of the renal artery trunk. The CTLA-4-Ig + microbubble exposure group exhibited significantly higher PSV, EDV and MV than the CTLA-4-Ig group, which had significantly higher values than the non-intervention group. The CTLA-4-Ig + microbubble exposure group exhibited significantly lower SAC, PI and RI than the CTLA-4-Ig group, which had significantly lower values than the non-intervention group. Our results indicate that both CTLA-4-Ig and CTLA-4-Ig + microbubble exposure can reduce the blood flow resistance and improve the blood flow velocity of renal arteries in rats. Moreover, the effect of CTLA-4-Ig + microbubble exposure is better than that of CTLA-4-Ig alone. Our study provides a new, effective and non-invasive strategy for the treatment of DN.
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Affiliation(s)
- Liang Wang
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiuyun Li
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanyan Dong
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pengfei Wang
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Maosheng Xu
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chao Zheng
- Diabetes Center and Department of Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yan Jiao
- Obstetrics and Gynecology Ultrasonic Department, Wenzhou City People's Hospital, Wenzhou, China
| | - Chunpeng Zou
- Department of Ultrasonic Diagnosis, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
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Abstract
Ultrasound and magneto-responsive nanosized drug delivery systems have been designed as novel carriers for controlled release. Colloidal bubbles (CBs) could be designed to incorporate different materials, such as protein, lipid, polymer, surfactants, and even nanoparticles in their shell, which makes them suitable for a wide range of drug delivery applications. The interior of CBs may be filled with different gases, which is essential for conferring the characteristics of an ultrasounds contrasting agent. Manipulating the core of CBs enhances features such as stability and duration of the echogenic effect. Thus CBs derivatized with nanoparticles combine functional properties of CBs and NPs to yield a versatile theranostics platform technology.
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Borden MA. Intermolecular Forces Model for Lipid Microbubble Shells. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2019; 35:10042-10051. [PMID: 30543753 DOI: 10.1021/acs.langmuir.8b03641] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Lipid-coated microbubbles are currently used clinically as ultrasound contrast agents for echocardiography and radiology and are being developed for many new diagnostic and therapeutic applications. Accordingly, there is a growing need to engineer specific formulations by employing rational design to guide lipid selection and processing. This approach requires a quantitative relationship between lipid chemistry and interfacial properties of the microbubble shell. Just such a model is proposed here on the basis of lateral Coulomb and van der Waals interactions between lipid head- and tailgroups, using previous coarse graining and force fields developed for molecular dynamics simulations. The model predicts with sufficient accuracy the monolayer permeability, the elasticity as a function of either lipid composition or temperature, and the equilibrium spreading surface tension of the lipid onto an air/water interface. In the future, the intermolecular forces model could be employed to elucidate more complex phenomena and to engineer novel microbubble formulations.
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Affiliation(s)
- Mark Andrew Borden
- Mechanical Engineering , University of Colorado , Boulder , Colorado 80309-0427 , United States
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35
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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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36
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Ultrasound Combined With Microbubbles Increase the Delivery of Doxorubicin by Reducing the Interstitial Fluid Pressure. Ultrasound Q 2019; 35:103-109. [DOI: 10.1097/ruq.0000000000000381] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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37
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White BD, Duan C, Townley HE. Nanoparticle Activation Methods in Cancer Treatment. Biomolecules 2019; 9:E202. [PMID: 31137744 PMCID: PMC6572460 DOI: 10.3390/biom9050202] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 05/17/2019] [Accepted: 05/22/2019] [Indexed: 12/25/2022] Open
Abstract
In this review, we intend to highlight the progress which has been made in recent years around different types of smart activation nanosystems for cancer treatment. Conventional treatment methods, such as chemotherapy or radiotherapy, suffer from a lack of specific targeting and consequent off-target effects. This has led to the development of smart nanosystems which can effect specific regional and temporal activation. In this review, we will discuss the different methodologies which have been designed to permit activation at the tumour site. These can be divided into mechanisms which take advantage of the differences between healthy cells and cancer cells to trigger activation, and those which activate by a mechanism extrinsic to the cell or tumour environment.
