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Harold KM, MacCuaig WM, Holter-Charkabarty J, Williams K, Hill K, Arreola AX, Sekhri M, Carter S, Gomez-Gutierrez J, Salem G, Mishra G, McNally LR. Advances in Imaging of Inflammation, Fibrosis, and Cancer in the Gastrointestinal Tract. Int J Mol Sci 2022; 23:16109. [PMID: 36555749 PMCID: PMC9781634 DOI: 10.3390/ijms232416109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Gastrointestinal disease is prevalent and broad, manifesting itself in a variety of ways, including inflammation, fibrosis, infection, and cancer. However, historically, diagnostic technologies have exhibited limitations, especially with regard to diagnostic uncertainty. Despite development of newly emerging technologies such as optoacoustic imaging, many recent advancements have focused on improving upon pre-existing modalities such as ultrasound, computed tomography, magnetic resonance imaging, and endoscopy. These advancements include utilization of machine learning models, biomarkers, new technological applications such as diffusion weighted imaging, and new techniques such as transrectal ultrasound. This review discusses assessment of disease processes using imaging strategies for the detection and monitoring of inflammation, fibrosis, and cancer in the context of gastrointestinal disease. Specifically, we include ulcerative colitis, Crohn's disease, diverticulitis, celiac disease, graft vs. host disease, intestinal fibrosis, colorectal stricture, gastric cancer, and colorectal cancer. We address some of the most recent and promising advancements for improvement of gastrointestinal imaging, including unique discussions of such advancements with regard to imaging of fibrosis and differentiation between similar disease processes.
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Affiliation(s)
- Kylene M. Harold
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | | | | | | | - Kaitlyn Hill
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Alex X. Arreola
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Malika Sekhri
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Steven Carter
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Jorge Gomez-Gutierrez
- Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65211, USA
| | - George Salem
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Girish Mishra
- Wake Forest Baptist Health, Winston-Salem, NC 27157, USA
| | - Lacey R. McNally
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Bartlett DJ, Ramos GP, Fletcher JG, Bruining DH. Imaging Evaluation of Inflammatory Bowel Disease Complications. Gastrointest Endosc Clin N Am 2022; 32:651-673. [PMID: 36202508 DOI: 10.1016/j.giec.2022.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition that can progress to fibrostenotic and penetrating complications. Cross-sectional imaging is often needed for accurate diagnosis of IBD complication and for planning the appropriate management strategy. Computed tomography enterography, magnetic resonance enterography, and IBD ultrasound have become key tools for clinicians and interventional endoscopists. This article highlights and discusses various radiologic imaging techniques and their application to the diagnosis and management of IBD complications.
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Affiliation(s)
- David J Bartlett
- Department of Radiology, Mayo Clinic College of Medicine, 200 1st Street, SW, Rochester, MN 55905, USA; Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st Street, SW, Rochester, MN 55905, USA
| | - Guilherme Piovezani Ramos
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st Street, SW, Rochester, MN 55905, USA
| | - Joel G Fletcher
- Department of Radiology, Mayo Clinic College of Medicine, 200 1st Street, SW, Rochester, MN 55905, USA
| | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st Street, SW, Rochester, MN 55905, USA.
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3
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Goncin U, Bernhard W, Curiel L, Geyer CR, Machtaler S. Rapid Copper-free Click Conjugation to Lipid-Shelled Microbubbles for Ultrasound Molecular Imaging of Murine Bowel Inflammation. Bioconjug Chem 2022; 33:848-857. [DOI: 10.1021/acs.bioconjchem.2c00104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Una Goncin
- Department of Medical Imaging, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Wendy Bernhard
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Laura Curiel
- Department of Electrical and Software Engineering, Schulich School of Engineering, University of Calgary, Calgary, Alberta T2N 4V8, Canada
| | - C. Ronald Geyer
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
| | - Steven Machtaler
- Department of Medical Imaging, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
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Wang H, Vilches-Moure JG, Bettinger T, Cherkaoui S, Lutz A, Paulmurugan R. Contrast Enhanced Ultrasound Molecular Imaging of Spontaneous Chronic Inflammatory Bowel Disease in an Interleukin-2 Receptor α−/− Transgenic Mouse Model Using Targeted Microbubbles. NANOMATERIALS 2022; 12:nano12020280. [PMID: 35055297 PMCID: PMC8779209 DOI: 10.3390/nano12020280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/09/2022] [Accepted: 01/14/2022] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) is a lifelong inflammatory disorder with relapsing–remission cycles, which is currently diagnosed by clinical symptoms and signs, along with laboratory and imaging findings. However, such clinical findings are not parallel to the disease activity of IBD and are difficult to use in treatment monitoring. Therefore, non-invasive quantitative imaging tools are required for the multiple follow-up exams of IBD patients in order to monitor the disease activity and determine treatment regimens. In this study, we evaluated a dual P- and E-selectin-targeted microbubble (MBSelectin) in an interleukin-2 receptor α deficient (IL-2Rα−/−) spontaneous chronic IBD mouse model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI). We used IL-2Rα−/− (male and female on a C57BL/6 genetic background; n = 39) and C57BL/6 wild-type (negative control; n = 6) mice for the study. USMI of the proximal, middle, and distal colon was performed with MBSelectin using a small animal scanner (Vevo 2100) up to six times in each IL-2Rα−/− mouse between 6–30 weeks of age. USMI signals were compared between IL-2Rα−/− vs. wild-type mice, and sexes in three colonic locations. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E-stained sections and for selectin expression by immunofluorescence staining. We successfully detected spontaneous chronic colitis in IL-2Rα−/− mice between 6–30 weeks (onset at 6–14 weeks) compared to wild-type mice. Both male and female IL-2Rα−/− mice were equally (p = 0.996) affected with the disease, and there was no significant (p > 0.05) difference in USMI signals of colitis between the proximal, middle, and distal colon. We observed the fluctuating USMI signals in IL-2Rα−/− mice between 6–30 weeks, which might suggest a resemblance of the remission-flare pattern of human IBD. The ex vivo H&E and immunostaining further confirmed the inflammatory changes, and the high expression of P- and E-selectin in the colon. The results of this study highlight the IL-2Rα−/− mice as a chronic colitis model and are suitable for the long-term assessment of treatment response using a dual P- and E-selectin-targeted USMI.
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Affiliation(s)
- Huaijun Wang
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (H.W.); (A.L.)
| | | | | | | | - Amelie Lutz
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (H.W.); (A.L.)
| | - Ramasamy Paulmurugan
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (H.W.); (A.L.)
- Correspondence: ; Tel.: +1-650-725-6097; Fax: +1-650-721-6921
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Miao X, Mao R, You Y, Zhou H, Qiu C, Li X, Chen Z, Ren J, Chen M, Wang P, Zheng R, Yin T. Intracolic ultrasound molecular imaging: a novel method for assessing colonic tumor necrosis factor-α expression in inflammatory bowel disease. Mol Med 2021; 27:119. [PMID: 34556023 PMCID: PMC8461918 DOI: 10.1186/s10020-021-00379-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 09/11/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND While anti-tumor necrosis factor alpha (TNF-α) therapy has been proven effective in inflammatory bowel disease (IBD), approximately 40% of patients lose the response. Transmembrane TNF-α (mTNF-α) expression in the intestinal mucosa is correlated with therapeutic efficacy, and quantification of mTNF-α expression is significant for predicting response. However, conventional intravenous application of microbubbles is unable to assess mTNF-α expression in intestinal mucosa. Herein, we proposed intracolic ultrasound molecular imaging with TNF-α-targeted microbubbles (MBTNF-α) to quantitatively detect mTNF-α expression in the intestinal mucosa. METHODS MBTNF-α was synthesized via a biotin-streptavidin bridging method. TNF-α-targeted ultrasound imaging was performed by intracolic application of MBTNF-α to detect mTNF-α expression in surgical specimens from a murine model and patients with IBD. Linear regression analyses were performed to confirm the accuracy of quantitative targeted ultrasound imaging. RESULTS On quantitative TNF-α-targeted ultrasound images, a greater signal intensity was observed in the mouse colons with colitis ([1.96 ± 0.45] × 106 a.u.) compared to that of the controls ([0.56 ± 0.21] × 106 a.u., P < 0.001). Targeted US signal intensities and inflammatory lesions were topographically coupled in mouse colons. Linear regression analyses in specimens of mice and patients demonstrated significant correlations between the targeted ultrasound signal intensity and mTNF-α expression (both P < 0.001). Furthermore, TNF-α-targeted ultrasound imaging qualitatively distinguished the varying inflammatory severity in intestinal specimens from IBD patients. CONCLUSION Intracolic ultrasound molecular imaging with MBTNF-α enables quantitative assessment of mTNF-α expression. It may be a potential tool for facilitating the implementation of personalized medicine in IBD.
