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Dong F, An J, Guo W, Dang J, Huang S, Feng F, Zhang J, Wang D, Yin J, Fang J, Cheng H, Zhang J. Programmable ultrasound imaging guided theranostic nanodroplet destruction for precision therapy of breast cancer. ULTRASONICS SONOCHEMISTRY 2024; 105:106854. [PMID: 38537562 PMCID: PMC11059134 DOI: 10.1016/j.ultsonch.2024.106854] [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: 06/02/2023] [Revised: 03/17/2024] [Accepted: 03/23/2024] [Indexed: 04/26/2024]
Abstract
Ultrasound-stimulated contrast agents have gained significant attention in the field of tumor treatment as drug delivery systems. However, their limited drug-loading efficiency and the issue of bulky, imprecise release have resulted in inadequate drug concentrations at targeted tissues. Herein, we developed a highly efficient approach for doxorubicin (DOX) precise release at tumor site and real-time feedback via an integrated strategy of "programmable ultrasonic imaging guided accurate nanodroplet destruction for drug release" (PND). We synthesized DOX-loaded nanodroplets (DOX-NDs) with improved loading efficiency (15 %) and smaller size (mean particle size: 358 nm). These DOX-NDs exhibited lower ultrasound activation thresholds (2.46 MPa). By utilizing a single diagnostic transducer for both ultrasound stimulation and imaging guidance, we successfully vaporized the DOX-NDs and released the drug at the tumor site in 4 T1 tumor-bearing mice. Remarkably, the PND group achieved similar tumor remission effects with less than half the dose of DOX required in conventional treatment. Furthermore, the ultrasound-mediated vaporization of DOX-NDs induced tumor cell apoptosis with minimal damage to surrounding normal tissues. In summary, our PND strategy offers a precise and programmable approach for drug delivery and therapy, combining ultrasound imaging guidance. This approach shows great potential in enhancing tumor treatment efficacy while minimizing harm to healthy tissues.
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Affiliation(s)
- Feihong Dong
- State Key Laboratory of Membrane Biology, National Biomedical Imaging Center, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Jian An
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Wenyu Guo
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jie Dang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Shuo Huang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Feng Feng
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jiabin Zhang
- State Key Laboratory of Membrane Biology, National Biomedical Imaging Center, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Di Wang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jingyi Yin
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
| | - Jing Fang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; College of Engineering, Peking University, Beijing 100871, China
| | - Heping Cheng
- State Key Laboratory of Membrane Biology, National Biomedical Imaging Center, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; National Biomedical Imaging Center, Peking University, Beijing, 100871, China; Research Unit of Mitochondria in Brain Diseases, Chinese Academy of Medical Sciences, PKU-Nanjing Institute of Translational Medicine, Nanjing, 211899, China.
| | - Jue Zhang
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; College of Engineering, Peking University, Beijing 100871, China; National Biomedical Imaging Center, Peking University, Beijing, 100871, China.
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Bai Y, Chen Y, Jin Q, Deng C, Xu L, Huang T, He S, Fu Y, Qiu J, Xu J, Gao T, Wu W, Lv Q, Yang Y, Zhang L, Xie M, Dong X, Wang J. Platelet membrane-derived biomimetic microbubbles with enhanced targeting ability for the early detection of myocardial ischemia-reperfusion injury. Colloids Surf B Biointerfaces 2024; 234:113680. [PMID: 38101143 DOI: 10.1016/j.colsurfb.2023.113680] [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: 09/18/2023] [Revised: 11/19/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023]
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is a widely recognized cardiovascular disease that significantly impacts the prognosis of patients undergoing myocardial infarction recanalization. This condition can be fatal and involves complex pathophysiological mechanisms. Early diagnosis of MIRI is crucial to minimize myocardial damage and reducing mortality. Based on the inherent relationship between platelets and MIRI, we developed biomimetic microbubbles coated with platelet membrane (MB-pla) for early identification of MIRI. The MB-pla were prepared through a recombination process involving platelet membrane obtained from rat whole blood and phospholipids, blended in appropriate proportions. By coating the microbubbles with platelet membrane, MB-pla acquired various adhesion molecules, thereby gaining the capability to selectively adhere to damaged endothelial cells in the context of MIRI. In vitro experiments demonstrated that MB-pla exhibited remarkable targeting characteristics, particularly toward type IV collagen and human umbilical vein endothelial cells that had been injured through hypoxia/reoxygenation procedures. In a rat model of MIRI, the signal intensity produced by MB-pla was notably higher than that of control microbubbles. These findings were consistent with results obtained from fluorescence imaging of isolated hearts and immunofluorescence staining of tissue sections. In conclusion, MB-pla has great potential as a non-invasive early detection method for MIRI. Furthermore, this approach can potentially find application in other conditions involving endothelial injury in the future.