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Affiliation(s)
- Benjamin D White
- Department of Engineering Science, Oxford University, Parks Road, OX1 3PJ, Oxford, UK.
| | - Chengchen Duan
- Nuffield department of Women's and Reproductive Health, Oxford University John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
| | - Helen E Townley
- Department of Engineering Science, Oxford University, Parks Road, OX1 3PJ, Oxford, UK.
- Nuffield department of Women's and Reproductive Health, Oxford University John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
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Helfield B. A Review of Phospholipid Encapsulated Ultrasound Contrast Agent Microbubble Physics. ULTRASOUND IN MEDICINE & BIOLOGY 2019; 45:282-300. [PMID: 30413335 DOI: 10.1016/j.ultrasmedbio.2018.09.020] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/11/2018] [Accepted: 09/20/2018] [Indexed: 06/08/2023]
Abstract
Ultrasound contrast agent microbubbles have expanded the utility of biomedical ultrasound from anatomic imaging to the assessment of microvascular blood flow characteristics and ultrasound-assisted therapeutic applications. Central to their effectiveness in these applications is their resonant and non-linear oscillation behaviour. This article reviews the salient physics of an oscillating microbubble in an ultrasound field, with particular emphasis on phospholipid-coated agents. Both the theoretical underpinnings of bubble vibration and the experimental evidence of non-linear encapsulated bubble dynamics and scattering are discussed and placed within the context of current and emerging applications.
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Affiliation(s)
- Brandon Helfield
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
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Ultrasound triggered phase-change nanodroplets for doxorubicin prodrug delivery and ultrasound diagnosis: An in vitro study. Colloids Surf B Biointerfaces 2018; 174:416-425. [PMID: 30481702 DOI: 10.1016/j.colsurfb.2018.11.046] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 10/24/2018] [Accepted: 11/19/2018] [Indexed: 11/22/2022]
Abstract
Ultrasound-triggered delivery system is among the various multifunctional and stimuli-responsive strategies that hold great potential as a robust solution to the challenges of localized drug delivery and gene therapy. In this work, we developed an ultrasound-triggered delivery system PFP/C9F17-PAsp(DET)/CAD/PGA-g-mPEG nanodroplet, which combined ultrasound responsive phase-change contrast agent, acid-cleavable doxorubicin prodrug and cationic amphiphilic fluorinated polymer carrier, aiming to achieve both high imaging contrast and preferable ultrasound-triggered anti-cancer therapeutic effect. The optimized nanodroplets were characterized as monodispersed particles with a diameter of about 400 nm, slightly positive surface charge and high drug-loading efficiency. The functional augmenter PGA-g-mPEG provided the nanodroplets good sustainability, low cytotoxicity and good serum compatibility, as confirmed by stability and biocompatibility tests. In ultrasound imaging study, the nanodroplets produced significant contrast with ultrasound irradiation (3.5 MHz, MI = 0.08) at 37 ℃. Cell uptake and cytotoxicity studies in HepG2 and CT-26 cells showed the enhanced drug uptake and therapeutic effect with the combination of nanodroplets and ultrasound irradiation. These results suggest that the PFP/CAD-loaded phase change nano-emulsion can be utilized as an efficient theranostic agent for both ultrasound contrast imaging and drug delivery.