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Affiliation(s)
- Xiaoyan Miao
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yujia You
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Huichao Zhou
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Chen Qiu
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Xuehua Li
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Zhihui Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jie Ren
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Ping Wang
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Rongqin Zheng
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
| | - Tinghui Yin
- Department of Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
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Jones MA, MacCuaig WM, Frickenstein AN, Camalan S, Gurcan MN, Holter-Chakrabarty J, Morris KT, McNally MW, Booth KK, Carter S, Grizzle WE, McNally LR. Molecular Imaging of Inflammatory Disease. Biomedicines 2021; 9:152. [PMID: 33557374 PMCID: PMC7914540 DOI: 10.3390/biomedicines9020152] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/25/2021] [Accepted: 01/31/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory diseases include a wide variety of highly prevalent conditions with high mortality rates in severe cases ranging from cardiovascular disease, to rheumatoid arthritis, to chronic obstructive pulmonary disease, to graft vs. host disease, to a number of gastrointestinal disorders. Many diseases that are not considered inflammatory per se are associated with varying levels of inflammation. Imaging of the immune system and inflammatory response is of interest as it can give insight into disease progression and severity. Clinical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) are traditionally limited to the visualization of anatomical information; then, the presence or absence of an inflammatory state must be inferred from the structural abnormalities. Improvement in available contrast agents has made it possible to obtain functional information as well as anatomical. In vivo imaging of inflammation ultimately facilitates an improved accuracy of diagnostics and monitoring of patients to allow for better patient care. Highly specific molecular imaging of inflammatory biomarkers allows for earlier diagnosis to prevent irreversible damage. Advancements in imaging instruments, targeted tracers, and contrast agents represent a rapidly growing area of preclinical research with the hopes of quick translation to the clinic.
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Affiliation(s)
- Meredith A. Jones
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA; (M.A.J.); (W.M.M.); (A.N.F.)
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
| | - William M. MacCuaig
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA; (M.A.J.); (W.M.M.); (A.N.F.)
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
| | - Alex N. Frickenstein
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA; (M.A.J.); (W.M.M.); (A.N.F.)
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
| | - Seda Camalan
- Department of Internal Medicine, Wake Forest Baptist Health, Winston-Salem, NC 27157, USA; (S.C.); (M.N.G.)
| | - Metin N. Gurcan
- Department of Internal Medicine, Wake Forest Baptist Health, Winston-Salem, NC 27157, USA; (S.C.); (M.N.G.)
| | - Jennifer Holter-Chakrabarty
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
- Department of Medicine, University of Oklahoma, Oklahoma City, OK 73104, USA
| | - Katherine T. Morris
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
- Department of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USA
| | - Molly W. McNally
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
| | - Kristina K. Booth
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
- Department of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USA
| | - Steven Carter
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
- Department of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USA
| | - William E. Grizzle
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Lacey R. McNally
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; (J.H.-C.); (K.T.M.); (M.W.M.); (K.K.B.); (S.C.)
- Department of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USA
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7
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Ham NS, Myung SJ. Endoscopic molecular imaging in inflammatory bowel disease. Intest Res 2021; 19:33-44. [PMID: 32299156 PMCID: PMC7873406 DOI: 10.5217/ir.2019.09175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 01/31/2020] [Indexed: 12/12/2022] Open
Abstract
Molecular imaging is a technique for imaging the processes occurring in a living body at a molecular level in real-time, combining molecular cell biology with advanced imaging technologies using molecular probes and fluorescence. Gastrointestinal endoscopic molecular imaging shows great promise for improving the identification of neoplasms, providing characterization for patient stratification and assessing the response to molecular targeted therapy. In inflammatory bowel disease, endoscopic molecular imaging can be used to assess disease severity and predict therapeutic response and prognosis. Endoscopic molecular imaging is also able to visualize dysplasia in the presence of background inflammation. Several preclinical and clinical trials have evaluated endoscopic molecular imaging; however, this area is just beginning to evolve, and many issues have not been solved yet. In the future, it is expected that endoscopic molecular imaging will be of increasing interest among clinicians as a new technology for the identification and evaluation of colorectal neoplasm and colitis-associated cancer.
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Affiliation(s)
- Nam Seok Ham
- Department of Gastroenterology, Veterans Health Service Medical Center, Seoul, Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, Digestive Diseases Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Correspondence to Seung-Jae Myung, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82-2-3010-3917, Fax: +82-2- 476-0824, E-mail:
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8
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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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9
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Le Fur M, Zhou IY, Catalano O, Caravan P. Toward Molecular Imaging of Intestinal Pathology. Inflamm Bowel Dis 2020; 26:1470-1484. [PMID: 32793946 PMCID: PMC7500524 DOI: 10.1093/ibd/izaa213] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD) is defined by a chronic relapsing and remitting inflammation of the gastrointestinal tract, with intestinal fibrosis being a major complication. The etiology of IBD remains unknown, but it is thought to arise from a dysregulated and excessive immune response to gut luminal microbes triggered by genetic and environmental factors. To date, IBD has no cure, and treatments are currently directed at relieving symptoms and treating inflammation. The current diagnostic of IBD relies on endoscopy, which is invasive and does not provide information on the presence of extraluminal complications and molecular aspect of the disease. Cross-sectional imaging modalities such as computed tomography enterography (CTE), magnetic resonance enterography (MRE), positron emission tomography (PET), single photon emission computed tomography (SPECT), and hybrid modalities have demonstrated high accuracy for the diagnosis of IBD and can provide both functional and morphological information when combined with the use of molecular imaging probes. This review presents the state-of-the-art imaging techniques and molecular imaging approaches in the field of IBD and points out future directions that could help improve our understanding of IBD pathological processes, along with the development of efficient treatments.
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Affiliation(s)
- Mariane Le Fur
- The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, The Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, MA, USA
| | - Iris Y Zhou
- The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, The Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, MA, USA
| | - Onofrio Catalano
- The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, The Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, MA, USA,The Division of Abdominal Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, MA, USA
| | - Peter Caravan
- The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, The Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, MA, USA,Address correspondence to: Peter Caravan, PhD, The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, The Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, 149 Thirteenth Street, Charlestown 02129, MA, USA. E-mail:
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10
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Molecular imaging of inflammation - Current and emerging technologies for diagnosis and treatment. Pharmacol Ther 2020; 211:107550. [PMID: 32325067 DOI: 10.1016/j.pharmthera.2020.107550] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 10/07/2019] [Indexed: 12/12/2022]
Abstract
Inflammation is a key factor in multiple diseases including primary immune-mediated inflammatory diseases e.g. rheumatoid arthritis but also, less obviously, in many other common conditions, e.g. cardiovascular disease and diabetes. Together, chronic inflammatory diseases contribute to the majority of global morbidity and mortality. However, our understanding of the underlying processes by which the immune response is activated and sustained is limited by a lack of cellular and molecular information obtained in situ. Molecular imaging is the visualization, detection and quantification of molecules in the body. The ability to reveal information on inflammatory biomarkers, pathways and cells can improve disease diagnosis, guide and monitor therapeutic intervention and identify new targets for research. The optimum molecular imaging modality will possess high sensitivity and high resolution and be capable of non-invasive quantitative imaging of multiple disease biomarkers while maintaining an acceptable safety profile. The mainstays of current clinical imaging are computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US) and nuclear imaging such as positron emission tomography (PET). However, none of these have yet progressed to routine clinical use in the molecular imaging of inflammation, therefore new approaches are required to meet this goal. This review sets out the respective merits and limitations of both established and emerging imaging modalities as clinically useful molecular imaging tools in addition to potential theranostic applications.
