Towards Ultrasound Molecular Imaging

  • Vincenzo Lionetti
  • Sergio Paddeu


Health systems are facing both health promotion and disease prevention thus requiring the discovery of new sustainable clinical and technological approaches concerning both (early) diagnosis and (personalized) therapy. This chapter aims to highlight the main steps forward toward the ultrasound molecular imaging, a new emerging technological approach which will contribute to accomplish the convergence of diagnosis and therapy in clinical practice. This convergence, which is called “theranostics”, is currently being developed as a combined diagnostic-therapeutic clinical platform whereas integrated therapy systems involve diagnostic technologies like ultrasound, magnetic resonance or computed tomography. Ultrasound molecular imaging represents a worthwhile step toward the full exploitation of imaging technologies in aiding treatment and surgery through the exploitation of combining molecular biology and emerging technologies, like nanotechnology. Although molecular imaging has been mainly concerned with nuclear imaging, magnetic resonance or optical imaging, today there is a growing interest in the exploitation of diagnostic ultrasound due to the possible merging of ultrasound advantages over other imaging modalities like real time, non-invasiveness, low cost, therapy and diagnosis application, short and efficient imaging protocol. The growing list of clinical conditions concerning the diagnostic potential of ultrasound include several areas like angiogenesis, atherosclerotic plaque investigation, inflammation marker detection, and identification, and other. Moreover, the progress of nanotechnology (nano-medicine) as well as of molecular biology supported the recent development and engineering of ultrasound contrast agents, based on gas filled microbubbles or nanoparticles providing new insights into early tumor detection (e.g., angiogenesis), local drug delivery, early responses to molecular therapies and in situ therapy. This approach is favoring the growth theranostics, namely the set-up of novel strategies about diagnosis, drug development and therapy, in fields like oncology, cardiology or rheumatology.


