Specific and high-resolution ultrasound cancer imaging

Summary

Principal Investigator: Katherine W Ferrara
Abstract: DESCRIPTION (provided by applicant): Methods for ultrasound imaging of targeted agents are progressing rapidly;we show that with our methods the tumor image intensity from targeted agents is more than 250 times that of the agent in the surrounding tissue and more than 32 times that of a scrambled agent. Our overall goals in the renewal are to create safe and effective targeted imaging strategies for a range of vascular receptors and to incorporate targeted imaging in cancer diagnostics and therapies. Phase III radiology trials of non-targeted agents are underway in the US and targeted agents, such as BR55, are likely to enter the clinic very soon. Contrast ultrasound imaging is a compelling imaging technique, as it is widely-used, inexpensive, portable, and permits real-time anatomical and molecular imaging. Within the past five years, we have created new imaging methods, evaluated the physics and bioeffects of microbubble contrast agents and developed new synthesis strategies. We developed a spectral approach to quantify bound agents and here will determine the sensitivity and accuracy of this strategy. This new method is insensitive to system gain and does not require the use of high mechanical index pulses. We apply these methods to evaluate the avidity of ligands for a set of receptors that are up-regulated in angiogenesis, focusing on breast, prostate and bladder cancer. Further, we will investigate the use of our targeted ultrasound imaging methods to guide and augment cancer therapy. Guiding ultrasound therapy with the targeted ultrasound image is an efficient, cost-effective strategy. In addition, assessment of the safety of targeted ultrasound contrast is essential and will be addressed here. We have previously mapped the range of insonation parameters under which non-targeted microbubble imaging can be performed safely and have demonstrated jetting of bound agents into the endothelium. Now, we demonstrate that in vivo insonation of targeted microbubbles creates biological effects using parameters that were previously found to be safe with a non-targeted agent;in particular, we observe reduced blood flow after high mechanical index insonation of targeted agents. We seek to fully define the mechanism, to define the range of parameters under which such effects occur and to validate the new safe range for targeted agents. Finally, the FDA has previously expressed concerns about complement mediated-anaphylaxis resulting from non-targeted agents but data are very limited for targeted agents. We will assess complement activation in vitro and in vivo, with a goal of estimating the risk of classes of ligands defined by length, charge, cyclization and arginine content.
Funding Period: 2005-01-01 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. pmc Observation of contrast agent response to chirp insonation with a simultaneous optical-acoustical system
    Yang Sun
    Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
    IEEE Trans Ultrason Ferroelectr Freq Control 53:1130-7. 2006
  2. pmc Novel ultrasound and DCE-MRI analyses after antiangiogenic treatment with a selective VEGF receptor inhibitor
    Katherine D Watson
    Department of Biomedical Engineering, University of California, Davis, CA 95327, USA
    Ultrasound Med Biol 37:909-21. 2011
  3. pmc Leveraging the power of ultrasound for therapeutic design and optimization
    Charles F Caskey
    Department of Biomedical Engineering, University of California, Davis, One Shields Ave, Davis, CA 95616, USA
    J Control Release 156:297-306. 2011
  4. pmc Fast ultrasound beam prediction for linear and regular two-dimensional arrays
    Mario Hlawitschka
    Universitat Leipzig, Computer Science, Leipzig, Germany
    IEEE Trans Ultrason Ferroelectr Freq Control 58:2001-12. 2011
  5. pmc Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors
    Katherine D Watson
    Department of Biomedical Engineering, University of California, Davis, California 95616, USA
    Cancer Res 72:1485-93. 2012
  6. pmc Ultrasound imaging of oxidative stress in vivo with chemically-generated gas microbubbles
    John Kangchun Perng
    The Wallace H Coulter Department of Biomedical Engineering, Parker H Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA
    Ann Biomed Eng 40:2059-68. 2012
  7. pmc Insonation of targeted microbubbles produces regions of reduced blood flow within tumor vasculature
    Xiaowen Hu
    Department of Biomedical Engineering, University of California, Davis 95616, USA
    Invest Radiol 47:398-405. 2012
  8. pmc Microfluidic system for facilitated quantification of nanoparticle accumulation to cells under laminar flow
    Jiro Kusunose
    Department of Biomedical Engineering, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
    Ann Biomed Eng 41:89-99. 2013
  9. pmc A comparison of image contrast with (64)Cu-labeled long circulating liposomes and (18)F-FDG in a murine model of mammary carcinoma
    Andrew W Wong
    Department of Biomedical Engineering, University of California Davis, CA 95616, USA
    Am J Nucl Med Mol Imaging 3:32-43. 2013
  10. pmc Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis
    Guodong Zhang
    Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:6530-5. 2013