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11
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Kosareva A, Abou-Elkacem L, Chowdhury S, Lindner JR, Kaufmann BA. Seeing the Invisible-Ultrasound Molecular Imaging. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:479-497. [PMID: 31899040 DOI: 10.1016/j.ultrasmedbio.2019.11.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 06/10/2023]
Abstract
Ultrasound molecular imaging has been developed in the past two decades with the goal of non-invasively imaging disease phenotypes on a cellular level not depicted on anatomic imaging. Such techniques already play a role in pre-clinical research for the assessment of disease mechanisms and drug effects, and are thought to in the future contribute to earlier diagnosis of disease, assessment of therapeutic effects and patient-tailored therapy in the clinical field. In this review, we first describe the chemical composition and structure as well as the in vivo behavior of the ultrasound contrast agents that have been developed for molecular imaging. We then discuss the strategies that are used for targeting of contrast agents to specific cellular targets and protocols used for imaging. Next we describe pre-clinical data on imaging of thrombosis, atherosclerosis and microvascular inflammation and in oncology, including the pathophysiological principles underlying the selection of targets in each area. Where applicable, we also discuss efforts that are currently underway for translation of this technique into the clinical arena.
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Affiliation(s)
- Alexandra Kosareva
- Cardiovascular Molecular Imaging, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Lotfi Abou-Elkacem
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford, California, USA
| | - Sayan Chowdhury
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford, California, USA
| | - Jonathan R Lindner
- Knight Cardiovascular Institute, Portland, Oregon, USA; Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon, USA
| | - Beat A Kaufmann
- Cardiovascular Molecular Imaging, Department of Biomedicine, University of Basel, Basel, Switzerland; Department of Cardiology, University Hospital and University of Basel, Basel, Switzerland.
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12
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Role of Gd 2O 3-doped carbon-11-choline-lenvatinib nanoparticles contrast agent PET/CT in the diagnosis of patients with lung cancer. Oncol Lett 2020; 19:1117-1124. [PMID: 32002026 PMCID: PMC6960386 DOI: 10.3892/ol.2019.11243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 05/31/2019] [Indexed: 01/15/2023] Open
Abstract
Positron emission tomography-computed tomography (PET/CT) is an efficient method for the diagnosis of various types of human cancer. Studies have demonstrated that Gd2O3-doped carbon-11-choline (GdCho) can be used as a contrast nanoparticle for PET/CT in the diagnosis of patients with lung cancer. The aim of the present study was to evaluate the effect of GdCho-lenvatinib nanoparticles contrast-PET/CT (GdCho-Len-PET) in the diagnosis and treatment planning of a cohort of patients suspected of having lung cancer. The results of the present study demonstrated that GdCho-Len could be used as an efficient PET/CT contrast agent for the diagnosis of patients with lung cancer. GdCho-Len nanoparticles contrast agent exhibited a significantly improved longitudinal relaxivity compared with GdCho. The outcomes of the present study were that GdCho-Len-PET diagnosed 152 patients with lung cancer, whereas GdCho-PET diagnosed 130 patients with lung cancer among the 172 patients. GdCho-Len-PET presented with higher accuracy and sensitivity compared with GdCho-PET in diagnosing patients with lung cancer. All patients were further confirmed via histological analysis. GdCho-Len-PET contributed to the anticancer treatments in 56 out of 62 (90.3%) patients with lung cancer who were candidates for radiation therapy, 52 out of 57 (91.2%) patients with lung cancer undergoing adjuvant radiotherapy, and 13 out of 17 (76.5%) patients with lung cancer undergoing comprehensive therapy. Patients diagnosed using GdCho-Len-PET improved the survival of patients with lung cancer during a 420-day follow up. In conclusion, GdCho-Len-PET increased the diagnostic efficacy and had a significant effect on survival for patients with lung cancer, and may therefore serve as a reliable method for human cancer diagnosis.
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Herbst EB, Unnikrishnan S, Klibanov AL, Mauldin FW, Hossack JA. Validation of Normalized Singular Spectrum Area as a Classifier for Molecularly Targeted Microbubble Adherence. ULTRASOUND IN MEDICINE & BIOLOGY 2019; 45:2493-2501. [PMID: 31227262 PMCID: PMC7480935 DOI: 10.1016/j.ultrasmedbio.2019.05.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/20/2019] [Accepted: 05/22/2019] [Indexed: 05/24/2023]
Abstract
Ultrasound molecular imaging is a diagnostic technique wherein molecularly targeted microbubble contrast agents are imaged to reveal disease markers on the blood vessel endothelium. Currently, microbubble adhesion to affected tissue can be quantified using differential targeted enhancement (dTE), which measures the late enhancement of adherent microbubbles through administration of destructive ultrasound pressures. In this study, we investigated a statistical parameter called the normalized singular spectrum area (NSSA) as a means to detect microbubble adhesion without microbubble destruction. We compared the signal differentiation capability of NSSA with matched dTE measurements in a mouse hindlimb tumor model. Results indicated that NSSA-based signal classification performance matches dTE when differentiating adherent microbubble from non-adherent microbubble signals (receiver operating characteristic area under the curve = 0.95), and improves classification performance when differentiating microbubble from tissue signals (p < 0.005). NSSA-based signal classification eliminates the need for destruction of contrast, and may offer better sensitivity, specificity and the opportunity for real-time microbubble detection and classification.
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Affiliation(s)
- Elizabeth B Herbst
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
| | - Sunil Unnikrishnan
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
| | - Alexander L Klibanov
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - F William Mauldin
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
| | - John A Hossack
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
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Wang H, Vilches-Moure JG, Cherkaoui S, Tardy I, Alleaume C, Bettinger T, Lutz A, Paulmurugan R. Chronic Model of Inflammatory Bowel Disease in IL-10 -/- Transgenic Mice: Evaluation with Ultrasound Molecular Imaging. Am J Cancer Res 2019; 9:6031-6046. [PMID: 31534535 PMCID: PMC6735517 DOI: 10.7150/thno.37397] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 07/22/2019] [Indexed: 12/13/2022] Open
Abstract
Objective: Acute mouse models of inflammatory bowel disease (IBD) fail to mirror the chronic nature of IBD in patients. We sought to develop a chronic mouse IBD model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI) by using dual P- and E-selectin targeted microbubbles (MBSelectin). Materials and Methods: Interleukin 10 deficient (IL-10-/- on a C57BL/6 genetic background; n=55) and FVB (n=16) mice were used. In IL-10-/-mice, various experimental regimens including piroxicam, 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS), respectively were used for promoting colitis; colitis was induced with DSS in FVB mice. Using clinical and small animal ultrasound scanners, evolution of inflammation in proximal, middle and distal colon, was monitored with USMI by using MBSelectin at multiple time points. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E staining and for P-selectin expression on immunofluorescence staining. Results: Sustained colitis was not detected with USMI in IL-10-/- or FVB mice with various experimental regimens. USMI signals either gradually decreased after the colitis enhancing/inducing drug/agents were discontinued, or the mortality rate of mice was high. Inflammation was observed on H&E staining in IL-10-/- mice with piroxicam promotion, while stable overexpression of P-selectin was not found on immunofluorescence staining in the same mice. Conclusion: Sustained colitis in IL-10-/- mice induced with piroxicam, TNBS or DSS, and in FVB mice induced with DSS, was not detected with USMI using MBSelectin, and this was verified by immunofluorescence staining for inflammation marker P-selectin. Thus, these models may not be appropriate for long-term monitoring of chronic colitis and subsequent treatment response with dual-selectin targeted USMI.