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40
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Santos MA, Wu SK, Li Z, Goertz DE, Hynynen K. Microbubble-assisted MRI-guided focused ultrasound for hyperthermia at reduced power levels. Int J Hyperthermia 2018; 35:599-611. [PMID: 30295119 DOI: 10.1080/02656736.2018.1514468] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE Ultrasound contrast agent microbubbles were combined with magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) as a means to achieve mild hyperthermia at reduced power levels. METHODS MRgFUS hyperthermia (42°C for 20 min) was evaluated in rabbit thigh muscle or Vx2 tumors using infusions of microbubbles (Definity, 20 µL/kg) or saline (sham) administered over 5 min. The impact of treatments on drug uptake was assessed with liposomal doxorubicin (Caelyx, 2.5 mg/kg). Applied power levels before and after the injection of microbubbles or saline were compared, and drug uptake was evaluated with fluorometry of tissues harvested 24 hr post-treatment. RESULTS MRgFUS hyperthermia in muscle and tumors resulted in accurate temperature control (mean =42.0°C, root mean square error (RMSE) = 0.3°C). The power dropped significantly following the injection of microbubbles in muscle and tumors compared to exposures without microbubbles (-21.9% ± 12.5% vs -5.9% ± 7.8%, p = .009 in muscle; -33.8% ± 9.9% vs -3.0% ± 7.2%, p < .001 in tumors). Cavitation monitoring indicated emission of subharmonic, ultraharmonic, and elevated levels of fourth to sixth harmonic frequencies following microbubble injection. The drug delivery was elevated significantly in muscle with the use of microbubble-assisted relative to conventional heating (0.5 ± 0.5 ng/mg vs 0.20 ± 0.04 ng/mg, p = .05), whereas in tumors similar levels were found (11 ± 3 ng/mg vs 16 ± 4 ng/mg, p = .13). CONCLUSIONS The finding that microbubbles reduce the applied power requirements for hyperthermia has considerable clinical implications. The elevated levels of drug found in muscle but not tumor tissue suggest a complex interplay between the heating effects of microbubbles with those of enhanced permeabilization and possible vascular damage.
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Affiliation(s)
- Marc A Santos
- a Physical Sciences Platform , Sunnybrook Research Institute , Toronto , Canada.,b Department of Medical Biophysics , University of Toronto , Toronto , Canada
| | - Sheng-Kai Wu
- a Physical Sciences Platform , Sunnybrook Research Institute , Toronto , Canada.,b Department of Medical Biophysics , University of Toronto , Toronto , Canada
| | - Zhe Li
- a Physical Sciences Platform , Sunnybrook Research Institute , Toronto , Canada
| | - David E Goertz
- a Physical Sciences Platform , Sunnybrook Research Institute , Toronto , Canada.,b Department of Medical Biophysics , University of Toronto , Toronto , Canada
| | - Kullervo Hynynen
- a Physical Sciences Platform , Sunnybrook Research Institute , Toronto , Canada.,b Department of Medical Biophysics , University of Toronto , Toronto , Canada.,c Institute of Biomaterials and Biomedical Engineering , University of Toronto , Toronto , Canada
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Eisenbrey JR, Shraim R, Liu JB, Li J, Stanczak M, Oeffinger B, Leeper DB, Keith SW, Jablonowski LJ, Forsberg F, O'Kane P, Wheatley MA. Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles. Int J Radiat Oncol Biol Phys 2018; 101:88-96. [PMID: 29477294 PMCID: PMC5886808 DOI: 10.1016/j.ijrobp.2018.01.042] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/05/2017] [Accepted: 01/10/2018] [Indexed: 10/18/2022]
Abstract
PURPOSE Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment that has been shown to result in both chemotherapy and radiation therapy resistance. The purpose of this study was to use localized microbubble delivery to overcome hypoxia prior to therapy. MATERIALS AND METHODS In this study, surfactant-shelled oxygen microbubbles were fabricated and injected intravenously to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound in mice with human breast cancer tumors. Changes in oxygen and sensitivity to radiation therapy were then measured. RESULTS In this work, we show that oxygen-filled microbubbles successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline solution or untriggered oxygen microbubbles (P < .001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (P < .03). CONCLUSIONS Our findings demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform.
