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.
Key Words
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References
- Ultrasound molecular imaging of tumor angiogenesis with an integrin targeted microbubble contrast agent.Invest Radiol. 2011; 46: 215-224
- Initialization, noise, singularities, and scale in height ridge traversal for tubular object centerline extraction.IEEE Trans Med Imaging. 2002; 21: 61-75
- Integrin receptor imaging of breast cancer: A proof-of-concept study to evaluate 99 mTc-NC100692.J Nucl Med. 2006; 47: 1434-1439
- Earlier detection of breast cancer with ultrasound molecular imaging in a transgenic mouse model.Cancer Res. 2013; 73: 1689-1698
- Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18 F-Galacto-RGD PET.J Nucl Med. 2008; 49: 255-259
- Harmonic chirp imaging method for ultrasound contrast agent.IEEE Trans Ultrason Ferroelectr Freq Control. 2005; 52: 241-249
- Super harmonic imaging: A new imaging technique for improved contrast detection.Ultrasound Med Biol. 2002; 28: 59-68
- Contrast superharmonic imaging: A feasibility study.Ultrasound Med Biol. 2003; 29: 547-553
Brock-Fisher G, Poland M, and Rafter P. Means for increasing sensitivity in non-linear ultrasound imaging systems. 1996; US Patent US 5577505
- Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels.Cell. 1994; 79: 1157-1164
- Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall.J Acoust Soc Am. 2007; 122: 1191-1200
- The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer.Ann Thorac Surg. 2004; 78 (discussion 1023): 1017-1023
- Ultrasonic analysis of peptide- and antibody-targeted microbubble contrast agents for molecular imaging of alphavbeta3-expressing cells.Mol Imaging. 2004; 3: 125-134
- VEGFR2-targeted molecular imaging in the mouse embryo: An alternative to the tumor model.Ultrasound Med Biol. 2014; 40: 389-399
- Resonance frequencies of lipid-shelled microbubbles in the regime of nonlinear oscillations.Ultrasonics. 2009; 49: 263-268
- Vascular channels formed by subpopulations of PECAM1+ melanoma cells.Nature Comm. 2014; 5: 5200
- Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3.Circulation. 2003; 108: 336-341
- Characterization of Definity ultrasound contrast agent at frequency range of 5-15 MHz.Ultrasound Med Biol. 2011; 37: 338-342
- Microbubble size isolation by differential centrifugation.J Colloid Interface Sci. 2009; 329: 316-324
- A new 15-50 MHz array-based micro-ultrasound scanner for preclinical imaging.Ultrasound Med Biol. 2009; 35: 1700-1708
- Micro-ultrasound for preclinical imaging.Interface Focus. 2011; 1: 576-601
- The value of 18-FDG PET/CT in early-stage breast cancer compared to traditional diagnostic modalities with an emphasis on changes in disease stage designation and treatment plan.Eur J Oncol. 2012; 38: 31-37
- Unbinding of targeted ultrasound contrast agent microbubbles by secondary acoustic forces.Phys Med Biol. 2011; 56: 6161-6177
- High-resolution, high-contrast ultrasound imaging using a prototype dual-frequency transducer: in vitro and in vivo studies.IEEE Trans Ultrason Ferroelectr Freq Control. 2010; 57: 1772-1781
- Mapping microvasculature with acoustic angiography yields quantifiable differences between healthy and tumor-bearing tissue volumes in a rodent model.Radiology. 2012; 264: 733-740
- An in vivo validation of the application of acoustic radiation force to enhance the diagnostic utility of molecular imaging using 3-d ultrasound.Ultrasound Med Biol. 2012; 38: 651-660
- Acoustic angiography: A new imaging modality for assessing microvasculature architecture.Int J Biomed Imaging. 2013; 2013: 936593
- Nonlinear resonance behavior and linear shell estimates for Definity and MicroMarker assessed with acoustic microbubble spectroscopy.J Acoust Soc Am. 2013; 133: 1158-1168