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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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16
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Single-Chain Variable Fragment Antibody of Vascular Cell Adhesion Molecule 1 as a Molecular Imaging Probe for Colitis Model Rabbit Investigation. CONTRAST MEDIA & MOLECULAR IMAGING 2019; 2019:2783519. [PMID: 30804723 PMCID: PMC6360587 DOI: 10.1155/2019/2783519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 10/27/2018] [Accepted: 11/12/2018] [Indexed: 12/18/2022]
Abstract
Vascular cell adhesion molecule-1 (VCAM-1) can be a promising target for colitis study because of its critical role in inflammation development. Single-chain variable fragment (scFv) antibody presents fast blood clearance when served as an imaging probe. We applied the probe of 99mTc-scFv-VCAM-1 to colitis rabbit to examine its imaging performance. The colitis model rabbit was prepared, and a typical inflammatory lesion was confirmed in the colon. The probe of 99mTc-scFv-VCAM-1 was synthesized and injected into the model animal before imaging examination. Scintigraphy detected colitis lesions in both SPECT planar and SPECT/CT fused images, with higher target-to-nontarget ratios in the model group (2.71 ± 0.31) than those in the control group (1.12 ± 0.10). Biodistribution study determined tracer uptake in different organs, and autoradiography (ARG) confirmed probe accumulation in colon lesions. The uptake ratio of the model colon to the control colon was 4.71 ± 0.61 in quantitative analysis of the ARG regions of interest. Stronger VCAM-1 expression in the model colon than that in the control colon was confirmed by western blotting and immunohistochemistry. Our imaging study indicates molecular imaging with scFv-VCAM-1 as a promising way for inflammatory bowel disease diagnosis and evaluation.
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Deepak P, Fowler KJ, Fletcher JG, Bruining DH. Novel Imaging Approaches in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2019; 25:248-260. [PMID: 30010908 DOI: 10.1093/ibd/izy239] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases are chronic autoimmune conditions of the gastrointestinal tract, mainly grouped into ulcerative colitis or Crohn's disease. Traditionally, symptoms have been used to guide IBD management, but this approach is fatally flawed, as symptoms don't correlate with disease activity and often fail to predict disease complications, especially with Crohn's disease. Hence, there is increasing recognition of the need for treatment algorithms based on objective measures of bowel inflammation. In this review, we will focus on advancements in the endoscopic and radiological imaging armamentarium that allow detailed assessments from intestinal mucosa to mesentery.
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Affiliation(s)
- Parakkal Deepak
- Division of Gastroenterology, John T. Milliken Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - Kathryn J Fowler
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - Joel G Fletcher
- Division of Abdominal Imaging, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
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18
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Wilkens R, Wilson A, Burns PN, Ghosh S, Wilson SR. Persistent Enhancement on Contrast-Enhanced Ultrasound Studies of Severe Crohn's Disease: Stuck Bubbles? ULTRASOUND IN MEDICINE & BIOLOGY 2018; 44:2189-2198. [PMID: 30076030 DOI: 10.1016/j.ultrasmedbio.2018.06.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 05/16/2018] [Accepted: 06/25/2018] [Indexed: 06/08/2023]
Abstract
A small population of patients with severe Crohn's disease (CD) exhibit atypical lack of intensity decline on intestinal contrast-enhanced ultrasound. From a retrospective CD cohort examined with contrast-enhanced ultrasound, 104 patients were identified. Twenty study patients with severe active disease exhibited high peak enhancement (>23 dB) and minimal decline. From the same cohort, 84 control patients also exhibited high peak enhancement >23dB, but with typical intensity decline. Patient outcomes were assessed. Time-intensity curve analysis revealed a significantly higher (p < 0.0001) area under the curve (44.7 ± 1.5 dB·s), washout time and intensities at 60s and 120s in the study population compared with controls (40.0 ± 1.1 dB·s). Study patients had a worse overall outcome with surgery in 30% versus 10% (p = 0.027) during follow-up. Heightened enhancement with lack of decline on contrast-enhanced ultrasound suggests microbubbles are stuck within the inflamed bowel wall for an extended period. This observation occurs in patients with severe disease and a bad outcome.
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Affiliation(s)
- Rune Wilkens
- Department of Radiology, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
| | - Alexandra Wilson
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Peter N Burns
- Department of Medical Imaging Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Subrata Ghosh
- Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
| | - Stephanie R Wilson
- Department of Radiology, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
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19
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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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20
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Wang H, Hyvelin JM, Felt SA, Guracar I, Vilches-Moure JG, Cherkaoui S, Bettinger T, Tian L, Lutz AM, Willmann JK. US Molecular Imaging of Acute Ileitis: Anti-Inflammatory Treatment Response Monitored with Targeted Microbubbles in a Preclinical Model. Radiology 2018; 289:90-100. [PMID: 30040040 PMCID: PMC6190483 DOI: 10.1148/radiol.2018172600] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 04/24/2018] [Accepted: 05/09/2018] [Indexed: 12/30/2022]
Abstract
Purpose To evaluate whether dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in an acute terminal ileitis model in swine. Materials and Methods The Institutional Animal Care and Use Committee approved all animal studies. Fourteen swine with chemically induced acute terminal ileitis (day 0) were randomized into the following groups: (a) an anti-inflammatory treatment group (n = 8; meloxicam, 0.25 mg per kilogram of body weight; prednisone, 0.5 mg/kg) and (b) a control group (n = 6; saline). US molecular imaging was performed with a clinical US machine after intravenous injection of clinically translatable dual P- and E-selectin-targeted microbubbles (5 × 108/kg). Three inflamed bowel segments per swine were imaged at baseline, as well as on days 1, 3, and 6 after treatment initiation. At day 6, bowel segments were analyzed ex vivo for selectin expression levels by using quantitative immunofluorescence. Results After induction of inflammation, US molecular imaging signal increased at day 1 in both animal groups (P < .001). At day 3, signal in the treatment group decreased (P < .001 vs day 1), while signal in control animals did not significantly change (P = .18 vs day 1) and was higher (P = .001) compared with that in the treatment group. At day 6, signal in the treatment group further decreased and remained lower (P = .02) compared with that in the control group. Immunofluorescence confirmed significant (P ≤ .04) downregulation of both P- and E-selectin expression levels in treated versus control bowel segments. Conclusion Dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in a large-animal model of acute ileitis. This supports further clinical development of this quantitative and radiation-free technique for monitoring inflammatory bowel disease. © RSNA, 2018 Online supplemental material is available for this article.
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Affiliation(s)
- Huaijun Wang
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Jean-Marc Hyvelin
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Stephen A. Felt
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Ismayil Guracar
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Jose G. Vilches-Moure
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Samir Cherkaoui
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Thierry Bettinger
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Lu Tian
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
| | - Amelie M. Lutz
- From the Department of Radiology, Stanford University School of
Medicine, 300 Pasteur Dr, Grant SO62B, Stanford, CA 94305-5105 (H.W., A.M.L.,
J.K.W.); Bracco Suisse SA, Geneva, Switzerland (J.M.H., S.C., T.B.); Departments
of Comparative Medicine (S.A.F., J.G.V.) and Health, Research & Policy
(L.T.), Stanford University, Stanford, Calif; and Ultrasound Business Unit,
Siemens Healthcare, Mountain View, Calif (I.G.)