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Affiliation(s)
- John R Eisenbrey
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania.
| | - Rawan Shraim
- School of Biomedical Engineering and Health Sciences, Drexel University, Philadelphia, Pennsylvania
| | - Ji-Bin Liu
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jingzhi Li
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Maria Stanczak
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Brian Oeffinger
- School of Biomedical Engineering and Health Sciences, Drexel University, Philadelphia, Pennsylvania
| | - Dennis B Leeper
- Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Scott W Keith
- Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Lauren J Jablonowski
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Flemming Forsberg
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Patrick O'Kane
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Margaret A Wheatley
- School of Biomedical Engineering and Health Sciences, Drexel University, Philadelphia, Pennsylvania
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Izadifar Z, Babyn P, Chapman D. Ultrasound Cavitation/Microbubble Detection and Medical Applications. J Med Biol Eng 2018. [DOI: 10.1007/s40846-018-0391-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Owen J, Crake C, Lee JY, Carugo D, Beguin E, Khrapitchev AA, Browning RJ, Sibson N, Stride E. A versatile method for the preparation of particle-loaded microbubbles for multimodality imaging and targeted drug delivery. Drug Deliv Transl Res 2018; 8:342-356. [PMID: 28299722 PMCID: PMC5830459 DOI: 10.1007/s13346-017-0366-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Microbubbles are currently in clinical use as ultrasound contrast agents and under active investigation as mediators of ultrasound therapy. To improve the theranostic potential of microbubbles, nanoparticles can be attached to the bubble shell for imaging, targeting and/or enhancement of acoustic response. Existing methods for fabricating particle-loaded bubbles, however, require the use of polymers, oil layers or chemical reactions for particle incorporation; embed/attach the particles that can reduce echogenicity; impair biocompatibility; and/or involve multiple processing steps. Here, we describe a simple method to embed nanoparticles in a phospholipid-coated microbubble formulation that overcomes these limitations. Magnetic nanoparticles are used to demonstrate the method with a range of different microbubble formulations. The size distribution and yield of microbubbles are shown to be unaffected by the addition of the particles. We further show that the microbubbles can be retained against flow using a permanent magnet, can be visualised by both ultrasound and magnetic resonance imaging (MRI) and can be used to transfect SH-SY5Y cells with fluorescent small interfering RNA under the application of a magnetic field and ultrasound field.
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Affiliation(s)
- Joshua Owen
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Calum Crake
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA
| | - Jeong Yu Lee
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Dario Carugo
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
- Faculty of Engineering and the Environment, University of Southampton, Southampton, UK
| | - Estelle Beguin
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Alexandre A Khrapitchev
- Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Richard J Browning
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Nicola Sibson
- Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Eleanor Stride
- Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
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Chong WK, Papadopoulou V, Dayton PA. Imaging with ultrasound contrast agents: current status and future. Abdom Radiol (NY) 2018; 43:762-772. [PMID: 29508011 DOI: 10.1007/s00261-018-1516-1] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Microbubble ultrasound contrast agents (UCAs) were recently approved by the Food and Drug administration for non-cardiac imaging. The physical principles of UCAs, methods of administration, dosage, adverse effects, and imaging techniques both current and future are described. UCAs consist of microbubbles in suspension which strongly interact with the ultrasound beam and are readily detectable by ultrasound imaging systems. They are confined to the blood pool when administered intravenously, unlike iodinated and gadolinium contrast agents. UCAs have a proven safety record based on over two decades of use, during which they have been used in echocardiography in the U.S. and for non-cardiac imaging in the rest of the world. Adverse effects are less common with UCAs than CT/MR contrast agents. Compared to CT and MR, contrast-enhanced ultrasound has the advantages of real-time imaging, portability, and reduced susceptibility to metal and motion artifact. UCAs are not nephrotoxic and can be used in renal failure. High acoustic amplitudes can cause microbubbles to fragment in a manner that can result in short-term increases in capillary permeability or capillary rupture. These bioeffects can be beneficial and have been used to enhance drug delivery under appropriate conditions. Imaging with a mechanical index of < 0.4 preserves the microbubbles and is not typically associated with substantial bioeffects. Molecularly targeted ultrasound contrast agents are created by conjugating the microbubble shell with a peptide, antibody, or other ligand designed to target an endothelial biomarker associated with tumor angiogenesis or inflammation. These microbubbles then accumulate in the microvasculature at target sites where they can be imaged. Ultrasound contrast agents are a valuable addition to the diagnostic imaging toolkit. They will facilitate cross-sectional abdominal imaging in situations where contrast-enhanced CT and MR are contraindicated or impractical.