- A sensitive TLRH targeted imaging technique for ultrasonic molecular imaging.IEEE Trans Ultrason Ferroelectr Freq Control. 2010; 57: 305-316
- In vivo validation and 3 D visualization of broadband ultrasound molecular imaging.Am J Nucl Med Mol Imaging. 2013; 3: 336-349
- 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: 224-235
- Molecular imaging of disease with targeted contrast ultrasound imaging.Transl Res. 2012; 159: 140-148
- Determinants of tumor blood flow: A review.Cancer Res. 1988; 48: 2641-2658
- Molecular imaging with targeted contrast ultrasound.Curr Opin Biotechnol. 2007; 18: 11-16
- Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1.Circulation. 2007; 116: 276-284
- Resonance frequency of microbubbles: Effect of viscosity.J Acoust Soc Am. 2004; 116: 1463-1473
- Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow.Contrast Media Mol Imaging. 2006; 1: 259-266
- A new imaging strategy using wideband transient response of ultrasound contrast agents.IEEE Trans Ultrason Ferroelectr Freq Control. 2005; 52: 1320-1329
- Golay pulse encoding for microbubble contrast imaging in ultrasound.IEEE Trans Ultrason Ferroelectr Freq Control. 2007; 54: 2082-2090
- Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins.Circulation. 2003; 107: 455-460
- Assessment of endogenous and therapeutic arteriogenesis by contrast ultrasound molecular Imaging of integrin expression.Circulation. 2005; 111: 3248-3254
- Improved sentinel node identification by SPECT/CT in overweight patients with breast cancer.J Nucl Med. 2007; 48: 201-206
- Acoustic characterization of contrast-to-tissue ratio and axial resolution for dual-frequency contrast-specific acoustic angiography imaging.IEEE Trans Ultrason Ferroelectr Freq Control. 2014; 61: 1668-1687
- Optimization of contrast-to-tissue ratio through pulse windowing in dual-frequency “acoustic angiography” imaging.Ultrasound Med Biol. 2015; 41: 1884-1895
- Evaluation of breast lesions with contrast-enhanced ultrasound using the microvascular imaging technique: Initial observations.Breast. 2008; 17: 532-539
- Ultrasound molecular imaging of vascular endothelial growth factor receptor 2 expression for endometrial receptivity evaluation.Theranostics. 2015; 5: 206-217
- Effect of ultrasound on adherent microbubble contrast agents.Phys Med Biol. 2012; 57: 6999-7014
- Dual-frequency piezoelectric transducers for contrast enhanced ultrasound imaging.Sensors. 2014; 14: 20825-20842
- Real-time technique for improving molecular imaging and guiding drug delivery in large blood vessels: in vitro and ex vivo results.Mol Imaging. 2011; 10: 238-247
Phillips P. Contrast pulse sequences (CPS): imaging nonlinear microbubbles. IEEE Ultrasonics Symposium, Atlanta, GA, 2, 2001, 1739–1745
- BR55: A lipopeptide-based VEGFR2-targeted ultrasound contrast agent for molecular imaging of angiogenesis.Invest Radiol. 2010; 45: 89-95
- Antiangiogenic cancer therapy: Monitoring with molecular US and a clinically translatable contrast agent (BR55).Radiology. 2010; 256: 519-527
- Assessment and monitoring tumor vascularity with contrast-enhanced ultrasound maximum intensity persistence imaging.Invest Radiol. 2011; 46: 187-195
- SPECT/CT imaging using a spiral CT scanner for anatomical localization: Impact on diagnostic accuracy and reporter confidence in clinical practice.Nucl Med Commun. 2006; 27: 977-987
- Microultrasound molecular imaging of vascular endothelial growth factor receptor 2 in a mouse model of tumor angiogenesis.Mol Imaging. 2007; 6: 289-296
- Forced linear oscillations of microbubbles in blood capillaries.J Acoust Soc Am. 2004; 115: 3235-3243
- Single-particle optical sizing of microbubbles.Ultrasound Med Biol. 2014; 40: 138-147
- Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18 F] Galacto-RGD positron emission tomography.Neuro-oncology. 2009; 11: 861-870