Research Grants

  1. CANCER CENTER SUPPORT GRANT
    TONY R HUNTER; Fiscal Year: 2013
  2. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
  3. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013

Detail Information

Publications36

  1. pmc Observation of contrast agent response to chirp insonation with a simultaneous optical-acoustical system
    Yang Sun
    Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
    IEEE Trans Ultrason Ferroelectr Freq Control 53:1130-7. 2006
    ..1 micros for increasing and decreasing chirp insonation, respectively (P = 0.02). The mean power in the low-frequency portion of the echoes was 8 (mV)2 and 13 (mV)2 for increasing and decreasing chirp insonation, respectively (P = 0.01)...
  2. pmc Novel ultrasound and DCE-MRI analyses after antiangiogenic treatment with a selective VEGF receptor inhibitor
    Katherine D Watson
    Department of Biomedical Engineering, University of California, Davis, CA 95327, USA
    Ultrasound Med Biol 37:909-21. 2011
    ..66 to 4.54 s and to fill with an MR contrast agent from 29.5 to 50.8 s. Measures of flow rate derived from MRI and ultrasound demonstrated a positive linear correlation of r2 = 0.86...
  3. pmc Leveraging the power of ultrasound for therapeutic design and optimization
    Charles F Caskey
    Department of Biomedical Engineering, University of California, Davis, One Shields Ave, Davis, CA 95616, USA
    J Control Release 156:297-306. 2011
    ....
  4. pmc Fast ultrasound beam prediction for linear and regular two-dimensional arrays
    Mario Hlawitschka
    Universitat Leipzig, Computer Science, Leipzig, Germany
    IEEE Trans Ultrason Ferroelectr Freq Control 58:2001-12. 2011
    ..Beam volumes containing 256(3) field points are calculated within 1 s for 1-D and 2-D arrays containing 512 and 20(2) pistons, respectively, thus facilitating future real-time thermal dose predictions...
  5. pmc Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors
    Katherine D Watson
    Department of Biomedical Engineering, University of California, Davis, California 95616, USA
    Cancer Res 72:1485-93. 2012
    ..Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability...
  6. pmc Ultrasound imaging of oxidative stress in vivo with chemically-generated gas microbubbles
    John Kangchun Perng
    The Wallace H Coulter Department of Biomedical Engineering, Parker H Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA
    Ann Biomed Eng 40:2059-68. 2012
    ....
  7. pmc Insonation of targeted microbubbles produces regions of reduced blood flow within tumor vasculature
    Xiaowen Hu
    Department of Biomedical Engineering, University of California, Davis 95616, USA
    Invest Radiol 47:398-405. 2012
    ..Here, we investigate the effect of high-pressure insonation of bound microbubbles and the potential for thrombogenic effects...
  8. pmc Microfluidic system for facilitated quantification of nanoparticle accumulation to cells under laminar flow
    Jiro Kusunose
    Department of Biomedical Engineering, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
    Ann Biomed Eng 41:89-99. 2013
    ..4 dyne/cm(2)), as compared with greater shear or the absence of shear. We describe here a robust flow chamber model that is applied to optimize the properties of 100 nm liposomes targeted to inflamed endothelium...
  9. pmc A comparison of image contrast with (64)Cu-labeled long circulating liposomes and (18)F-FDG in a murine model of mammary carcinoma
    Andrew W Wong
    Department of Biomedical Engineering, University of California Davis, CA 95616, USA
    Am J Nucl Med Mol Imaging 3:32-43. 2013
    ..The imaging of radiolabeled nanoparticles can facilitate tumor detection, identification of tumor margins, therapeutic evaluation and interventional guidance...
  10. pmc Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis
    Guodong Zhang
    Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:6530-5. 2013
    ..These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers...
  11. pmc Complete regression of local cancer using temperature-sensitive liposomes combined with ultrasound-mediated hyperthermia
    Azadeh Kheirolomoom
    University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA Electronic address
    J Control Release 172:266-73. 2013
    ..Systemic toxicity indicators, such as cardiac hypertrophy, leukopenia, and weight and hair loss were not detected with CuDox-LTSLs after the 28-day therapy...