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Affiliation(s)
- Ying Bai
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yihan Chen
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China; Department of Ultrasonography, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qiaofeng Jin
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Cheng Deng
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Lingling Xu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Tian Huang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Shukun He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yanan Fu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jiani Qiu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jia Xu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Tang Gao
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Wenqian Wu
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Qing Lv
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yali Yang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China; Shenzhen Huazhong University of Science and Technology Research Institute, China
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China; Shenzhen Huazhong University of Science and Technology Research Institute, China
| | - Xiaoqiu Dong
- Department of Ultrasonography, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Jing Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Research Center for Medical Imaging in Hubei Province, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
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Molecular Ultrasound Imaging. NANOMATERIALS 2020; 10:nano10101935. [PMID: 32998422 PMCID: PMC7601169 DOI: 10.3390/nano10101935] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
In the last decade, molecular ultrasound imaging has been rapidly progressing. It has proven promising to diagnose angiogenesis, inflammation, and thrombosis, and many intravascular targets, such as VEGFR2, integrins, and selectins, have been successfully visualized in vivo. Furthermore, pre-clinical studies demonstrated that molecular ultrasound increased sensitivity and specificity in disease detection, classification, and therapy response monitoring compared to current clinically applied ultrasound technologies. Several techniques were developed to detect target-bound microbubbles comprising sensitive particle acoustic quantification (SPAQ), destruction-replenishment analysis, and dwelling time assessment. Moreover, some groups tried to assess microbubble binding by a change in their echogenicity after target binding. These techniques can be complemented by radiation force ultrasound improving target binding by pushing microbubbles to vessel walls. Two targeted microbubble formulations are already in clinical trials for tumor detection and liver lesion characterization, and further clinical scale targeted microbubbles are prepared for clinical translation. The recent enormous progress in the field of molecular ultrasound imaging is summarized in this review article by introducing the most relevant detection technologies, concepts for targeted nano- and micro-bubbles, as well as their applications to characterize various diseases. Finally, progress in clinical translation is highlighted, and roadblocks are discussed that currently slow the clinical translation.
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Scoping Review of Targeted Ultrasound Contrast Agents in the Detection of Myocardial Ischemia. JOURNAL OF DIAGNOSTIC MEDICAL SONOGRAPHY 2020. [DOI: 10.1177/8756479320935393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Objective: A systematic search was conducted to categorize targeted ultrasound contrast agents used in the detection of myocardial ischemia. Methods: The search identified 14 primary research articles published from 2000 to August 2019 that fulfilled the selection criteria. All studies were conducted in animal models ranging from mice to rhesus monkeys, with the most common targets being P-selectin and E-selectin. Results: These studies show that targeted ultrasound contrast agents produced greater signal enhancement in regions with prolonged ischemia and maintained enhancement hours after reperfusion. Conclusion: This review identified gaps in the literature, such as a need for comparative studies among different molecular markers and between current standard of care with the use of targeted contrast agents in cardiac ultrasound.
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Luong A, Smith D, Tai CH, Cotter B, Luo C, Strachan M, DeMaria A, Rychak JJ. Development of a Translatable Ultrasound Molecular Imaging Agent for Inflammation. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:690-702. [PMID: 31899038 DOI: 10.1016/j.ultrasmedbio.2019.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 11/06/2019] [Accepted: 11/13/2019] [Indexed: 06/10/2023]
Abstract
This study details the development, characterization and non-clinical efficacy of an ultrasound molecular imaging agent intended for molecular imaging of P-selectin in humans. A targeting ligand based on a recently discovered human selectin ligand was manufactured as fusion protein, and activity for human and mouse P- and E-selectin was evaluated by functional immunoassay. The targeting ligand was covalently conjugated to a lipophilic anchor inserted into a phospholipid microbubble shell. Three lots of the targeted microbubble drug product, TS-07-009, were produced, and assays for size distribution, zeta potential and morphology were established. The suitability of TS-07-009 as a molecular imaging agent was evaluated in vitro in a flow-based adhesion assay and in vivo using a canine model of transient myocardial ischemia. Selectivity for P-selectin over E-selectin was observed in both the human and murine systems. Contrast agent adhesion increased with P-selectin concentration in a dynamic adhesion assay. Significant contrast enhancement was observed on ultrasound imaging with TS-07-009 in post-ischemic canine myocardium at 30 or 90 min of re-perfusion. Negligible enhancement was observed in resting (no prior ischemia) hearts or with a control microbubble 90 min after ischemia. The microbubble contrast agent described here exhibits physiochemical properties and in vivo behavior suitable for development as a clinical imaging agent.