- Quantification of microvascular tortuosity during tumor evolution utilizing acoustic angiography.Ultrasound Med Biol. 2015; 41: 1896-1904
- Effect of microbubble size on fundamental mode high frequency ultrasound imaging in mice.Ultrasound Med Biol. 2010; 36: 935-948
- Clinical impact of 18 F-choline PET/CT in patients with recurrent prostate cancer.Eur J Nucl Med Mol Imaging. 2012; 39: 936-943
Stephens DN, Lu XM, Proulx T, Walters W, Dayton P, Tartis M, Kruse DE, Lum AFH, Kitano T, Stieger SM, Ferrara KW. Multi-frequency Array Development for Drug Delivery Therapies: Characterization and First Use of a Triple Row Ultrasound Probe. IEEE International Ultrasonics Symposium, Vancouver, B.C., Canada, 2006, 66−69
- Biomedical image processing.Computer. 1983; 16: 22-34
- Improving sensitivity in ultrasound molecular imaging by tailoring contrast agent size distribution: in vivo studies.Mol Imaging. 2010; 9: 87-95
- Assessment of molecular imaging of angiogenesis with three-dimensional ultrasonography.Mol Imaging. 2011; 10: 460-468
- An in vivo evaluation of the effect of repeated administration and clearance of targeted contrast agents on molecular imaging signal enhancement.Theranostics. 2013; 3: 93-98
- Observation of contrast agent response to chirp insonation with a simultaneous optical-acoustical system.IEEE Trans Ultrason Ferroelectr Freq Control. 2006; 53: 1130-1137
- Contrast imaging with chirped excitation.IEEE Trans Ultrason Ferroelectr Freq Control. 2007; 54: 520-529
- Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow.J Control Release. 2004; 96: 473-482
- Tailoring the size distribution of ultrasound contrast agents: possible method for improving sensitivity in molecular imaging.Mol Imaging. 2007; 6: 384-392
- Ultrasound molecular imaging of VEGFR2 in a rat prostate tumor model using BR55.Invest Radiol. 2010; 45: 573-578
- Impact of I-131-SPECT/CT images obtained with an integrated system in the follow-up of patients with thyroid carcinoma.Eur J Nucl Med Mol Imaging. 2004; 31: 1435-1442
- Near-infrared fluorescence imaging of both colorectal cancer and ureters using a low-dose integrin targeted probe.Ann Surg Oncol. 2014; 21: S528-S537
- Ultrasound molecular imaging.Methods. 2009; 48: 92-97
- Molecular imaging of inflammation in inflammatory bowel disease with a clinically translatable dual-selectin-targeted US contrast agent: Comparison with FDG PET/CT in a mouse model.Radiology. 2013; 267: 818-829
- Binding dynamics of targeted microbubbles in response to modulated acoustic radiation force.Phys Med Biol. 2014; 59: 465-484
- Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer.Invest Radiol. 2015; 50: 322-329
- Ultrasound-based measurement of molecular marker concentration in large blood vessels: A feasibility study.Ultrasound Med Biol. 2015; 41: 222-234
- US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice.Radiology. 2008; 246: 508-518
- Targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with contrast microbubbles conjugated to integrin-binding knottin peptides.J Nucl Med. 2010; 51: 433-440
- Ultrasonic imaging of endothelial CD81 expression using CD81-targeted contrast agents in in vitro and in vivo studies.Ultrasound Med Biol. 2012; 38: 670-680
- Intertumoral differences in hypoxia selectivity of the PET imaging agent 64 Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone).J Nucl Med. 2006; 47: 989-998
- Radiation-force assisted targeting facilitates ultrasonic molecular imaging.Mol Imaging. 2004; 3: 135-148
Article info
Publication history
Published online: December 08, 2015
Accepted:
October 18,
2015
Received in revised form:
October 14,
2015
Received:
April 30,
2015
Identification
Copyright
© 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