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Bourdeau RW, Lee-Gosselin A, Lakshmanan A, Farhadi A, Kumar SR, Nety SP, Shapiro MG. Acoustic reporter genes for noninvasive imaging of microorganisms in mammalian hosts. Nature 2018; 553:86-90. [PMID: 29300010 PMCID: PMC5920530 DOI: 10.1038/nature25021] [Citation(s) in RCA: 243] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 11/09/2017] [Indexed: 12/26/2022]
Affiliation(s)
- Raymond W Bourdeau
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Audrey Lee-Gosselin
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Anupama Lakshmanan
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Arash Farhadi
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Sripriya Ravindra Kumar
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Suchita P Nety
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
| | - Mikhail G Shapiro
- Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
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22
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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: 73] [Impact Index Per Article: 10.4] [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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24
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Wang H, Felt SA, Guracar I, Taviani V, Zhou J, Sigrist RMS, Zhang H, Liau J, Vilches-Moure JG, Tian L, Saenz Y, Bettinger T, Hargreaves BA, Lutz AM, Willmann JK. Anatomical Road Mapping Using CT and MR Enterography for Ultrasound Molecular Imaging of Small Bowel Inflammation in Swine. Eur Radiol 2017; 28:2068-2076. [PMID: 29170798 DOI: 10.1007/s00330-017-5148-6] [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: 07/24/2017] [Revised: 09/27/2017] [Accepted: 10/18/2017] [Indexed: 10/18/2022]
Abstract
OBJECTIVES To evaluate the feasibility and time saving of fusing CT and MR enterography with ultrasound for ultrasound molecular imaging (USMI) of inflammation in an acute small bowel inflammation of swine. METHODS Nine swine with ileitis were scanned with either CT (n = 3) or MR (n = 6) enterography. Imaging times to load CT/MR images onto a clinical ultrasound machine, fuse them to ultrasound with an anatomical landmark-based approach, and identify ileitis were compared to the imaging times without anatomical road mapping. Inflammation was then assessed by USMI using dual selectin-targeted (MBSelectin) and control (MBControl) contrast agents in diseased and healthy control bowel segments, followed by ex vivo histology. RESULTS Cross-sectional image fusion with ultrasound was feasible with an alignment error of 13.9 ± 9.7 mm. Anatomical road mapping significantly reduced (P < 0.001) scanning times by 40%. Localising ileitis was achieved within 1.0 min. Subsequently performed USMI demonstrated significantly (P < 0.001) higher imaging signal using MBSelectin compared to MBControl and histology confirmed a significantly higher inflammation score (P = 0.006) and P- and E-selectin expression (P ≤ 0.02) in inflamed vs. healthy bowel. CONCLUSIONS Fusion of CT and MR enterography data sets with ultrasound in real time is feasible and allows rapid anatomical localisation of ileitis for subsequent quantification of inflammation using USMI. KEY POINTS • Real-time fusion of CT/MRI with ultrasound to localise ileitis is feasible. • Anatomical road mapping using CT/MRI significantly decreases the scanning time for USMI. • USMI allows quantification of inflammation in swine, verified with ex vivo histology.
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Affiliation(s)
- Huaijun Wang
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Stephen A Felt
- Department of Comparative Medicine, Stanford University, Stanford, CA, USA
| | - Ismayil Guracar
- Siemens Healthcare, Ultrasound Business Unit, Mountain View, CA, USA
| | - Valentina Taviani
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Jianhua Zhou
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Rosa Maria Silveira Sigrist
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Huiping Zhang
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Joy Liau
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | | | - Lu Tian
- Department of Health, Research & Policy, Stanford University, Stanford, CA, USA
| | - Yamil Saenz
- Department of Comparative Medicine, Stanford University, Stanford, CA, USA
| | | | - Brian A Hargreaves
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Amelie M Lutz
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Jürgen K Willmann
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, 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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Molecular Contrast-Enhanced Ultrasound Imaging of Radiation-Induced P-Selectin Expression in Healthy Mice Colon. Int J Radiat Oncol Biol Phys 2017; 97:581-585. [DOI: 10.1016/j.ijrobp.2016.10.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/14/2016] [Accepted: 10/23/2016] [Indexed: 12/30/2022]
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Kachramanoglou C, Rafailidis V, Philippidou M, Bertolotto M, Huang DY, Deganello A, Sellars ME, Sidhu PS. Multiparametric Sonography of Hematologic Malignancies of the Testis: Grayscale, Color Doppler, and Contrast-Enhanced Ultrasound and Strain Elastographic Appearances With Histologic Correlation. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2017; 36:409-420. [PMID: 28032907 DOI: 10.7863/ultra.16.02013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/06/2016] [Indexed: 06/06/2023]
Abstract
Primary testicular lymphoma is rare and appears with nonspecific findings on grayscale and color Doppler sonography. We present 8 patients further examined with contrast-enhanced sonography, strain elastography, and histologic analysis after orchiectomy. Seven of 8 patients had a diagnosis of large B-cell lymphoma, and 1 of 8 had a diagnosis of granulocytic sarcoma, with solitary lesions (2 of 8), multiple lesions (3 of 8), or entire testicular involvement (3 of 8). Lesions appeared hypoechoic (7 of 8) or isoechoic (1 of 8), all with increased vascularity on color Doppler sonography and a nonbranching linear pattern of intratumoral vessels (7 of 8). Contrast-enhanced ultrasound (CEUS) confirmed this pattern and showed increased enhancement in all lesions. On strain elastography, all lesions were hard, with an elasticity score of greater than 4. Multiparametric sonography of testicular lymphoma identifies increased vascularity on color Doppler and contrast-enhanced ultrasound and increased lesion stiffness on strain elastography.
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Affiliation(s)
| | | | | | | | - Dean Y Huang
- Department of Radiology, King's College Hospital, London, England
| | | | - Maria E Sellars
- Department of Radiology, King's College Hospital, London, England
| | - Paul S Sidhu
- Department of Radiology, King's College Hospital, London, England
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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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Spivak I, Rix A, Schmitz G, Fokong S, Iranzo O, Lederle W, Kiessling F. Low-Dose Molecular Ultrasound Imaging with E-Selectin-Targeted PBCA Microbubbles. Mol Imaging Biol 2016; 18:180-90. [PMID: 26391990 DOI: 10.1007/s11307-015-0894-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE Our objective was to determine the lowest diagnostically effective dose for E-selectin-targeted poly n-butyl cyanoacrylate (PBCA)-shelled microbubbles and to apply it to monitor antiangiogenic therapy effects. PROCEDURES PBCA-shelled microbubbles (MBs) coupled to an E-selectin-specific peptide were applied in mice carrying MLS or A431 carcinoma xenografts scaling down the MB dosage to the lowest level where binding could be examined with a 18-MHz small animal ultrasound transducer. Differences in E-selectin expression in the two carcinoma xenografts were confirmed by enzyme-linked immunosorbent assay (ELISA). In addition, MLS tumor-bearing mice under antiangiogenic therapy were monitored using E-selectin-targeted MBs at the lowest applicable dose. Therapy effects on tumor vascularization were verified by immunohistological analyses. RESULTS The minimally required dosage was 7 × 10(7) MBs/kg body weight. This dosage was sufficient to enable E-selectin detection in high E-selectin-expressing MLS tumors, while low E-selectin-expressing A431 tumors required almost 2.5-fold higher doses. At the dose of 7 × 10(7) MBs/kg body weight, a decrease in E-selectin MB binding under antiangiogenic therapy could be assessed (being significant after 3 days of treatment; p < 0.0001), which was in line with the significant drop in E-selectin-positive area fractions that was found histologically (p < 0.05). CONCLUSIONS Molecular ultrasound imaging with our E-selectin-targeted MB and therapy monitoring was possible down to a dose of 7 × 10(7) MBs/kg body weight (equates to 66 μg PBCA/kg and 4.6 mg PBCA/70 kg). Improvements in choice of targets, MB composition, and other MB detection methods may improve sensitivity and lead to reliable detection results of clinically transferrable MBs at even lower dosage levels.