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Affiliation(s)
| | - Dan Smith
- Targeson, Inc., San Diego, California, USA
| | | | - Bruno Cotter
- Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California, USA
| | - Colin Luo
- Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California, USA
| | - Monet Strachan
- Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California, USA
| | - Anthony DeMaria
- Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California, USA
| | - Joshua J Rychak
- Targeson, Inc., San Diego, California, USA; Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
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Kanoulas E, Butler M, Rowley C, Voulgaridou V, Diamantis K, Duncan WC, McNeilly A, Averkiou M, Wijkstra H, Mischi M, Wilson RS, Lu W, Sboros V. Super-Resolution Contrast-Enhanced Ultrasound Methodology for the Identification of In Vivo Vascular Dynamics in 2D. Invest Radiol 2019; 54:500-516. [PMID: 31058661 PMCID: PMC6661242 DOI: 10.1097/rli.0000000000000565] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/20/2019] [Accepted: 02/20/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The aim of this study was to provide an ultrasound-based super-resolution methodology that can be implemented using clinical 2-dimensional ultrasound equipment and standard contrast-enhanced ultrasound modes. In addition, the aim is to achieve this for true-to-life patient imaging conditions, including realistic examination times of a few minutes and adequate image penetration depths that can be used to scan entire organs without sacrificing current super-resolution ultrasound imaging performance. METHODS Standard contrast-enhanced ultrasound was used along with bolus or infusion injections of SonoVue (Bracco, Geneva, Switzerland) microbubble (MB) suspensions. An image analysis methodology, translated from light microscopy algorithms, was developed for use with ultrasound contrast imaging video data. New features that are tailored for ultrasound contrast image data were developed for MB detection and segmentation, so that the algorithm can deal with single and overlapping MBs. The method was tested initially on synthetic data, then with a simple microvessel phantom, and then with in vivo ultrasound contrast video loops from sheep ovaries. Tracks detailing the vascular structure and corresponding velocity map of the sheep ovary were reconstructed. Images acquired from light microscopy, optical projection tomography, and optical coherence tomography were compared with the vasculature network that was revealed in the ultrasound contrast data. The final method was applied to clinical prostate data as a proof of principle. RESULTS Features of the ovary identified in optical modalities mentioned previously were also identified in the ultrasound super-resolution density maps. Follicular areas, follicle wall, vessel diameter, and tissue dimensions were very similar. An approximately 8.5-fold resolution gain was demonstrated in vessel width, as vessels of width down to 60 μm were detected and verified (λ = 514 μm). Best agreement was found between ultrasound measurements and optical coherence tomography with 10% difference in the measured vessel widths, whereas ex vivo microscopy measurements were significantly lower by 43% on average. The results were mostly achieved using video loops of under 2-minute duration that included respiratory motion. A feasibility study on a human prostate showed good agreement between density and velocity ultrasound maps with the histological evaluation of the location of a tumor. CONCLUSIONS The feasibility of a 2-dimensional contrast-enhanced ultrasound-based super-resolution method was demonstrated using in vitro, synthetic and in vivo animal data. The method reduces the examination times to a few minutes using state-of-the-art ultrasound equipment and can provide super-resolution maps for an entire prostate with similar resolution to that achieved in other studies.
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Affiliation(s)
- Evangelos Kanoulas
- From the Institute of Biochemistry, Biological Physics, and Bio Engineering, and
| | - Mairead Butler
- From the Institute of Biochemistry, Biological Physics, and Bio Engineering, and
| | - Caitlin Rowley
- Department of Physics, Heriot-Watt University, Riccarton
| | - Vasiliki Voulgaridou
- From the Institute of Biochemistry, Biological Physics, and Bio Engineering, and
| | | | - William Colin Duncan
- Center for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom
| | - Alan McNeilly
- Center for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom
| | | | | | - Massimo Mischi
- Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; and
| | - Rhodri Simon Wilson
- **Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Weiping Lu
- From the Institute of Biochemistry, Biological Physics, and Bio Engineering, and
| | - Vassilis Sboros
- From the Institute of Biochemistry, Biological Physics, and Bio Engineering, and
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Boutagy NE, Feher A, Alkhalil I, Umoh N, Sinusas AJ. Molecular Imaging of the Heart. Compr Physiol 2019; 9:477-533. [PMID: 30873600 DOI: 10.1002/cphy.c180007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Multimodality cardiovascular imaging is routinely used to assess cardiac function, structure, and physiological parameters to facilitate the diagnosis, characterization, and phenotyping of numerous cardiovascular diseases (CVD), as well as allows for risk stratification and guidance in medical therapy decision-making. Although useful, these imaging strategies are unable to assess the underlying cellular and molecular processes that modulate pathophysiological changes. Over the last decade, there have been great advancements in imaging instrumentation and technology that have been paralleled by breakthroughs in probe development and image analysis. These advancements have been merged with discoveries in cellular/molecular cardiovascular biology to burgeon the field of cardiovascular molecular imaging. Cardiovascular molecular imaging aims to noninvasively detect and characterize underlying disease processes to facilitate early diagnosis, improve prognostication, and guide targeted therapy across the continuum of CVD. The most-widely used approaches for preclinical and clinical molecular imaging include radiotracers that allow for high-sensitivity in vivo detection and quantification of molecular processes with single photon emission computed tomography and positron emission tomography. This review will describe multimodality molecular imaging instrumentation along with established and novel molecular imaging targets and probes. We will highlight how molecular imaging has provided valuable insights in determining the underlying fundamental biology of a wide variety of CVDs, including: myocardial infarction, cardiac arrhythmias, and nonischemic and ischemic heart failure with reduced and preserved ejection fraction. In addition, the potential of molecular imaging to assist in the characterization and risk stratification of systemic diseases, such as amyloidosis and sarcoidosis will be discussed. © 2019 American Physiological Society. Compr Physiol 9:477-533, 2019.
