Research Interests
Research in Molecular Imaging with Ultrasound
(Currently supported by NIH Roadmap for Medical Research, NIBIB EB005325)

Molecular imaging with ultrasound can be accomplished through the use of targeted microbubble contrast agents: acoustically-detectable 1-10 m stabilized microbubbles which incorporate targeting ligands into their exterior shell. These blood-pool agents can be detected with extremely high sensitivitysingle microbubbles can be detected in the bloodstream with various ultrasound imaging techniquesand good spatial resolution, typically on the order of hundreds of microns. Thus, they are ideal candidates for detection of molecular epitopes associated with several important pathologies. Examples of good targets for targeted imaging with ultrasound include angiogenesis, which is associated with small spontaneous tumors or metastases, and inflammation, which is associated with cardiovascular disease as well as other significant diseases. Dayton lab research involves the use of ultrasound contrast agents specifically designed to target cancer through adhesion to the v3 integrin, and the investigation and optimization of new technology specifically designed to deliver and detect these agents with a signal-to-noise ratio much greater than achievable with current methods.
Targeted imaging with ultrasound is a relatively new concept; only within the past few years has research progressed to the point of studies in animal models. These initial investigations into the use of targeted ultrasound contrast agents have clearly demonstrated proof-of-concept, but in-vivo, researchers have detected only small increases in the ultrasound signal at targeted sites. I hypothesize three reasons for this lack of sensitivity.
First, all currently available contrast agents have a relatively broad size distribution. Since contrast microbubbles are echogenic because of resonance effects, and a bubble's resonance frequency is directly related to its size, transducers of limited bandwidth are sensitive to only a fraction of injected contrast agents. One can estimate that current imaging systems are only optimized to interrogate less than 20% of the contrast agent population.
Second, in arterioles and venules, microbubble rheology is similar to that of erythrocytes: agents normally experience little contact with the vessel walls, resulting in minimal opportunity for adhesion. Current targeted imaging methods rely on hemodynamic interactions to cause contrast agent-target adhesion. Considering that the number of adhesion ligands at the target site may be sparse, targeted contrast agents need every possible opportunity to bind to the endothelium. Indeed, researchers have shown with intra-vital microscopy that the density of adherent bubbles retained in the vasculature at a target site is extremely low, on the order of only 10 bubbles per mm3.
Third, although current detection techniques can be sensitive to single microbubbles, they cannot discriminate small numbers of bound targeted agents from free agents in the circulation.
Our research in this area addresses these three fundamental challenges, and aims to improve approaches to the current technique of targeted imaging with ultrasound for improved sensitivity and specificity. Only with such improvements will molecular imaging with ultrasound truly become a clinically useful methodology.
We hypothesize that detection and acoustic manipulation of microbubble contrast agents can be vastly improved with a monodisperse agent population. Microbubble acoustic response is determined largely by bubble size, and therefore a monodisperse distribution of bubbles will have a completely predictable and uniform ultrasound response, vastly improving our ability to detect and manipulate the agents. A monodisperse contrast agent will revolutionize the field of ultrasound imaging. We estimate that a 500% increase in ultrasound sensitivity to contrast agents can be achieved by improving the size distribution alone.
We also hypothesize that directing the contrast microbubbles towards and against the vascular endothelium using ultrasound radiation force before imaging will increase the probability and strength of bubble adhesion. Previous research by Dayton with collaborators has demonstrated that ultrasound radiation force rapidly causes a significant increase (over 20 fold) in the amount of targeted contrast agents which bind to a target site in-vitro. If a similar signal increase is possible in-vivo, this technique will overcome current shortcomings in the quantity of targeted bubbles retained in tissue for molecular imaging.
Lastly, we hypothesize that new detection algorithms specifically designed to detect targeted contrast agents (little work has been done in this area to date) will substantially improve imaging sensitivity. Currently, sensitive detection of molecularly targeted agents is challenging with the noise background of freely circulating agents. Our research group is developing methods to separate the signal of targeted agents from freely circulating agents to improve image sensitivity.

