@article{tsuruta_schaub_rojas_streeter_klauber-demore_dayton_2017, title={Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma}, volume={12}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0174281}, abstractNote={Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. Previously, we showed ultrasound molecular imaging with SFRP2-targeted contrast increased average video pixel intensity (VI) of angiosarcoma vessels by 2.2 ± 0.6 VI versus streptavidin contrast. We hypothesized that redesigning our contrast agents would increase imaging performance. Improved molecular imaging reagents were created by combining NeutrAvidin™-functionalized microbubbles with biotinylated SFRP2 or IgY control antibodies. When angiosarcoma tumors in nude mice reached 8 mm, time-intensity, antibody loading, and microbubble dose experiments optimized molecular imaging. 10 minutes after injection, the control-subtracted time-intensity curve (TIC) for SFRP2-targeted contrast reached a maximum, after subtracting the contribution of free-flowing contrast. SFRP2 antibody-targeted VI was greater when contrast was formulated with 10-fold molar excess of maleimide-activated NeutrAvidin™ versus 3-fold (4.5 ± 0.18 vs. 0.32 ± 0.15, VI ± SEM, 5 x 106 dose, p < 0.001). Tumor vasculature returned greater average video pixel intensity using 5 x 107 versus 5 x 106 microbubbles (21.2 ± 2.5 vs. 4.5 ± 0.18, p = 0.0011). Specificity for tumor vasculature was confirmed by low VI for SFRP2-targeted, and control contrast in peri-tumoral vasculature (3.2 ± 0.52 vs. 1.6 ± 0.71, p = 0.92). After optimization, average video pixel intensity of tumor vasculature was 14.2 ± 3.0 VI units higher with SFRP2-targeted contrast versus IgY-targeted control (22.1 ± 2.5 vs. 7.9 ± 1.6, p < 0.001). After log decompression, 14.2 ΔVI was equal to ~70% higher signal, in arbitray acoustic units (AU), for SFRP2 versus IgY. This provided ~18- fold higher acoustic signal enhancement than provided previously by 2.2 ΔVI. Basing our targeted contrast on NeutrAvidin™-functionalized microbubbles, using IgY antibodies for our control contrast, and optimizing our imaging protocol significantly increased the SFRP2-specific signal returned from angiosarcoma vasculature, and may provide new opportunities for targeted molecular imaging.}, number={3}, journal={PLOS ONE}, author={Tsuruta, James K. and Schaub, Nicholas P. and Rojas, Juan D. and Streeter, Jason and Klauber-DeMore, Nancy and Dayton, Paul}, year={2017}, month={Mar} }
 @article{tsuruta_klauber-demore_streeter_samples_patterson_mumper_ketelsen_dayton_2014, title={Ultrasound Molecular Imaging of Secreted Frizzled Related Protein-2 Expression in Murine Angiosarcoma}, volume={9}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0086642}, abstractNote={Angiosarcoma is a biologically aggressive vascular malignancy with a high metastatic potential. In the era of targeted medicine, knowledge of specific molecular tumor characteristics has become more important. Molecular imaging using targeted ultrasound contrast agents can monitor tumor progression non-invasively. Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. We hypothesize that SFRP2-directed imaging could be a novel approach to imaging the tumor vasculature. To develop an SFRP2 contrast agent, SFRP2 polyclonal antibody was biotinylated and incubated with streptavidin-coated microbubbles. SVR angiosarcoma cells were injected into nude mice, and when tumors were established the mice were injected intravenously with the SFRP2 -targeted contrast agent, or a control streptavidin-coated contrast agent. SFRP2 -targeted contrast agent detected tumor vasculature with significantly more signal intensity than control contrast agent: the normalized fold-change was 1.6±0.27 (n = 13, p = 0.0032). The kidney was largely devoid of echogenicity with no significant difference between the control contrast agent and the SFRP2-targeted contrast agent demonstrating that the SFRP2-targeted contrast agent was specific to tumor vessels. Plotting average pixel intensity obtained from SFRP2-targeted contrast agent against tumor volume showed that the average pixel intensity increased as tumor volume increased. In conclusion, molecularly-targeted imaging of SFRP2 visualizes angiosarcoma vessels, but not normal vessels, and intensity increases with tumor size. Molecular imaging of SFRP2 expression may provide a rapid, non-invasive method to monitor tumor regression during therapy for angiosarcoma and other SFRP2 expressing cancers, and contribute to our understanding of the biology of SFRP2 during tumor development and progression.}, number={1}, journal={PLOS ONE}, author={Tsuruta, James K. and Klauber-DeMore, Nancy and Streeter, Jason and Samples, Jennifer and Patterson, Cam and Mumper, Russell J. and Ketelsen, David and Dayton, Paul}, year={2014}, month={Jan} }