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Affiliation(s)
- Nabil E Boutagy
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Attila Feher
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Imran Alkhalil
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Nsini Umoh
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA
| | - Albert J Sinusas
- Department of Medicine, Yale Translational Research Imaging Center, Yale University School of Medicine, Section of Cardiovascular Medicine, New Haven, Connecticut, USA.,Yale University School of Medicine, Department of Radiology and Biomedical Imaging, New Haven, Connecticut, USA
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Kiessling F. US Molecular Imaging Sensitively Captures Acute Ileitis Therapy Response. Radiology 2018; 289:101-102. [DOI: 10.1148/radiol.2018181211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Fabian Kiessling
- From the Institute for Experimental Molecular Imaging, Helmholtz-Institute for Biomedical Engineering, Rheinisch-Westfaelische Technische Hochschule Aachen (RWTH), Aachen University, Forckenbeckstrasse 55, 52074 Aachen, Germany
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Rix A, Lederle W, Theek B, Lammers T, Moonen C, Schmitz G, Kiessling F. Advanced Ultrasound Technologies for Diagnosis and Therapy. J Nucl Med 2018; 59:740-746. [DOI: 10.2967/jnumed.117.200030] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 02/20/2018] [Indexed: 12/27/2022] Open
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Wang S, Hossack JA, Klibanov AL. Targeting of microbubbles: contrast agents for ultrasound molecular imaging. J Drug Target 2018; 26:420-434. [PMID: 29258335 DOI: 10.1080/1061186x.2017.1419362] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
For contrast ultrasound imaging, the most efficient contrast agents comprise highly compressible gas-filled microbubbles. These micrometer-sized particles are typically filled with low-solubility perfluorocarbon gases, and coated with a thin shell, often a lipid monolayer. These particles circulate in the bloodstream for several minutes; they demonstrate good safety and are already in widespread clinical use as blood pool agents with very low dosage necessary (sub-mg per injection). As ultrasound is an ubiquitous medical imaging modality, with tens of millions of exams conducted annually, its use for molecular/targeted imaging of biomarkers of disease may enable wider implementation of personalised medicine applications, precision medicine, non-invasive quantification of biomarkers, targeted guidance of biopsy and therapy in real time. To achieve this capability, microbubbles are decorated with targeting ligands, possessing specific affinity towards vascular biomarkers of disease, such as tumour neovasculature or areas of inflammation, ischaemia-reperfusion injury or ischaemic memory. Once bound to the target, microbubbles can be selectively visualised to delineate disease location by ultrasound imaging. This review discusses the general design trends and approaches for such molecular ultrasound imaging agents, which are currently at the advanced stages of development, and are evolving towards widespread clinical trials.
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Affiliation(s)
- Shiying Wang
- a Department of Biomedical Engineering , University of Virginia , Charlottesville , VA , USA
| | - John A Hossack
- a Department of Biomedical Engineering , University of Virginia , Charlottesville , VA , USA
| | - Alexander L Klibanov
- a Department of Biomedical Engineering , University of Virginia , Charlottesville , VA , USA.,b Cardiovascular Division (Department of Medicine), Robert M Berne Cardiovascular Research Center , University of Virginia , Charlottesville , VA , USA
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Volz KR, Evans KD, Kanner CD, Buford JA, Freimer M, Sommerich CM, Basso DM. Molecular Ultrasound Imaging for the Detection of Neural Inflammation: A Longitudinal Dosing Pilot Study. JOURNAL OF DIAGNOSTIC MEDICAL SONOGRAPHY 2017. [DOI: 10.1177/8756479317736250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Molecular ultrasound imaging provides the ability to detect physiologic processes noninvasively by targeting a variety of biomarkers in vivo. The current study was performed by exploiting an inflammatory biomarker, P-selectin, known to be present following spinal cord injury. Using a murine model (n = 6), molecular ultrasound imaging was performed using contrast microbubbles modified to target and adhere to P-selectin, prior to spinal cord injury (0D), acute stage postinjury (7D), and chronic stage (42D). Additionally, two imaging sessions were performed on each subject at specific time points, using doses of 30 μL and 100 μL. Upon analysis, targeted contrast analysis parameters were appreciably increased during the 7D scan compared with the 42D scan, without statistical significance. When examining the dose levels, the 30-μL dose demonstrated greater values than the 100-μL dose but lacked statistical significance. These findings provide additional preclinical evidence for the use of molecular ultrasound imaging for the possible detection of inflammation.