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Affiliation(s)
- Igor Spivak
- Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Anne Rix
- Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Georg Schmitz
- Institute of Medical Engineering, Ruhr-University Bochum, Bochum, Germany
| | - Stanley Fokong
- Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Olga Iranzo
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.,Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
| | - Wiltrud Lederle
- Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Fabian Kiessling
- Department of Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany. .,Institute for Experimental Molecular Imaging, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
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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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Optical Verification of Microbubble Response to Acoustic Radiation Force in Large Vessels With In Vivo Results. Invest Radiol 2016; 50:772-84. [PMID: 26135018 DOI: 10.1097/rli.0000000000000185] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE The objective of this study was to optically verify the dynamic behaviors of adherent microbubbles in large blood vessel environments in response to a new ultrasound technique using modulated acoustic radiation force. MATERIALS AND METHODS Polydimethylsiloxane (PDMS) flow channels coated with streptavidin were used in targeted groups to mimic large blood vessels. The custom-modulated acoustic radiation force beam sequence was programmed on a Verasonics research scanner. In vitro experiments were performed by injecting a biotinylated lipid-perfluorobutane microbubble dispersion through flow channels. The dynamic response of adherent microbubbles was detected acoustically and simultaneously visualized using a video camera connected to a microscope. In vivo verification was performed in a large abdominal blood vessel of a murine model for inflammation with injection of biotinylated microbubbles conjugated with P-selectin antibody. RESULTS Aggregates of adherent microbubbles were observed optically under the influence of acoustic radiation force. Large microbubble aggregates were observed solely in control groups without targeted adhesion. Additionally, the dispersion of microbubble aggregates were demonstrated to lead to a transient acoustic signal enhancement in control groups (a new phenomenon we refer to as "control peak"). In agreement with in vitro results, the control peak phenomenon was observed in vivo in a murine model. CONCLUSIONS This study provides the first optical observation of microbubble-binding dynamics in large blood vessel environments with application of a modulated acoustic radiation force beam sequence. With targeted adhesion, secondary radiation forces were unable to produce large aggregates of adherent microbubbles. Additionally, the new phenomenon called control peak was observed both in vitro and in vivo in a murine model for the first time. The findings in this study provide us with a better understanding of microbubble behaviors in large blood vessel environments with application of acoustic radiation force and could potentially guide future beam sequence designs or signal processing routines for enhanced ultrasound molecular imaging.
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Deepak P, Kolbe AB, Fidler JL, Fletcher JG, Knudsen JM, Bruining DH. Update on Magnetic Resonance Imaging and Ultrasound Evaluation of Crohn's Disease. Gastroenterol Hepatol (N Y) 2016; 12:226-236. [PMID: 27231453 PMCID: PMC4872852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Magnetic resonance enterography (MRE) and abdominal ultrasound are integral parts of multimodality assessments for patients with inflammatory bowel disease. Applications include assessing Crohn's disease (CD) extent and severity, differentiating CD from ulcerative colitis, detecting CD complications, evaluating response to therapy, and demonstrating postoperative recurrence. Magnetic resonance imaging protocols are being developed that may reduce or eliminate the need for intravenous contrast agents and better differentiate inflammatory from fibrotic strictures. MRE scoring systems have been created to objectively quantify disease activity and response to therapy. By utilizing advanced sonographic imaging techniques, including ultrasound contrast and Doppler assessments, the role of abdominal ultrasonography in the evaluation and management of CD continues to expand. Abdominal ultrasound may function as a low-cost, point-of care assessment tool, especially in CD restricted to the terminal ileum and ileocolic anastomosis.
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Affiliation(s)
- Parakkal Deepak
- Dr Deepak is an instructor in medicine and fellow and Dr Bruining is an associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Dr Kolbe is an assistant professor of radiology and senior associate consultant, Dr Fidler and Dr Fletcher are professors of radiology and consultants, and Dr Knudsen is an assistant professor of radiology and consultant in the Department of Radiology at the Mayo Clinic College of Medicine
| | - Amy B Kolbe
- Dr Deepak is an instructor in medicine and fellow and Dr Bruining is an associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Dr Kolbe is an assistant professor of radiology and senior associate consultant, Dr Fidler and Dr Fletcher are professors of radiology and consultants, and Dr Knudsen is an assistant professor of radiology and consultant in the Department of Radiology at the Mayo Clinic College of Medicine
| | - Jeff L Fidler
- Dr Deepak is an instructor in medicine and fellow and Dr Bruining is an associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Dr Kolbe is an assistant professor of radiology and senior associate consultant, Dr Fidler and Dr Fletcher are professors of radiology and consultants, and Dr Knudsen is an assistant professor of radiology and consultant in the Department of Radiology at the Mayo Clinic College of Medicine
| | - Joel G Fletcher
- Dr Deepak is an instructor in medicine and fellow and Dr Bruining is an associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Dr Kolbe is an assistant professor of radiology and senior associate consultant, Dr Fidler and Dr Fletcher are professors of radiology and consultants, and Dr Knudsen is an assistant professor of radiology and consultant in the Department of Radiology at the Mayo Clinic College of Medicine
| | - John M Knudsen
- Dr Deepak is an instructor in medicine and fellow and Dr Bruining is an associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Dr Kolbe is an assistant professor of radiology and senior associate consultant, Dr Fidler and Dr Fletcher are professors of radiology and consultants, and Dr Knudsen is an assistant professor of radiology and consultant in the Department of Radiology at the Mayo Clinic College of Medicine
| | - David H Bruining
- Dr Deepak is an instructor in medicine and fellow and Dr Bruining is an associate professor of medicine and consultant in the Division of Gastroenterology and Hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Dr Kolbe is an assistant professor of radiology and senior associate consultant, Dr Fidler and Dr Fletcher are professors of radiology and consultants, and Dr Knudsen is an assistant professor of radiology and consultant in the Department of Radiology at the Mayo Clinic College of Medicine
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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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Brückner M, Lenz P, Mücke MM, Gohar F, Willeke P, Domagk D, Bettenworth D. Diagnostic imaging advances in murine models of colitis. World J Gastroenterol 2016; 22:996-1007. [PMID: 26811642 PMCID: PMC4716050 DOI: 10.3748/wjg.v22.i3.996] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/09/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis are chronic-remittent inflammatory disorders of the gastrointestinal tract still evoking challenging clinical diagnostic and therapeutic situations. Murine models of experimental colitis are a vital component of research into human IBD concerning questions of its complex pathogenesis or the evaluation of potential new drugs. To monitor the course of colitis, to the present day, classical parameters like histological tissue alterations or analysis of mucosal cytokine/chemokine expression often require euthanasia of animals. Recent advances mean revolutionary non-invasive imaging techniques for in vivo murine colitis diagnostics are increasingly available. These novel and emerging imaging techniques not only allow direct visualization of intestinal inflammation, but also enable molecular imaging and targeting of specific alterations of the inflamed murine mucosa. For the first time, in vivo imaging techniques allow for longitudinal examinations and evaluation of intra-individual therapeutic response. This review discusses the latest developments in the different fields of ultrasound, molecularly targeted contrast agent ultrasound, fluorescence endoscopy, confocal laser endomicroscopy as well as tomographic imaging with magnetic resonance imaging, computed tomography and fluorescence-mediated tomography, discussing their individual limitations and potential future diagnostic applications in the management of human patients with IBD.
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A novel dual-targeted ultrasound contrast agent provides improvement of gene delivery efficiency in vitro. Tumour Biol 2016; 37:8609-19. [DOI: 10.1007/s13277-015-4681-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 12/16/2015] [Indexed: 12/20/2022] Open
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Kiessling F. Science to Practice: Molecularly Targeted US of Inflammation—Important Steps toward Clinical Translation. Radiology 2015; 276:621-3. [DOI: 10.1148/radiol.2015150589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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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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Machtaler S, Knieling F, Luong R, Tian L, Willmann JK. Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging. Am J Cancer Res 2015; 5:1175-86. [PMID: 26379784 PMCID: PMC4568446 DOI: 10.7150/thno.13048] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 07/16/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background. METHODS Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology. RESULTS Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%). CONCLUSIONS Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent.