  12. pmc A physiological perspective on the use of imaging to assess the in vivo delivery of therapeutics
    Shengping Qin
    Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
    Ann Biomed Eng 42:280-98. 2014
    ....
  13. pmc Evaluation of doxorubicin-loaded 3-helix micelles as nanocarriers
    Nikhil Dube
    Department of Materials Science and Engineering, University of California, Berkeley, California 94720, United States
    Biomacromolecules 14:3697-705. 2013
    ..In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics...
  14. pmc Quantitation of nanoparticle accumulation in flow using optimized microfluidic chambers
    J Kusunose
    Department of Biomedical Engineering, University of California, Davis, CA, USA
    J Drug Target 22:48-56. 2014
    ..The vascular cell adhesion molecule-1 (VCAM-1) targeting peptide sequence, VHPKQHR, is a promising moiety for targeting atherosclerosis through incorporation into nanoparticles such as dendrimers and liposomes...
  15. pmc Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases
    Frits Thorsen
    Department of Biomedicine, University of Bergen, Bergen, Norway Electronic address
    J Control Release 172:812-22. 2013
    ..Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies...
  16. ncbi (64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque
    Jai Woong Seo
    Department of Biomedical Engineering, University of California, Davis, California 95616, United States
    Bioconjug Chem 25:231-9. 2014
    ..Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles. ..
  17. pmc Ultrasound molecular imaging of tumor angiogenesis with an integrin targeted microbubble contrast agent
    Christopher R Anderson
    Targeson, Inc, San Diego, CA, USA
    Invest Radiol 46:215-24. 2011
    ..The MB and the imaging methods were evaluated in a mouse model of breast cancer in vivo...
  18. pmc Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies
    Dana D Hu-Lowe
    Oncology Research Unit, Drug Safety, Research, and Development, and Translational Oncology, Pfizer Inc, San Diego, California, USA
    Cancer Res 71:1362-73. 2011
    ....
  19. ncbi Therapeutic effects of paclitaxel-containing ultrasound contrast agents
    Michaelann Shortencarier Tartis
    Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA
    Ultrasound Med Biol 32:1771-80. 2006
    ..Lastly, ultrasound and molecular targeting are combined to deliver a model drug to the endothelium and interstitium of chorioallantoic membrane vasculature in vivo...
  20. pmc Acoustic response from adherent targeted contrast agents
    Shukui Zhao
    J Acoust Soc Am 120:EL63-9. 2006
    ..0003). Mechanisms for the observed acoustical difference and potential techniques to utilize these differences for molecular imaging are proposed...
  21. ncbi Contrast imaging with chirped excitation
    Yang Sun
    Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
    IEEE Trans Ultrason Ferroelectr Freq Control 54:520-9. 2007
    ..The difference in the mainlobe width between experimental and predicted compressed echoes is less than 20%. The side-lobe amplitude is 9 dB to 16 dB below the mainlobe with a transmitted I(SPTA) from 0.1 to 6.6 mW/cm2...
  22. pmc Selective imaging of adherent targeted ultrasound contrast agents
    S Zhao
    Department of Biomedical Engineering, University of California, Davis, USA
    Phys Med Biol 52:2055-72. 2007
    ..The performance of these algorithms is compared, emphasizing the significance and potential applications in ultrasonic molecular imaging...
  23. ncbi Ultrasound-driven microbubble oscillation and translation within small phantom vessels
    Hairong Zheng
    Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
    Ultrasound Med Biol 33:1978-87. 2007
    ..This study has implications for contrast-assisted ultrasound applications, aiding the manipulation of targeted microbubbles and for further theoretical understanding of the complex bubble dynamics within constrained vessel...
  24. pmc Driving delivery vehicles with ultrasound
    Katherine W Ferrara
    Department of Biomedical Engineering, 451 Health Sciences Drive, University of California, Davis, CA 95616, USA
    Adv Drug Deliv Rev 60:1097-102. 2008
    ..In this commentary, the identified mechanisms, delivery vehicles, applications and current bottlenecks for translation of these techniques are summarized...
  25. pmc Efficient array design for sonotherapy