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Affiliation(s)
- Kevin R. Volz
- College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Kevin D. Evans
- College of Medicine, The Ohio State University, Columbus, OH, USA
| | | | - John A. Buford
- College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Miriam Freimer
- College of Medicine, The Ohio State University, Columbus, OH, USA
| | | | - D. Michele Basso
- College of Medicine, The Ohio State University, Columbus, OH, USA
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Volz KR, Evans KD, Kanner CD, Buford JA, Freimer M, Sommerich CM. Targeted Contrast-Enhanced Ultrasound for Inflammation Detection. JOURNAL OF DIAGNOSTIC MEDICAL SONOGRAPHY 2016. [DOI: 10.1177/8756479316678616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Molecular imaging is a form of nanotechnology that enables the noninvasive examination of biological processes in vivo. Radiopharmaceutical agents are used to target biochemical markers, permitting their detection and evaluation. Early visualization of molecular variations indicative of pathophysiological processes can aid in patient diagnoses and management decisions. Molecular imaging is performed by introducing into the body molecular probes, which are often contrast agents that have been nanoengineered to target and tether to molecules, thus enabling their radiologic identification. Through a nanoengineering process, ultrasound contrast agents can be targeted to specific molecules, extending ultrasound’s capabilities from the tissue to molecular level. Molecular ultrasound, or targeted contrast-enhanced ultrasound (TCEUS), has recently emerged as a popular molecular imaging technique due to its ability to provide real-time anatomic and functional information without ionizing radiation. However, molecular ultrasound represents a novel form of molecular imaging and consequently remains largely preclinical. This review explores the commonalities of TCEUS across several molecular targets and points to the need for standardization of kinetic behavior analysis. The literature underscores evidence gaps and the need for additional research. The application of TCEUS is unlimited but needs further standardization to ensure that future research studies are comparable.
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Affiliation(s)
- Kevin R. Volz
- College of Medicine, School of Health and Rehabilitation Science, The Ohio State University, Columbus, OH, USA
| | - Kevin D. Evans
- College of Medicine, School of Health and Rehabilitation Science, The Ohio State University, Columbus, OH, USA
| | - Christopher D. Kanner
- College of Medicine, School of Health and Rehabilitation Science, The Ohio State University, Columbus, OH, USA
| | - John A. Buford
- College of Medicine, School of Health and Rehabilitation Science, The Ohio State University, Columbus, OH, USA
| | - Miriam Freimer
- College of Medicine, School of Health and Rehabilitation Science, The Ohio State University, Columbus, OH, USA
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Abstract
BACKGROUND Contrast-enhanced ultrasound imaging is increasingly being used in clinical applications, particularly for cardiovascular and liver diagnostics. In this context the availability of new molecular contrast agents and the initiation of clinical translation promises new options for pathomechanistic diagnostics. MATERIAL AND METHODS Analysis of the current literature on the development of molecular ultrasound contrast agents, the detection methods as well as the applications in preclinical and clinical studies. RESULTS Molecular contrast agents have become established in preclinical research for the detection of inflammation and angiogenesis and have been continuously refined over recent years. They consist of gas filled microbubbles with a diameter of 1-5 µm and the gas core is stabilized by a shell made of lipids, proteins or polymers to which biomolecules are conjugated that determine the target specificity. The agent BR55 is the first clinically evaluated molecular ultrasound contrast agent. It binds to the angiogenesis marker vascular endothelial growth factor receptor 2 (VEGFR2) and has been studied in several preclinical and clinical phase I and II studies on tumor diagnostics and characterization. CONCLUSION Molecular ultrasound imaging is rapidly evolving in preclinical research for a broad field of applications. Translation to clinical practice is conceivable for many indications and is already ongoing for BR55.
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Affiliation(s)
- A Rix
- Institut für Experimentelle Molekulare Bildgebung, Pauwelsstrasse 30, 52074, Aachen, Deutschland
| | - M Palmowski
- Institut für Experimentelle Molekulare Bildgebung, Pauwelsstrasse 30, 52074, Aachen, Deutschland
| | - F Kiessling
- Institut für Experimentelle Molekulare Bildgebung, Pauwelsstrasse 30, 52074, Aachen, Deutschland.