Ultrasound Contrast Agent Diagnostic Ultrasound Microbubble Destruction IEEE Trans Ultrason Ferroelectr Freq Early Tumor Detection 
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  1. 1.
    Bloch SH, Wan M and Dayton PA et al. (2004) Optical observation of lipidand polymer-shelled ultrasound microbubble contrast agents. Appl Phys Letts 84:631–3CrossRefGoogle Scholar
  2. 2.
    Christiansen JP, French BA and Klibanov AL et al. (2003) Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles. Ultrasound Med Biol 29:1759–1767CrossRefGoogle Scholar
  3. 3.
    Christiansen JP and Lindner JR (2005) Molecular and Cellular Imaging with Targeted Contrast Ultrasound. Proceedings of the IEEE 93:809–818CrossRefGoogle Scholar
  4. 4.
    Dayton PA, Chomas JE and Lum AF et al. (2001) Optical and acoustical dynamics of micro-bubble contrast agents inside neutrophils. J Biophys 80:1547–1556CrossRefGoogle Scholar
  5. 5.
    Debbage P and Jaschke W (2008) Molecular imaging with nanoparticles: giant roles for dwarf actors. Histochem Cell Biol 130(5):845–875CrossRefGoogle Scholar
  6. 6.
    Ellegala DB, Leong-Poi H and Carpenter JE et al. (2003) Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3. Circulation 108:336–341CrossRefGoogle Scholar
  7. 7.
    Forsberg F, Liu JB and Merton DA et al. (1995) Parenchymal enhancement and tumor visualization using a new sonographic contrast agent. J Ultrasound Med 14:949–57Google Scholar
  8. 8.
    Goldberg BB, Raichlen JS and Forsberg F (2001) Ultrasound Contrast Agents. Martin Dunitz Ltd, LondonGoogle Scholar
  9. 9.
    Guo H, Leung JC and Chan LY et al. (2007) Ultrasound-contrast agent mediated naked gene delivery in the peritoneal cavità of adult rat. Gene Ther. 14(24):1712–1720CrossRefGoogle Scholar
  10. 10.
    Hamilton AJ, Huang SL and Warnick D et al. (2004) Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol 43:453–460CrossRefGoogle Scholar
  11. 11.
    Hashizume H, Baluk P and Morikawa S et al. (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156:1363–1380Google Scholar
  12. 12.
    Hundley WG, Kizilbash AM and Afridi I et al. (1998) Administration of an intravenous per-fluorocarbon contrast agent improves echocardiographic determination of left ventricular volumes and ejection fraction: Comparison with cine magnetic resonance imaging. J Am Coll Cardiol 32:1426–1432CrossRefGoogle Scholar
  13. 13.
    Iyer A, Khaled G and Fang J et al. (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11:812–818CrossRefGoogle Scholar
  14. 14.
    Kassan DG, Lynch AM and Stiller MJ (1996) Physical enhancement of dermatologic drug delivery: iontophoresis and phonophoresis. J Am Acad Dermatol 34:657–666CrossRefGoogle Scholar
  15. 15.
    Kheirolomoom A, Dayton PA and Lum AF et al. (2007) Acoustically-active microbubbles conjugated to liposomes: characterization of a proposed drug delivery vehicle. J Control Release 118:275–284CrossRefGoogle Scholar
  16. 16.
    Klibanov AL (1999) Targeted delivery of gas-filled microspheres, contrast agents for ultrasound imaging. Adv Drug Deliv Rev 37:139–157CrossRefGoogle Scholar
  17. 17.
    Lanza GM, Abendschein DR and Hall CS et al. (2000) Molecular imaging of stretch-induced tissue factor expression in carotid arteries with intravascular ultrasound. Invest Radiol. 35(4):227–234CrossRefGoogle Scholar
  18. 18.
    Lee DJ, Lyshchik A and Huamani J et al. (2008) Relationship between retention of a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted ultrasonographic contrast agent and the level of VEGFR2 expression in an in vivo breast cancer model. J Ultrasound Med 27(6): 855–866Google Scholar
  19. 19.
    Lentacker I, De Smedt SC and Demeester J et al. (2006) Microbubbles which bind and protect DNA against nucleases. J Control Release 116:e73–e75CrossRefGoogle Scholar
  20. 20.
    Leong-Poi H, Christiansen J and Klibanov AL et al. (2003) Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation 107:455CrossRefGoogle Scholar
  21. 21.
    Liang HD and Blomley MJK (2003) The role of ultrasound in molecular imaging. The British Journal of Radiology 76: S140–S150CrossRefGoogle Scholar
  22. 22.
    Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874CrossRefGoogle Scholar
  23. 23.
    Lindner JR, Coggins MP and Kaul S et al. (2000) Microbubble persistence in the microcirculation during ischemia/reperfusion and inflammation is caused by integrin-and complement-mediated adherence to activated leukocytes. Circulation 101(6):668–675Google Scholar
  24. 24.
    Lindner JR, Song J and Xu F et al. (2000) Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes. Circulation 102:2745–2750Google Scholar
  25. 25.
    Lindner JR (2004) Molecular imaging with contrast ultrasound and targeted microbubbles. J Nuc Cardiol 11(2):215–221CrossRefGoogle Scholar
  26. 26.
    Marmottant P and Hilgenfeldt S (2003) Controlled vesicle deformation and lysis by single oscillating bubbles. Nature 423:153–156CrossRefGoogle Scholar
  27. 27.
    Marsh JN, Hall CS and Scott MJ et al. (2002) Improvements in the ultrasonic contrast of targeted perfluorocarbon nanoparticles using an acoustic transmission line model. IEEE Trans Ultrason Ferroelectr Freq Control 49:29–38CrossRefGoogle Scholar
  28. 28.
    Palmowski M, Huppert J and Ladewig G et al. (2007) Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst 99:1095–1106CrossRefGoogle Scholar
  29. 29.
    Price RJ, Skyba DM and Kaul S et al. (1998) Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation 98(13):1264–1267Google Scholar
  30. 30.
    Rapoport N, Gao Z and Kennedy A (2007) Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J Natl Cancer Inst 99(14):1095–1106CrossRefGoogle Scholar
  31. 31.
    Rychak JJ, Klibanov AL and Hossack JA (2005) Acoustic radiation force enhances targeted delivery of ultrasound contrast microbubbles: in vitro verification. IEEE Trans Ultrason Ferroelectr Freq Control 52:421–433CrossRefGoogle Scholar
  32. 32.
    Schumann PA, Christiansen JP and Quigley RM et al. (2002) Targetedmicrobubble binding selectively to GPIIb IIIa receptors of platelet thrombi. Invest Radiol 37:587–593CrossRefGoogle Scholar
  33. 33.
    Skyba DM, Price RJ and Linka AZ et al. (1998) Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 98(4):290–293Google Scholar
  34. 34.
    Simons M (2005) Angiogenesis: where do we stand now? Circulation 111:1556–1566CrossRefGoogle Scholar
  35. 35.
    Takalkar AM, Klibanov AL and Rychak JJ et al. (2004) Binding and detachment of microbubbles targeted to P-selectin under controlled shear flow. J Control Release 96:473–482CrossRefGoogle Scholar
  36. 36.
    Unger EC, McCreery TP and Sweitzer RH et al. (1998a) Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. Invest Radiol 33:886–892CrossRefGoogle Scholar
  37. 37.
    Unger EC, McCreery TP and Sweitzer RH (1998b) MRX-501: a novel ultrasound contrast agent with therapeutic properties. Acad Radiol 5 (1):S247–S249CrossRefGoogle Scholar
  38. 38.
    Wei K and Kaul S (1997) Recent advances in myocardial contrast echocardiography. Curr Opin Cardiol 12:539CrossRefGoogle Scholar
  39. 39.
    Wells PNT (2001) Physics and engineering: milestones in medicine. Med Eng Phys 23:147–153CrossRefGoogle Scholar
  40. 40.
    Wheatley MA, Forsberg F and Oum K et al. (2006) Comparison of in vitro and in vivo acoustic response of a novel 50:50 PLGA contrast agent. Ultrasonics 44:360–367CrossRefGoogle Scholar
  41. 41.
    Willmann JK, Lutz AM and Paulmurugan R et al. (2008) Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo. Radiology 248(3):936–944CrossRefGoogle Scholar
  42. 42.
    Zhao S, Kruse DE and Ferrara KW et al. (2007) Selective imaging of adherent targeted ultra-sound contrast agents. Phys Med Biol 52(8):2055–2072CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2010

Authors and Affiliations

  • Vincenzo Lionetti
    • 1
  • Sergio Paddeu
    • 2
  1. 1.Sector of MedicineScuola Superiore Sant’AnnaPisaItaly
  2. 2.Esaote S.p.A.GenoaItaly

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