    Douglas N Stephens
    University of California, Davis, CA, USA
    Phys Med Biol 53:3943-69. 2008
    ....
  26. pmc Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering
    Shengping Qin
    Department of Biomedical Engineering, University of California, 451 East Health Sciences Drive, Davis, CA 95616, USA
    Phys Med Biol 54:R27-57. 2009
    ..In this review, we focus on the physical aspects of these agents, exploring microbubble imaging modes, models for microbubble oscillation and the interaction of the microbubble with the endothelium...
  27. pmc Microbubble tunneling in gel phantoms
    Charles F Caskey
    Department of Biomedical Engineering, University of California, Davis, 451 East Health Sciences Drive, Davis, California 95616, USA
    J Acoust Soc Am 125:EL183-9. 2009
    ..Combinations of ultrasonic parameters and microbubble concentrations that are relevant for diagnostic imaging and drug delivery and that lead to tunnel formation were applied and the resulting tunnel formation was quantified...
  28. pmc Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery
    Katherine W Ferrara
    Department of Biomedical Engineering, University of California, Davis, California 95616, USA
    Acc Chem Res 42:881-92. 2009
    ..Lipid-shelled vehicles offer many opportunities for chemists and engineers; ultrasound-based applications beyond the few currently in common use will undoubtedly soon multiply as molecular construction techniques are further refined...
  29. pmc An imaging-driven model for liposomal stability and circulation
    Shengping Qin
    Department of Biomedical Engineering, University of California, 451 East Health Sciences Drive, Davis, California 95616, USA
    Mol Pharm 7:12-21. 2010
    ..Finally, we develop a transport constant for the transport of liposomes from the blood pool to the tumor interstitium, which is on the order of 0.01 h(-1) for the Met-1 tumor system...
  30. ncbi Imaging nanoparticle stability and activation in vivo
    Katherine W Ferrara
    University of California Davis, CA, USA
    Conf Proc IEEE Eng Med Biol Soc 2009:4580-1. 2009
    ..Here, we describe our efforts to label the shell and drug core of lipid-shelled particles with a goal of facilitating translation of activatable particles...
  31. pmc A sensitive TLRH targeted imaging technique for ultrasonic molecular imaging
    Xiaowen Hu
    Department of Biomedical Engineering, University of California, Davis, CA, USA
    IEEE Trans Ultrason Ferroelectr Freq Control 57:305-16. 2010
    ..The TLRH targeted imaging method is demonstrated in this study to provide sensitive and selective detection of bound microbubbles for ultrasound molecularly targeted imaging...
  32. pmc A model for the dynamics of ultrasound contrast agents in vivo
    Shengping Qin
    Department of Biomedical Engineering, University of California, 451 East Health Sciences Drive, Davis, California 95616, USA
    J Acoust Soc Am 128:1511-21. 2010
    ..Dynamics of UCAs with a shell of lipid, polymer, albumin and liquid are investigated for typical therapeutic ultrasound pulses. The effects of liquid compressibility and shell and tissue parameters are analyzed...
  33. pmc Noninvasive thermometry assisted by a dual-function ultrasound transducer for mild hyperthermia
    Chun Yen Lai
    University of California at Davis, Department of Biomedical Engineering, Davis, CA, USA
    IEEE Trans Ultrason Ferroelectr Freq Control 57:2671-84. 2010
    ..1 to 1.0°C following correction. This study demonstrates the feasibility of combining therapy and monitoring using a commercial system. In the future, real-time temperature estimation will be incorporated into this system...
  34. pmc Accumulation, internalization and therapeutic efficacy of neuropilin-1-targeted liposomes
    Eric E Paoli
    University of California, Davis, Department of Biomedical Engineering, 451 Health Sciences Drive, Davis, CA 95616, USA Electronic address
    J Control Release 178:108-17. 2014
    ..Taken together, our results demonstrate that a carboxyl-terminated RXXR peptide sequence, conjugated to liposomes at a concentration of 0.63mol%, retains long circulation but enhances binding and internalization, and reduces toxicity. ..

Research Grants30

  1. CANCER CENTER SUPPORT GRANT
    TONY R HUNTER; Fiscal Year: 2013
    ....
  2. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
  3. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....