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14
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Contrast Ultrasound Ischemic Memory Imaging. JACC Cardiovasc Imaging 2016; 9:947-9. [DOI: 10.1016/j.jcmg.2015.12.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 12/22/2015] [Indexed: 11/23/2022]
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15
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Knieling F, Waldner MJ. Light and sound - emerging imaging techniques for inflammatory bowel disease. World J Gastroenterol 2016; 22:5642-5654. [PMID: 27433080 PMCID: PMC4932202 DOI: 10.3748/wjg.v22.i25.5642] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/02/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease are known to have a high demand of recurrent evaluation for therapy and disease activity. Further, the risk of developing cancer during the disease progression is increasing from year to year. New, mostly non-radiant, quick to perform and quantitative methods are challenging, conventional endoscopy with biopsy as gold standard. Especially, new physical imaging approaches utilizing light and sound waves have facilitated the development of advanced functional and molecular modalities. Besides these advantages they hold the promise to predict personalized therapeutic responses and to spare frequent invasive procedures. Within this article we highlight their potential for initial diagnosis, assessment of disease activity and surveillance of cancer development in established techniques and recent advances such as wide-view full-spectrum endoscopy, chromoendoscopy, autofluorescence endoscopy, endocytoscopy, confocal laser endoscopy, multiphoton endoscopy, molecular imaging endoscopy, B-mode and Doppler ultrasound, contrast-enhanced ultrasound, ultrasound molecular imaging, and elastography.
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16
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Shelton SE, Lindsey BD, Tsuruta JK, Foster FS, Dayton PA. Molecular Acoustic Angiography: A New Technique for High-resolution Superharmonic Ultrasound Molecular Imaging. ULTRASOUND IN MEDICINE & BIOLOGY 2016; 42:769-81. [PMID: 26678155 PMCID: PMC5653972 DOI: 10.1016/j.ultrasmedbio.2015.10.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 10/14/2015] [Accepted: 10/18/2015] [Indexed: 05/09/2023]
Abstract
Ultrasound molecular imaging utilizes targeted microbubbles to bind to vascular targets such as integrins, selectins and other extracellular binding domains. After binding, these microbubbles are typically imaged using low pressures and multi-pulse imaging sequences. In this article, we present an alternative approach for molecular imaging using ultrasound that relies on superharmonic signals produced by microbubble contrast agents. Bound bubbles were insonified near resonance using a low frequency (4 MHz) element and superharmonic echoes were received at high frequencies (25-30 MHz). Although this approach was observed to produce declining image intensity during repeated imaging in both in vitro and in vivo experiments because of bubble destruction, the feasibility of superharmonic molecular imaging was demonstrated for transmit pressures, which are sufficiently high to induce shell disruption in bound microbubbles. This approach was validated using microbubbles targeted to the αvβ3 integrin in a rat fibrosarcoma model (n = 5) and combined with superharmonic images of free microbubbles to produce high-contrast, high-resolution 3-D volumes of both microvascular anatomy and molecular targeting. Image intensity over repeated scans and the effect of microbubble diameter were also assessed in vivo, indicating that larger microbubbles yield increased persistence in image intensity. Using ultrasound-based acoustic angiography images rather than conventional B-mode ultrasound to provide the underlying anatomic information facilitates anatomic localization of molecular markers. Quantitative analysis of relationships between microvasculature and targeting information indicated that most targeting occurred within 50 μm of a resolvable vessel (>100 μm diameter). The combined information provided by these scans may present new opportunities for analyzing relationships between microvascular anatomy and vascular targets, subject only to limitations of the current mechanically scanned system and microbubble persistence to repeated imaging at moderate mechanical indices.
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Affiliation(s)
- Sarah E Shelton
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA
| | - Brooks D Lindsey
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA
| | - James K Tsuruta
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - F Stuart Foster
- Department of Medical Biophysics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Paul A Dayton
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA; Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
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17
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Deng MH, Lin CW, Sun YN, Zeng XL, Wen F. Role of E-selectin for diagnosing myocardial injury in paediatric patients with mycoplasma pneumoniae pneumonia. Ann Clin Biochem 2016; 54:49-54. [PMID: 26843511 DOI: 10.1177/0004563216631570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Backgrounds Effects of myocardial injury on E-selectin remain unclear. Thus, we investigated the diagnostic value of E-selectin for myocardial injury in paediatric patients with mycoplasma pneumoniae pneumonia. Methods In this prospective and blinded clinical study, plasma E-selectin, cardiac troponin I, creatine kinase isoenzyme MB, interleukin-6 and tumor necrosis factor alpha concentrations were measured in paediatric patients with mycoplasma pneumoniae pneumonia (MPP group, n = 138). The control group comprised 120 healthy children. The definition of cardiac injury was based on cardiac troponin I or CK-MB (with or possibly without abnormal electrocardiogram evidence). Diagnostic value of E-selectin for myocardial injury was determined by analysing receiver operating characteristic curves. Results Among the 138 mycoplasma pneumoniae pneumonia patients, 40 patients were identified with myocardial injury, while 98 patients were identified without myocardial injury. Plasma E-selectin concentrations were: 40.22 ± 4.80 ng/mL, in patients with myocardial injury; 18.55 ± 2.16 ng/mL, in patients without myocardial injury and 12.39 ± 3.27 ng/mL, in healthy children. For the 40 patients identified with myocardial injury, area under the receiver operating characteristic curve value for plasma E-selectin concentrations was 0.945 (95% CI: 0.899-0.991), and optimal diagnostic cut-off value was 29.93 ng/mL (positive likelihood ratio = 72.5). Conclusion E-selectin was shown to be an effective index for myocardial injury in paediatric patients with mycoplasma pneumoniae pneumonia, and its role in other causes of myocardial injury warrants further investigation.
