Microbubble contrast agents are used to enhance ultrasound images of the vascular space, as non-contrast ultrasound is only very weakly sensitive to blood flow in small vessels. Currently, microbubbles are approved clinically for left ventricular border enhancement in sub-optimal echocardiography, and are used pre-clinically for perfusion imaging and molecular imaging of diseased tissue. However, due to their size, microbubbles cannot extravasate into the tissue and therefore cannot be used as extravascular contrast agents. Recently, we have developed nanodroplet perfluorohexane emulsions that can extravasate out of the vasculature. Surprisingly, despite their boiling point (bp = 610 C) these droplets were found to vaporize and form gas deposits in tissue. Based upon this knowledge, we have preliminarily formed liquid perfluorocarbon nanodroplets which can be turned into microbubbles with acoustic energy (referred to as """"""""pro-bubbles""""""""). For this proposal, we hypothesize that if we add a known amount of perfluorohexane to a pro-bubble, we can create a particle which can extravasate, and then can be activated by ultrasound energy to form a micron-sized gas bubble. A targeted pro-bubble which can extravasate into the extravascular space/tissue will be able to accumulate at diseased tissue such as micrometastases, which would not normally be accessible by microbubbles. After extravasation and localization at a target site, we can use ultrasound to activate the """"""""pro- bubble"""""""" into a microbubble of defined size for high-sensitivity ultrasound imaging.

Public Health Relevance

Microbubble contrast agents are used with ultrasound to image for disease and abnormalities inside the vasculature. However, because of their size, microbubbles cannot diffuse outside the vessels to image tissue. We propose the development of a targeted liquid drop or """"""""pro-bubble"""""""" which is small enough to diffuse outside the vasculature and target diseased tissue. Once targeted to diseased tissue, the pro-bubble can be converted to a bubble by ultrasound where it can now be imaged. This pro-bubble could allow clinicians to image very small metastatic tumors that heretofore may not be identified and could eventually be used to destroy the small tumors using non-invasive ultrasound techniques. This new and innovative methodology could potentially advance early detection and treatment of cancer.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SBIB-S (91))
Program Officer
Lopez, Hector
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arizona
Schools of Medicine
United States
Zip Code
Sheeran, Paul S; Matsuura, Naomi; Borden, Mark A et al. (2017) Methods of Generating Submicrometer Phase-Shift Perfluorocarbon Droplets for Applications in Medical Ultrasonography. IEEE Trans Ultrason Ferroelectr Freq Control 64:252-263
Li, Sinan; Lin, Shengtao; Cheng, Yi et al. (2015) Quantifying activation of perfluorocarbon-based phase-change contrast agents using simultaneous acoustic and optical observation. Ultrasound Med Biol 41:1422-31
Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying et al. (2013) Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets. J Control Release 172:795-804
Martin, K Heath; Dayton, Paul A (2013) Current status and prospects for microbubbles in ultrasound theranostics. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:329-45
Mullin, Lee B; Phillips, Linsey C; Dayton, Paul A (2013) Nanoparticle delivery enhancement with acoustically activated microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control 60:65-77
Phillips, Linsey C; Puett, Connor; Sheeran, Paul S et al. (2013) Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating. J Acoust Soc Am 134:1473-82
Sheeran, Paul S; Streeter, Jason E; Mullin, Lee B et al. (2013) Toward ultrasound molecular imaging with phase-change contrast agents: an in vitro proof of principle. Ultrasound Med Biol 39:893-902
Sheeran, Paul S; Matsunaga, Terry O; Dayton, Paul A (2013) Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy. Phys Med Biol 58:4513-34
Matsunaga, Terry O; Sheeran, Paul S; Luois, Samantha et al. (2012) Phase-change nanoparticles using highly volatile perfluorocarbons: toward a platform for extravascular ultrasound imaging. Theranostics 2:1185-98
Martz, Thomas D; Bardin, David; Sheeran, Paul S et al. (2012) Microfluidic generation of acoustically active nanodroplets. Small 8:1876-9

Showing the most recent 10 out of 15 publications