 @article{streeter_herrera-loeza_neel_yeh_dayton_2013, title={A Comparative Evaluation of Ultrasound Molecular Imaging, Perfusion Imaging, and Volume Measurements in Evaluating Response to Therapy in Patient-Derived Xenografts}, volume={12}, ISSN={["1533-0346"]}, DOI={10.7785/tcrt.2012.500321}, abstractNote={ Most pre-clinical therapy studies use the change in tumor volume as a measure for disease response. However, tumor size measurements alone may not reflect early changes in tumor physiology that occur as a response to treatment. Ultrasonic molecular imaging (USMI) and Dynamic Contrast Enhanced-Perfusion Imaging (DCE-PI) with ultrasound are two attractive alternatives to tumor volume measurements. Since these techniques can provide information prior to the appearance of gross phenotypic changes, it has been proposed that USMI and DCE-PI could be used to characterize response to treatment earlier than traditional methods. This study evaluated the ability of tumor volume measurements, DCE-PI, and USMI to characterize response to therapy in two different types of patient-derived xenografts (known responders and known non-responders). For both responders and non-responders, 7 animals received a dose of 30 mg/kg of MLN8237, an investigational aurora-A kinase inhibitor, for 14 days or a vehicle control. Volumetric USMI (target integrin: αvβ3) and DCE-PI were performed on day 0, day 2, day 7, and day 14 in the same animals. For USMI, day 2 was the earliest point at which there was a statistical difference between the untreated and treated populations in the responder cohort (Untreated: 1.20 ± 0.53 vs. Treated: 0.49 ± 0.40; p < 0.05). In contrast, statistically significant differences between the untreated and treated populations as detected using DCE-PI were not observed until day 14 (Untreated: 0.94 ± 0.23 vs. Treated: 1.31 ± 0.22; p < 0.05). Volume measurements alone suggested no statistical differences between treated and untreated populations at any read-point. Monitoring volumetric changes is the “gold standard” for evaluating treatment in preclinical studies, however, our data suggests that volumetric USMI and DCE-PI may be used to earlier classify and robustly characterize tumor response. }, number={4}, journal={TECHNOLOGY IN CANCER RESEARCH & TREATMENT}, author={Streeter, J. E. and Herrera-Loeza, S. G. and Neel, N. F. and Yeh, J. J. and Dayton, P. A.}, year={2013}, month={Aug}, pages={311–321} }
 @article{streeter_dayton_2013, title={An In Vivo Evaluation of the Effect of Repeated Administration and Clearance of Targeted Contrast Agents on Molecular Imaging Signal Enhancement}, volume={3}, ISSN={["1838-7640"]}, DOI={10.7150/thno.5341}, abstractNote={Competitive inhibition diminishes ligand adhesion as receptor sites become occupied with competing ligands. It is unknown if this effect occurs in ultrasound molecular imaging studies where endothelial binding sites become occupied with adherent bubbles or bubble fragments. The goal of this pilot study was to assess the effect that repeated administration and clearance of targeted agents has on successive adhesion. Two groups of animals were imaged with 3-D ultrasonic molecular imaging. Injections and imaging were performed on Group 1 at time 0 and 60 minutes. Group 2 received injections of microbubbles at 0, 15, 30, 45 and 60 minutes with imaging at 0 and 60 minutes. At 60 minutes, Group 1 targeting relative to baseline was not significantly different from Group 2 (1.06±0.27 vs. 1.08±0.34, p=0.93). Data suggest that multiple injections of targeted microbubbles do not block sufficient binding sites to bias molecular imaging data in serial studies.}, number={2}, journal={THERANOSTICS}, author={Streeter, Jason E. and Dayton, Paul A.}, year={2013}, pages={93–98} }