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Affiliation(s)
- Ming-Hong Deng
- The Affiliated Shunde Women and Children's Hospital of Jinan University, Shunde, Guangdong, P. R. China
| | - Chun-Wang Lin
- The Affiliated Shunde Women and Children's Hospital of Jinan University, Shunde, Guangdong, P. R. China
| | - Yan-Na Sun
- The Affiliated Shunde Women and Children's Hospital of Jinan University, Shunde, Guangdong, P. R. China
| | - Xiang-Lin Zeng
- The Affiliated Shunde Women and Children's Hospital of Jinan University, Shunde, Guangdong, P. R. China
| | - Fang Wen
- The Affiliated Shunde Women and Children's Hospital of Jinan University, Shunde, Guangdong, P. R. China
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18
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Zeisbrich M, Kihm LP, Drüschler F, Zeier M, Schwenger V. When is contrast-enhanced sonography preferable over conventional ultrasound combined with Doppler imaging in renal transplantation? Clin Kidney J 2015; 8:606-14. [PMID: 26413289 PMCID: PMC4581388 DOI: 10.1093/ckj/sfv070] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 07/10/2015] [Indexed: 12/18/2022] Open
Abstract
Conventional ultrasound in combination with colour Doppler imaging is still the standard diagnostic procedure for patients after renal transplantation. However, while conventional ultrasound in combination with Doppler imaging can diagnose renal artery stenosis and vein thrombosis, it is not possible to display subtle microvascular tissue perfusion, which is crucial for the evaluation of acute and chronic allograft dysfunctions. In contrast, real-time contrast-enhanced sonography (CES) uses gas-filled microbubbles not only to visualize but also to quantify renal blood flow and perfusion even in the small renal arterioles and capillaries. It is an easy to perform and non-invasive imaging technique that augments diagnostic capabilities in patients after renal transplantation. Specifically in the postoperative setting, CES has been shown to be superior to conventional ultrasound in combination with Doppler imaging in uncovering even subtle microvascular disturbances in the allograft perfusion. In addition, quantitative perfusion parameters derived from CES show predictive capability regarding long-term kidney function.
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Affiliation(s)
- Markus Zeisbrich
- Department of Nephrology , University Hospital , Heidelberg , Germany
| | - Lars P Kihm
- Department of Nephrology , University Hospital , Heidelberg , Germany
| | - Felix Drüschler
- Department of Nephrology , University Hospital , Heidelberg , Germany
| | - Martin Zeier
- Department of Nephrology , University Hospital , Heidelberg , Germany
| | - Vedat Schwenger
- Department of Nephrology , University Hospital , Heidelberg , Germany
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19
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Yeh JSM, Sennoga CA, McConnell E, Eckersley R, Tang MX, Nourshargh S, Seddon JM, Haskard DO, Nihoyannopoulos P. A Targeting Microbubble for Ultrasound Molecular Imaging. PLoS One 2015; 10:e0129681. [PMID: 26161541 PMCID: PMC4498921 DOI: 10.1371/journal.pone.0129681] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 05/12/2015] [Indexed: 11/30/2022] Open
Abstract
Rationale Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld. Objective To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging. Methods and Results Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab’)2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification. Conclusions Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)–(iii) desired for clinical applications.