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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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Мokrozub VV, Lazarenko LM, Sichel LM, Babenko LP, Lytvyn PM, Demchenko OM, Melnichenko YO, Boyko NV, Biavati B, DiGioia D, Bubnov RV, Spivak MY. The role of beneficial bacteria wall elasticity in regulating innate immune response. EPMA J 2015; 6:13. [PMID: 26110044 PMCID: PMC4479350 DOI: 10.1186/s13167-015-0035-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 05/22/2015] [Indexed: 01/12/2023]
Abstract
BACKGROUND Probiotics have great potential to contribute to development of healthy dietary regimes, preventive care, and an integrated approach to immunity-related disease management. The bacterial wall is a dynamic entity, depending on many components and playing an essential role in modulating immune response. The impact of cell wall elasticity on the beneficial effects of probiotic strains has not been sufficiently studied. The aim was to investigate the effect of lactic acid bacteria (LAB) and bifidobacteria strains on phagocytic system cells (macrophages) as related to bacterial wall elasticity, estimated using atomic force microscopy (AFM). METHODS We conducted studies on Balb/c line mice 18-20 g in weight using lyophilized strains of LAB-Lactobacillus acidophilus IMV B-7279, Lactobacillus casei IMV B-7280, Lactobacillus delbrueckii subsp. bulgaricus IMV B-7281, and bifidobacteria-Bifidobacterium animalis VKL and Bifidobacterium animalis VKB. We cultivated the macrophages obtained from the peritoneal cavity of mice individually with the strains of LAB and bifidobacteria and evaluated their effect on macrophages, oxygen-dependent bactericidal activity, nitric oxide production, and immunoregulatory cytokines. We used AFM scanning to estimate bacterial cell wall elasticity. RESULTS All strains had a stimulating effect on the functional activity of macrophages and ability to produce NO/NO2 in vitro. Lactobacilli strains increased the production of IL-12 and IFN-γ in vitro. The AFM demonstrated different cell wall elasticity levels in various strains of LAB and bifidobacteria. The rigidity of the cell walls among lactobacilli was distributed as follows: Lactobacillus acidophilus IMV B-7279 > Lactobacillus casei IMV B-7280 > Lactobacillus delbrueckii subsp. bulgaricus IMV B-7281; among the strains of bifidobacteria: B. animalis VKB > B. animalis VKL. Probiotic strain survival in the macrophages depended on the bacterial cell wall elasticity and on the time of their joint cultivation. CONCLUSION LAB and bifidobacteria strains stimulate immune-modulatory cytokines and active oxygen and nitrogen oxide compound production in macrophages. Strains with a more elastic cell wall according to AFM data demonstrated higher resistance to intracellular digestion in macrophages and higher level of their activation. AFM might be considered as a fast and accurate method to assess parameters of probiotic strain cell wall to predict their immune-modulatory properties.
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Affiliation(s)
- Viktoria V. Мokrozub
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
| | - Liudmyla M. Lazarenko
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
| | - Liubov M. Sichel
- />Pure Research Products, LLC, 6107, Chelsea Manor Court, Boulder, CO 80301 USA
| | - Lidia P. Babenko
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
| | - Petro M. Lytvyn
- />Lashkaryov Institute of Semiconductor Physics, National Academy of Sciences of Ukraine, 41, pr. Nauky, Kyiv, 03028 Ukraine
| | | | - Yulia O. Melnichenko
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
| | - Nadiya V. Boyko
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
| | - Bruno Biavati
- />Dipartimento di Scienze Agrarie, Alma Mater Studiorum—Bologna University, Bologna, 40127 Italy
| | - Diana DiGioia
- />Dipartimento di Scienze Agrarie, Alma Mater Studiorum—Bologna University, Bologna, 40127 Italy
| | - Rostyslav V. Bubnov
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
- />Clinical Hospital “Pheophania” of State Affairs Department, Zabolotny str., 21, Kyiv, 03680 Ukraine
| | - Mykola Ya Spivak
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, 154, Zabolotny st., Kyiv, D03680 Ukraine
- />LCL «Diaprof», Svitlycky Str., 35, Kyiv, 04123 Ukraine
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Cantisani V, Wilson SR. CEUS: Where are we in 2015? Eur J Radiol 2015; 84:1621-2. [PMID: 26093473 DOI: 10.1016/j.ejrad.2015.05.028] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 05/19/2015] [Indexed: 12/14/2022]
Abstract
Contrast enhanced ultrasound (CEUS), performed with the intravenous injection of microbubble contrast agents, has expanded the horizon for ultrasound imaging by providing a technique with superb sensitivity to arterial phase enhancement in dynamic realtime. For the first time, demonstration of blood flow at the microcirculatory or perfusion level is possible on ultrasound. Further, the purely intravascular microbubbles allow ultrasound to be used to monitor changes in the blood flow to tumors and in inflammatory sites. Its safe performance without any requirement for ionizing radiation and with no nephrotoxicity makes it a compelling choice in many clinical arenas and certainly for children. Here, we describe the wide and growing uses of CEUS in abdominal imaging.
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Walldorf J, Hermann M, Porzner M, Pohl S, Metz H, Mäder K, Zipprich A, Christ B, Seufferlein T. In-vivo monitoring of acute DSS-Colitis using Colonoscopy, high resolution Ultrasound and bench-top Magnetic Resonance Imaging in Mice. Eur Radiol 2015; 25:2984-91. [PMID: 25981216 DOI: 10.1007/s00330-015-3714-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Revised: 01/07/2015] [Accepted: 03/11/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The aim of this study was to establish and evaluate (colour Doppler-) high-resolution-ultrasound (hrUS) and bench-top magnetic resonance imaging (btMRI) as new methods to monitor experimental colitis. MATERIALS AND METHODS hrUS, btMRI and endoscopy were performed in mice without colitis (n = 15), in mice with acute colitis (n = 14) and in mice with acute colitis and simultaneous treatment with infliximab (n = 19). RESULTS Determination of colon wall thickness using hrUS (32 MHz) and measurement of the cross-sectional colonic areas by btMRI allowed discrimination between the treatment groups (mean a vs. b vs. c - btMRI: 922 vs. 2051 vs. 1472 pixel, hrUS: 0.26 vs. 0.45 vs. 0.31 mm). btMRI, endoscopy, hrUS and colour Doppler-hrUS correlated to histological scoring (p < 0.05), while endoscopy and btMRI correlated to post-mortem colon length (p < 0.05). CONCLUSIONS The innovative in vivo techniques btMRI and hrUS are safe and technically feasible. They differentiate between distinct grades of colitis in an experimental setting, and correlate with established post-mortem parameters. In addition to endoscopic procedures, these techniques provide information regarding colon wall thickness and perfusion. Depending on the availability of these techniques, their application increases the value of in vivo monitoring in experimental acute colitis in small rodents. KEY POINTS • Improved in vivo monitoring might balance interindividual differences in murine colitis. • In monitoring murine colitis, btMRI and hrUS are safe and technically feasible. • Very short examination times underline the usefulness especially of hrUS. • Results of btMRI and hrUS correlate with endoscopic and post-mortem findings.
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Affiliation(s)
- J Walldorf
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle, Germany,
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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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Curaj A, Wu Z, Fokong S, Liehn EA, Weber C, Burlacu A, Lammers T, van Zandvoort M, Kiessling F. Noninvasive molecular ultrasound monitoring of vessel healing after intravascular surgical procedures in a preclinical setup. Arterioscler Thromb Vasc Biol 2015; 35:1366-73. [PMID: 25838431 DOI: 10.1161/atvbaha.114.304857] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 03/22/2015] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Cardiovascular interventions induce damage to the vessel wall making antithrombotic therapy inevitable until complete endothelial recovery. Without a method to accurately determine the endothelial status, many patients undergo prolonged anticoagulation therapy, denying them any invasive medical procedures, such as surgical operations and dental interventions. Therefore, we aim to introduce molecular ultrasound imaging of the vascular cell adhesion molecule (VCAM)-1 using targeted poly-n-butylcyanoacrylate microbubbles (MB(VCAM-1)) as an easy accessible method to monitor accurately the reendothelialization of vessels. APPROACH AND RESULTS ApoE(-/-) mice were fed with an atherogenic diet for 1 and 12 weeks and subsequently, endothelial denudation was performed in the carotid arteries using a guidewire. Molecular ultrasound imaging was performed at different time points after denudation (1, 3, 7, and 14 days). An increased MB(VCAM-1) binding after 1 day, a peak after 3 days, and a decrease after 7 days was found. After 12 weeks of diet, MB(VCAM-1) binding also peaked after 3 days but remained high until 7 days, indicating a delay in endothelial recovery. Two-photon laser scanning microscopy imaging of double fluorescence staining confirmed the exposure of VCAM-1 on the superficial layer after arterial injury only during the healing phase. After complete reendothelialization, VCAM-1 expression persisted in the subendothelial layer but was not reachable for the MBV(CAM-1) anymore. CONCLUSION Molecular ultrasound imaging with MB(VCAM-1) is promising to assess vascular damage and to monitor endothelial recovery after arterial interventions. Thus, it may become an important diagnostic tool supporting the development of adequate therapeutic strategies to personalize anticoagulant and anti-inflammatory therapy after cardiovascular intervention.