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Affiliation(s)
- Wui K Chong
- Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Unit 1473 | FCT15.5092, 1400 Pressler Street, Houston, TX, 77030, USA.
| | - Virginie Papadopoulou
- UNC-NC State Joint Department of Biomedical Engineering, Chapel Hill, NC, 27599, USA
| | - Paul A Dayton
- UNC Biomedical Research Imaging Center, Chapel Hill, NC, 27599, USA
- UNC-NC State Joint Department of Biomedical Engineering, Chapel Hill, NC, 27599, USA
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Helfield BL, Chen X, Qin B, Watkins SC, Villanueva FS. Mechanistic Insight into Sonoporation with Ultrasound-Stimulated Polymer Microbubbles. ULTRASOUND IN MEDICINE & BIOLOGY 2017; 43:2678-2689. [PMID: 28847500 PMCID: PMC5644032 DOI: 10.1016/j.ultrasmedbio.2017.07.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 07/19/2017] [Accepted: 07/22/2017] [Indexed: 05/06/2023]
Abstract
Sonoporation is emerging as a feasible, non-viral gene delivery platform for the treatment of cardiovascular disease and cancer. Despite promising results, this approach remains less efficient than viral methods. The objective of this work is to help substantiate the merit of polymeric microbubble sonoporation as a non-viral, localized cell permeation and payload delivery strategy by taking a ground-up approach to elucidating the fundamental mechanisms at play. In this study, we apply simultaneous microscopy of polymeric microbubble sonoporation over its intrinsic biophysical timescales-with sub-microsecond resolution to examine microbubble cavitation and millisecond resolution over several minutes to examine local macromolecule uptake through enhanced endothelial cell membrane permeability-bridging over six orders of magnitude in time. We quantified microbubble behavior and resulting sonoporation thresholds at transmit frequencies of 0.5, 1 and 2 MHz, and determined that sonic cracking is a necessary but insufficient condition to induce sonoporation. Further, sonoporation propensity increases with the extent of sonic cracking, namely, from partial to complete gas escape from the polymeric encapsulation. For the subset that exhibited complete gas escape from sonic cracking, a proportional relationship between the maximum projected gas area and resulting macromolecule uptake was observed. These results have revealed one aspect of polymeric bubble activity on the microsecond time scale that is associated with eliciting sonoporation in adjacent endothelial cells, and contributes toward an understanding of the physical rationale for sonoporation with polymer-encapsulated microbubble contrast agents.
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Affiliation(s)
- Brandon L Helfield
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Xucai Chen
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Bin Qin
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Simon C Watkins
- Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Flordeliza S Villanueva
- Center for Ultrasound Molecular Imaging and Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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47
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Browning RJ, Reardon PJT, Parhizkar M, Pedley RB, Edirisinghe M, Knowles JC, Stride E. Drug Delivery Strategies for Platinum-Based Chemotherapy. ACS NANO 2017; 11:8560-8578. [PMID: 28829568 DOI: 10.1021/acsnano.7b04092] [Citation(s) in RCA: 162] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Few chemotherapeutics have had such an impact on cancer management as cis-diamminedichloridoplatinum(II) (CDDP), also known as cisplatin. The first member of the platinum-based drug family, CDDP's potent toxicity in disrupting DNA replication has led to its widespread use in multidrug therapies, with particular benefit in patients with testicular cancers. However, CDDP also produces significant side effects that limit the maximum systemic dose. Various strategies have been developed to address this challenge including encapsulation within micro- or nanocarriers and the use of external stimuli such as ultrasound to promote uptake and release. The aim of this review is to look at these strategies and recent scientific and clinical developments.