 @article{czernuszewicz_streeter_dayton_gallippi_2013, title={Experimental Validation of Displacement Underestimation in ARFI Ultrasound}, volume={35}, ISSN={["1096-0910"]}, DOI={10.1177/0161734613493262}, abstractNote={ Acoustic radiation force impulse (ARFI) imaging is an elastography technique that uses ultrasonic pulses to displace and track tissue motion. Previous modeling studies have shown that ARFI displacements are susceptible to underestimation due to lateral and elevational shearing that occurs within the tracking resolution cell. In this study, optical tracking was utilized to experimentally measure the displacement underestimation achieved by acoustic tracking using a clinical ultrasound system. Three optically translucent phantoms of varying stiffness were created, embedded with subwavelength diameter microspheres, and ARFI excitation pulses with F/1.5 or F/3 lateral focal configurations were transmitted from a standard linear array to induce phantom motion. Displacements were tracked using confocal optical and acoustic methods. As predicted by earlier finite element method studies, significant acoustic displacement underestimation was observed for both excitation focal configurations; the maximum underestimation error was 35% of the optically measured displacement for the F/1.5 excitation pulse in the softest phantom. Using higher F/#, less tightly focused beams in the lateral dimension improved accuracy of displacements by approximately 10 percentage points. This work experimentally demonstrates limitations of ARFI implemented on a clinical scanner using a standard linear array and sets up a framework for future displacement tracking validation studies. }, number={3}, journal={ULTRASONIC IMAGING}, author={Czernuszewicz, Tomasz J. and Streeter, Jason E. and Dayton, Paul A. and Gallippi, Caterina M.}, year={2013}, month={Jul}, pages={196–213} }
 @article{borden_streeter_sirsi_dayton_2013, title={In Vivo Demonstration of Cancer Molecular Imaging with Ultrasound Radiation Force and Buried-Ligand Microbubbles}, volume={12}, ISSN={["1536-0121"]}, DOI={10.2310/7290.2013.00052}, abstractNote={In designing targeted contrast agent materials for imaging, the need to present a targeting ligand for recognition and binding by the target is counterbalanced by the need to minimize interactions with plasma components and to avoid recognition by the immune system. We have previously reported on a microbubble imaging probe for ultrasound molecular imaging that uses a buried-ligand surface architecture to minimize unwanted interactions and immunogenicity. Here we examine for the first time the utility of this approach for in vivo molecular imaging. In accordance with previous results, we showed a threefold increase in circulation persistence through the tumor of a fibrosarcoma model in comparison with controls. The buried-ligand microbubbles were then activated for targeted adhesion through the application of noninvasive ultrasound radiation forces applied specifically to the tumor region. Using a clinical ultrasound scanner, microbubbles were activated, imaged, and silenced. The results showed visually conspicuous images of tumor neovasculature and a twofold increase in ultrasound radiation force enhancement of acoustic contrast intensity for buried-ligand microbubbles, whereas no such increase was found for exposed-ligand microbubbles. We therefore conclude that the use of acoustically active buried-ligand microbubbles for ultrasound molecular imaging bridges the demand for low immunogenicity with the necessity of maintaining targeting efficacy and imaging conspicuity in vivo.}, number={6}, journal={MOLECULAR IMAGING}, author={Borden, Mark A. and Streeter, Jason E. and Sirsi, Shashank R. and Dayton, Paul A.}, year={2013}, month={Sep} }
 @article{sheeran_streeter_mullin_matsunaga_dayton_2013, title={TOWARD ULTRASOUND MOLECULAR IMAGING WITH PHASE-CHANGE CONTRAST AGENTS: AN IN VITRO PROOF OF PRINCIPLE}, volume={39}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2012.11.017}, abstractNote={Phase-change contrast agents (PCCAs), which normally consist of nanoscale or microscale droplets of liquid perfluorocarbons in an encapsulating shell, can be triggered to undergo a phase transition to the highly echogenic gaseous state upon the input of sufficient acoustic energy. As a result of the subsequent volumetric expansion, a number of unique applications have emerged that are not possible with traditional ultrasound microbubble contrast agents. Although many studies have explored the therapeutic aspects of the PCCA platform, few have examined the potential of PCCAs for molecular imaging purposes. In this study, we demonstrate a PCCA-based platform for molecular imaging using α(v)β(3)-targeted nanoscale PCCAs composed of low-boiling-point perfluorocarbons. In vitro, nanoscale PCCAs adhered to target cells, could be activated and imaged with a clinical ultrasound system and produced a six-fold increase in image contrast compared with non-targeted control PCCAs and a greater than fifty-fold increase over baseline. Data suggest that low-boiling-point nanoscale PCCAs could enable future ultrasound-based molecular imaging techniques in both the vascular and extravascular spaces.}, number={5}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Streeter, Jason E. and Mullin, Lee B. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2013}, month={May}, pages={893–902} }