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Affiliation(s)
- James Shue-Min Yeh
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Department of Cardiology, Hammersmith Hospital, London, United Kingdom
- Imaging Sciences Department, Medical Research Council, Imperial College London, London, United Kingdom
| | - Charles A. Sennoga
- Imaging Sciences Department, Medical Research Council, Imperial College London, London, United Kingdom
- Department of Chemistry, Imperial College London, London, United Kingdom
| | - Ellen McConnell
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Robert Eckersley
- Imaging Sciences Department, Medical Research Council, Imperial College London, London, United Kingdom
| | - Meng-Xing Tang
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Sussan Nourshargh
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- William Harvey Research Institute, Queen Mary, University of London, London, United Kingdom
| | - John M. Seddon
- Department of Chemistry, Imperial College London, London, United Kingdom
| | - Dorian O. Haskard
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Petros Nihoyannopoulos
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Department of Cardiology, Hammersmith Hospital, London, United Kingdom
- * E-mail:
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20
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Wang H, Felt SA, Machtaler S, Guracar I, Luong R, Bettinger T, Tian L, Lutz AM, Willmann JK. Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent. Radiology 2015; 276:809-17. [PMID: 25965901 DOI: 10.1148/radiol.2015142478] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin-targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. MATERIALS AND METHODS The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin-targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 10(8) MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. RESULTS Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 10(8) MB/kg and plateaued between a dose of 10 and a dose of 20 × 10(8) MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). CONCLUSION Quantitative measurements of inflammation obtained by using dual-selectin-targeted US are reproducible and correlate well with the extent of inflammation at histologic examination in a porcine acute ileitis model as a next step toward clinical translation.
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Affiliation(s)
- Huaijun Wang
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Stephen A Felt
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Steven Machtaler
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Ismayil Guracar
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Richard Luong
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Thierry Bettinger
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Lu Tian
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Amelie M Lutz
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
| | - Jürgen K Willmann
- From the Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621 (H.W., S.M., A.M.L., J.K.W.); Department of Comparative Medicine (S.A.F., R.L.) and Department of Health, Research and Policy (L.T.), Stanford University, Stanford, Calif; Ultrasound Business Unit, Siemens Healthcare, Mountain View, Calif (I.G.); and Bracco Suisse, Geneva, Switzerland (T.B.)
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Abou-Elkacem L, Bachawal SV, Willmann JK. Ultrasound molecular imaging: Moving toward clinical translation. Eur J Radiol 2015; 84:1685-93. [PMID: 25851932 DOI: 10.1016/j.ejrad.2015.03.016] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 03/13/2015] [Indexed: 12/11/2022]
Abstract
Ultrasound is a widely available, cost-effective, real-time, non-invasive and safe imaging modality widely used in the clinic for anatomical and functional imaging. With the introduction of novel molecularly-targeted ultrasound contrast agents, another dimension of ultrasound has become a reality: diagnosing and monitoring pathological processes at the molecular level. Most commonly used ultrasound molecular imaging contrast agents are micron sized, gas-containing microbubbles functionalized to recognize and attach to molecules expressed on inflamed or angiogenic vascular endothelial cells. There are several potential clinical applications currently being explored including earlier detection, molecular profiling, and monitoring of cancer, as well as visualization of ischemic memory in transient myocardial ischemia, monitoring of disease activity in inflammatory bowel disease, and assessment of arteriosclerosis. Recently, a first clinical grade ultrasound contrast agent (BR55), targeted at a molecule expressed in neoangiogenesis (vascular endothelial growth factor receptor type 2; VEGFR2) has been introduced and safety and feasibility of VEGFR2-targeted ultrasound imaging is being explored in first inhuman clinical trials in various cancer types. This review describes the design of ultrasound molecular imaging contrast agents, imaging techniques, and potential future clinical applications of ultrasound molecular imaging.
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Affiliation(s)
- Lotfi Abou-Elkacem
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA
| | - Sunitha V Bachawal
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA
| | - Jürgen K Willmann
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, School of Medicine, Stanford, CA, USA.
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Unger E, Porter T, Lindner J, Grayburn P. Cardiovascular drug delivery with ultrasound and microbubbles. Adv Drug Deliv Rev 2014; 72:110-26. [PMID: 24524934 DOI: 10.1016/j.addr.2014.01.012] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Revised: 01/23/2014] [Accepted: 01/29/2014] [Indexed: 01/14/2023]
Abstract
Microbubbles lower the threshold for cavitation of ultrasound and have multiple potential therapeutic applications in the cardiovascular system. One of the first therapeutic applications to enter into clinical trials has been microbubble-enhanced sonothrombolysis. Trials were conducted in acute ischemic stroke and clinical trials are currently underway for sonothrombolysis in treatment of acute myocardial infarction. Microbubbles can be targeted to epitopes expressed on endothelial cells and thrombi by incorporating targeting ligands onto the surface of the microbubbles. Targeted microbubbles have applications as molecular imaging contrast agents and also for drug and gene delivery. A number of groups have shown that ultrasound with microbubbles can be used for gene delivery yielding robust gene expression in the target tissue. Work has progressed to primate studies showing delivery of therapeutic genes to generate islet cells in the pancreas to potentially cure diabetes. Microbubbles also hold potential as oxygen therapeutics and have shown promising results as a neuroprotectant in an ischemic stroke model. Regulatory considerations impact the successful clinical development of therapeutic applications of microbubbles with ultrasound. This paper briefly reviews the field and suggests avenues for further development.
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