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Affiliation(s)
- Richard J Browning
- Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford , Oxford OX1 2JD, United Kingdom
| | | | | | | | | | - Jonathan C Knowles
- Department of Nanobiomedical Science and BK21 Plus NBM, Global Research Center for Regenerative Medicine, Dankook University , 518-10 Anseo-dong, Dongnam-gu, Cheonan, Chungcheongnam-do, Republic of Korea
- The Discoveries Centre for Regenerative and Precision Medicine, UCL Campus , Gower Street, London WC1E 6BT, United Kingdom
| | - Eleanor Stride
- Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford , Oxford OX1 2JD, United Kingdom
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Shen ZY, Liu C, Wu MF, Shi HF, Zhou YF, Zhuang W, Xia GL. Spiral computed tomography evaluation of rabbit VX2 hepatic tumors treated with 20 kHz ultrasound and microbubbles. Oncol Lett 2017; 14:3124-3130. [PMID: 28928850 DOI: 10.3892/ol.2017.6557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 05/11/2017] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to explore the therapeutic effect of 20 kHz ultrasound (US) and microbubbles (MBs) on rabbit VX2 liver tumors by spiral computed tomography (CT) scanning. A total of 16 New Zealand rabbits with hepatic VX2 tumors were divided into four groups: Control, MB, low-frequency US and US + MB. The treatment effect was evaluated by spiral CT scanning prior to, during and following treatment (at 0 weeks and the end of 1 and 2 weeks). The tumor growth rate was recorded. The specimens of VX2 tumors were collected for histological examination and transmission electron microscopy (TEM). No significant differences were observed between tumor areas measured by CT and pathology after 2-week treatment (P>0.05). The mean tumor growth rates in the control, MB, US and US + MB groups after 2 weeks of treatment were 385±21, 353±12, 302±14 and 154±9%, respectively (P<0.05, US + MB vs. the other three groups). Hematoxylin and eosin staining in the US + MB group revealed coagulation necrosis, interstitial hemorrhage and intravascular thrombosis. In the control, MB and US groups, tumor cells exhibited clear nuclear hyperchromatism. TEM of US + MB revealed vascular endothelial cell wall rupture, widened endothelial cell gaps, interstitial erythrocyte leakage and microvascular thrombosis, while intact vascular endothelial cells and normal erythrocytes in the tumor vessels were observed in the control, MB and US groups. A combination of 20 kHz US and MBs may effectively inhibit rabbit VX2 tumors. Spiral CT scanning is an ideal method to evaluate the US treatment on rabbit tumors.
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Affiliation(s)
- Zhi-Yong Shen
- Department of Radiology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Chun Liu
- Laboratory Animal Center of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Ming-Feng Wu
- Department of Radiology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Hai-Feng Shi
- Department of Radiology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Yu-Feng Zhou
- Department of Radiology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Wei Zhuang
- Department of Radiology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Gan-Lin Xia
- Department of Radiology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
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Santos MA, Goertz DE, Hynynen K. Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy. Am J Cancer Res 2017; 7:2718-2731. [PMID: 28819458 PMCID: PMC5558564 DOI: 10.7150/thno.19662] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/28/2017] [Indexed: 12/25/2022] Open
Abstract
The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.
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Izadifar Z, Babyn P, Chapman D. Mechanical and Biological Effects of Ultrasound: A Review of Present Knowledge. ULTRASOUND IN MEDICINE & BIOLOGY 2017; 43:1085-1104. [PMID: 28342566 DOI: 10.1016/j.ultrasmedbio.2017.01.023] [Citation(s) in RCA: 154] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 01/26/2017] [Accepted: 01/30/2017] [Indexed: 05/12/2023]
Abstract
Ultrasound is widely used for medical diagnosis and increasingly for therapeutic purposes. An understanding of the bio-effects of sonography is important for clinicians and scientists working in the field because permanent damage to biological tissues can occur at high levels of exposure. Here the underlying principles of thermal mechanisms and the physical interactions of ultrasound with biological tissues are reviewed. Adverse health effects derived from cellular studies, animal studies and clinical reports are reviewed to provide insight into the in vitro and in vivo bio-effects of ultrasound.
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Affiliation(s)
- Zahra Izadifar
- Division of Biomedical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
| | - Paul Babyn
- Department of Medical Imaging, Royal University Hospital, University of Saskatchewan and Saskatoon Health Region, Saskatoon, Saskatchewan, Canada
| | - Dean Chapman
- Anatomy & Cell Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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