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Affiliation(s)
- Adelina Curaj
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Zhuojun Wu
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Stanley Fokong
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Elisa A Liehn
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Christian Weber
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Alexandrina Burlacu
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Twan Lammers
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.)
| | - Marc van Zandvoort
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
| | - Fabian Kiessling
- From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
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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: 139] [Impact Index Per Article: 13.9] [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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Leguerney I, Scoazec JY, Gadot N, Robin N, Pénault-Llorca F, Victorin S, Lassau N. Molecular ultrasound imaging using contrast agents targeting endoglin, vascular endothelial growth factor receptor 2 and integrin. ULTRASOUND IN MEDICINE & BIOLOGY 2015; 41:197-207. [PMID: 25308938 DOI: 10.1016/j.ultrasmedbio.2014.06.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 06/18/2014] [Accepted: 06/24/2014] [Indexed: 05/21/2023]
Abstract
Expression levels of endoglin, αv integrin and vascular endothelial growth factor receptor 2 (VEGFR2) were investigated using targeted, contrast-enhanced ultrasonography in murine melanoma tumor models. Microvasculature and expression levels of biomarkers were investigated using specific contrast agents conjugated with biotinylated monoclonal antibodies. Ultrasound signal intensity from bound contrast agents was evaluated in two groups of mice: control mice and mice treated with sorafenib. Expression levels were analyzed by immunohistochemistry. Endoglin biomarkers were more highly expressed than αv integrin and VEGFR2. Endoglin decreased in the sorafenib group, whereas it tended to increase with time in the control group. Targeted ultrasound contrast agents may be used for non-invasive longitudinal evaluation of tumor angiogenesis during tumor growth or therapeutic treatment in preclinical studies. Endoglin protein, which plays an important role in angiogenesis, seems to be a target of interest for detection of cancer and for prediction of therapeutic efficacy.
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Affiliation(s)
| | | | - Nicolas Gadot
- Anipath, Faculté Laennec, Université Lyon 1, Lyon, France
| | - Nina Robin
- Département d'anatomie et de cytologie pathologiques, Centre Jean Perrin, Clermont-Ferrand, France
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Ultrasound molecular imaging of transient acute myocardial ischemia with a clinically translatable P- and E-selectin targeted contrast agent: correlation with the expression of selectins. Invest Radiol 2014; 49:224-35. [PMID: 24442162 DOI: 10.1097/rli.0000000000000018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The diagnosis of acute coronary syndrome remains challenging especially in patients without clear symptoms or electrocardiographic and/or biomarker features. A hallmark of ischemia/reperfusion is activation of endothelial cells leading to altered expression of molecular markers, including selectins. In this context, we aimed to validate the value of ultrasound molecular imaging for detecting transient myocardial ischemia by using a clinically translatable dual P- and E-selectin-targeted ultrasound contrast agent (UCA) and microbubble (MB(selectin)). MATERIAL AND METHODS Transient (20 minutes) myocardial ischemia of rat heart was produced by ligation of the left anterior descending coronary artery ligation followed by 2-, 5-, or 24-hour reperfusion. Imaging of the transient ischemic event was achieved by the use of MB(selectin). Performance of this clinically translatable targeted UCA was compared with that of antibody-targeted streptavidin MBs. Finally, immunohistochemistry staining of rat myocardial ischemic tissue was performed to assess expression of selectins accessible to targeted UCA. RESULTS In rats subjected to myocardial ischemia (20 minutes) followed by reperfusion (2 hours), injection of MB(selectin) produced high late phase (ie, 10-minute postinjection) ultrasound molecular imaging enhancement in the myocardium, which colocalized with the ischemic area. Late phase enhancement persisted 5 and 24 hours after reperfusion. Similarly, the use of MBP and MBE, comprising antibodies specific for P- and E-selectin, respectively, showed high late-phase enhancement within the ischemic area compared with remote myocardial tissue. Two and 5 hours after ischemia has resolved, a persistent expression of these 2 selectins was detected. After 24 hours of reperfusion, only MBE produced late phase enhancement within the ischemic myocardium. Immunohistochemical findings revealed that both P- and E-selectin were expressed and accessible on the surface of the activated endothelium 2 and 5 hours after the acute ischemic event, whereas only E-selectin remained accessible after 24 hours. CONCLUSIONS Ultrasound molecular imaging of transient myocardial ischemia using dual selectin-targeted UCA is able to monitor the time course of expression of selectins after resolution of the ischemic event, paving the way for a large clinical diagnostic window.
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Lau CY, Maldarelli F, Eckelman WC, Neumann RD. Rational development of radiopharmaceuticals for HIV-1. Nucl Med Biol 2014; 41:299-308. [PMID: 24607432 PMCID: PMC3954989 DOI: 10.1016/j.nucmedbio.2014.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 12/18/2013] [Accepted: 01/10/2014] [Indexed: 12/29/2022]
Abstract
The global battle against HIV-1 would benefit from a sensitive and specific radiopharmaceutical to localize HIV-infected cells. Ideally, this probe would be able to identify latently infected host cells containing replication competent HIV sequences. Clinical and research applications would include assessment of reservoirs, informing clinical management by facilitating assessment of burden of infection in different compartments, monitoring disease progression and monitoring response to therapy. A "rational" development approach could facilitate efficient identification of an appropriate targeted radiopharmaceutical. Rational development starts with understanding characteristics of the disease that can be effectively targeted and then engineering radiopharmaceuticals to hone in on an appropriate target, which in the case of HIV-1 (HIV) might be an HIV-specific product on or in the host cell, a differentially expressed gene product, an integrated DNA sequence specific enzymatic activity, part of the inflammatory response, or a combination of these. This is different from the current approach that starts with a radiopharmaceutical for a target associated with a disease, mostly from autopsy studies, without a strong rationale for the potential to impact patient care. At present, no targeted therapies are available for HIV latency, although a number of approaches are under study. Here we discuss requirements for a radiopharmaceutical useful in strategies targeting persistently infected cells. The radiopharmaceutical for HIV should be developed based on HIV biology, studied in an animal model and then in humans, and ultimately used in clinical and research settings.
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Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models. Inflamm Bowel Dis 2014; 20:363-77. [PMID: 24374874 PMCID: PMC4618379 DOI: 10.1097/01.mib.0000440612.98950.79] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Activatable near-infrared fluorescent (NIRF) probes have been used for ex vivo and in vivo detection of intestinal tumors in animal models. We hypothesized that NIRF probes activatable by cathepsins or metalloproteinases will detect and quantify dextran sulphate sodium (DSS)-induced acute colonic inflammation in wild type mice or chronic colitis in interleukin-10 (IL-10)-null mice ex vivo or in vivo. METHODS Wild type mice given DSS, water controls, and IL-10-null mice with chronic colitis were administered probes by retro-orbital injection. FMT2500 LX system imaged fresh and fixed intestine ex vivo and mice in vivo. Inflammation detected by probes was verified by histology and colitis scoring. NIRF signal intensity was quantified using 2-dimensional region of interest ex vivo or 3-dimensional region of interest analysis in vivo. RESULTS Ex vivo, 7 probes tested yielded significant higher NIRF signals in colon of DSS-treated mice versus controls. A subset of probes was tested in IL-10-null mice and yielded strong ex vivo signals. Ex vivo fluorescence signal with 680 series probes was preserved after formalin fixation. In DSS and IL-10-null models, ex vivo NIRF signal strongly and significantly correlated with colitis scores. In vivo, ProSense680, CatK680FAST, and MMPsense680 yielded significantly higher NIRF signals in DSS-treated mice than controls, but background was high in controls. CONCLUSIONS Both cathepsin or metalloproteinase-activated NIRF probes can detect and quantify colonic inflammation ex vivo. ProSense680 yielded the strongest signals in DSS colitis ex vivo and in vivo, but background remains a problem for in vivo quantification of colitis.
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