 @article{gessner_streeter_kothadia_feingold_dayton_2012, title={AN IN VIVO VALIDATION OF THE APPLICATION OF ACOUSTIC RADIATION FORCE TO ENHANCE THE DIAGNOSTIC UTILITY OF MOLECULAR IMAGING USING 3-D ULTRASOUND}, volume={38}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2011.12.005}, abstractNote={For more than a decade, the application of acoustic radiation force (ARF) has been proposed as a mechanism to increase ultrasonic molecular imaging (MI) sensitivity in vivo. Presented herein is the first noninvasive in vivo validation of ARF-enhanced MI with an unmodified clinical system. First, an in vitro optical-acoustical setup was used to optimize system parameters and ensure sufficient microbubble translation when exposed to ARF. 3-D ARF-enhanced MI was then performed on 7 rat fibrosarcoma tumors using microbubbles targeted to αvβ3 and nontargeted microbubbles. Low-amplitude (<25 kPa) 3-D ARF pulse sequences were tested and compared with passive targeting studies in the same animal. Our results demonstrate that a 78% increase in image intensity from targeted microbubbles can be achieved when using ARF relative to the passive targeting studies. Furthermore, ARF did not significantly increase image contrast when applied to nontargeted agents, suggesting that ARF did not increase nonspecific adhesion.}, number={4}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Gessner, Ryan C. and Streeter, Jason E. and Kothadia, Roshni and Feingold, Steven and Dayton, Paul A.}, year={2012}, month={Apr}, pages={651–660} }
 @misc{matsunaga_sheeran_luois_streeter_mullin_banerjee_dayton_2012, title={Phase-change nanoparticles using highly volatile perfluorocarbons: Toward a platform for extravascular ultrasound imaging}, volume={2}, number={12}, journal={Theranostics}, author={Matsunaga, T. O. and Sheeran, P. S. and Luois, S. and Streeter, J. E. and Mullin, L. B. and Banerjee, B. and Dayton, P. A.}, year={2012}, pages={1185–1198} }
 @article{streeter_gessner_miles_dayton_2010, title={Improving sensitivity in ultrasound molecular imaging by tailoring contrast agent size distribution: In vivo studies}, volume={9}, number={2}, journal={Molecular Imaging}, author={Streeter, J. E. and Gessner, R. and Miles, I. and Dayton, P. A.}, year={2010}, pages={87–95} }
 @article{bouchard_palmeri_pinton_trahey_streeter_dayton_2009, title={Optical tracking of acoustic radiation force impulse-induced dynamics in a tissue-mimicking phantom}, volume={126}, ISSN={["1520-8524"]}, DOI={10.1121/1.3238235}, abstractNote={Optical tracking was utilized to investigate the acoustic radiation force impulse (ARFI)-induced response, generated by a 5-MHz piston transducer, in a translucent tissue-mimicking phantom. Suspended 10-μm microspheres were tracked axially and laterally at multiple locations throughout the field of view of an optical microscope with 0.5-μm displacement resolution, in both dimensions, and at frame rates of up to 36 kHz. Induced dynamics were successfully captured before, during, and after the ARFI excitation at depths of up to 4.8 mm from the phantom’s proximal boundary. Results are presented for tracked axial and lateral displacements resulting from on-axis and off-axis (i.e., shear wave) acquisitions; these results are compared to matched finite element method modeling and independent ultrasonically based empirical results and yielded reasonable agreement in most cases. A shear wave reflection, generated by the proximal boundary, consistently produced an artifact in tracked displacement data later in time (i.e., after the initial ARFI-induced displacement peak). This tracking method provides high-frame-rate, two-dimensional tracking data and thus could prove useful in the investigation of complex ARFI-induced dynamics in controlled experimental settings.}, number={5}, journal={JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA}, author={Bouchard, Richard R. and Palmeri, Mark L. and Pinton, Gianmarco F. and Trahey, Gregg E. and Streeter, Jason E. and Dayton, Paul A.}, year={2009}, month={Nov}, pages={2733–2745} }
 @article{streeter_gessner_tsuruta_feingold_dayton, title={Assessment of molecular imaging of angiogenesis with three-dimensional ultrasonography}, volume={10}, number={6}, journal={Molecular Imaging}, author={Streeter, J. E. and Gessner, R. C. and Tsuruta, J. and Feingold, S. and Dayton, P. A.}, pages={460–468} }