Research in Ultrasound-Mediated Therapeutics
One of the biggest limitations with currently available chemotherapeutics is their systemic toxicity. Despite years of research, there are still only a few methods available to deliver anticancer drugs selectively to tumor tissues. Intravenous or oral administration may cause severe toxicity, impeding the therapeutic potential of anticancer drugs.
Due to this systemic toxicity, many researchers believe the most important goal of anticancer drug delivery is to maximize therapeutic concentration in tumors while minimizing the exposure of normal tissues. In addition to the challenge of site-specificity, an additional challenge with administration of chemotherapeutics is that subtherapeutic doses of chemotherapeutic may actually cause tumors to develop drug resistance as a result of biochemical changes.
One of the advances in chemotherapeutics has been to encapsulate these cytotoxic drugs in a liposome or other vehicle. Liposomes can be designed to contain the drug so as to minimize systemic effects. By tailoring the size, materials characteristics, or shell components of the liposome, researchers have been able to achieve some specificity for where these drug-laden liposomes accumulate preferentially in tumors. Indeed, several major FDA-approved drugs, such as DOXIL, use liposome encapsulation technology.
Despite these advantages and demonstration of promise to date, liposomes have the disadvantage in that their biodistribution after injection is still relatively nonspecific, and accumulation of liposomes by size selection or molecular targeting is a slow process. This nonspecificity can be overcome by the design of new multi-layer acoustically active delivery vehicles combined with the application of ultrasound. Standard liposomes are not acoustically active (or at most, very weakly acoustically active) because their density and compressiblity are similar to the surrounding blood. Acoustically active drug carriers must possess the combination of a layer with drug-carrying capacity, yet at the same time, they must have a core with significantly different density and compressibility than the surrounding media such as a gas. A vehicle with the drug carrying capacity of a liposome, but the acoustic activity of a microbubble can be concentrated at the target site by ultrasound, eliminating the need to rely on molecular targeting or passive mechanisms. Disruption of the acoustically-active vehicles at the target site can result in sub-micron fragments which can then extravasate in leaky tumor microvasculature. We hypothesize that improved chemotherapeutic delivery, with reduced systemic toxicity, can be achieved by utilizing ultrasound to concentrate and disrupt acoustically-active drug delivery vehicles at a target site. Additionally, acoustically active drug delivery vehicles can be directly imaged by ultrasound, providing instant feedback as to their location.

Recent Accomplishments and Honors
Biomedical Engineering Merit Award, presented by the University of Virginia, September, 1998.
Best Paper Award (first author), Observations of Contrast Agent Behavior During Insonation Using a Laser-Based High-Speed Imaging System, presented at the 1999 Ultrasound Contrast Research Symposium, Feb. 1999.
Best Student Paper (first author), Observations of contrast agents during insonation with a high-speed imaging system, presented at the 138th meeting of the Acoustical Society of America, Nov. 1999.
Young Investigator Award (co-author), High- Speed Optical Experimental Analysis of Microbubble Destruction Supported by Theoretical Development, the Fourth Heart Center European Symposium on Ultrasound Contrast Imaging, Jan. 1999.
Best Poster Award (co-author), A method for radiation-force localized drug delivery using gas filled lipospheres, presented at the 10th annual UC Davis Cancer Research Symposium, October 2004.
Featured Article (senior author) Selective imaging of adherent targeted ultrasound contrast agents, Physics in Medicine in Biology, March, 2007.
Finalist, UC Davis Academic Federation Excellence in Research Award
Best podium talk award (co-author) - On-Chip Generation of Lipid-Stabilized Microbubble Contrast Agents for Echocardiography, Kanaka Hettiarachchi, Esra Talu, Marjorie L. Longo, Paul A. Dayton, Abraham P. Lee, University of California Systemwide Bioengineering Symposium, June, 2007.

Training
Post-Doctoral Research
University of California, Davis
Department of Biomedical Engineering (2001).
Ph.D. Biomedical Engineering, Medical Imaging Program
University of Virginia, Charlottesville VA, (8/2001).
M.E. Electrical Engineering
University of Virginia, Charlottesville VA, (1/1998).
B.S. Physics,
B.S. Comprehensive Science,
Chemistry Minor
Villanova University, Villanova, PA, (5/1995).

Publications
Relevant Patents:
Ultrasonic concentration of drug delivery capsules, #7,358,226

Selected Cancer-Relevant Publications
1. 2004 P. A. Dayton, D. Pearson, J. Clark, S. Simon, P. A. Schumann, R. Zutshi, T. O. Matsunaga, K. W. Ferrara, Ultrasonic analysis of peptide- and antibody-targeted microbubble contrast agents for molecular imaging of alpha(v)beta(3)-expressing cells, Molecular Imaging, Vol. 3(2), pp. 125-34.
2. 2006 Paul A. Dayton and Terry O. Matsunaga, Ultrasound-Mediated Therapies Using Oil and Perfluorocarbon-filled Nanodroplets, Drug Development Research, vol 67(1), p. 42-46.
3. 2006 Susanne M. Stieger, Susannah H. Bloch, Oded Foreman, Erik R. Wisner, Katherine W. Ferrara, Paul A. Dayton, Ultrasound assessment of a matrigel model for angiogenesis in rats, Ultrasound in Medicine and Biology, vol 32(5), p. 673-81.
4. 2007 Azadeh Kheirolomoom, Paul A. Dayton, Aaron F. H. Lum, Erika Little, Eric. E. Paoli, Hua Zheng, Katherine W. Ferrara, Acoustically-active microbubbles conjugated to liposomes: Characterization of a proposed drug delivery vehicle., Journal of Controlled Release, Apr 23;118(3):275-84. Epub 2006 Dec 23.
5. 2007 Esra Talu, Kanaka Hettiarachchi, Shukui Zhao, Robert L. Powell, Marjorie L. Longo, Abraham. P. Lee, Paul A. Dayton, Improving Sensitivity in Molecular Imaging with Ultrasound by Tailoring Contrast Agent Size Distribution, Mol Imaging. 2007 Nov-Dec;6(6):384-92.
6. 2008 Susanne Stieger, Paul. A. Dayton, Mark Borden, Charles Caskey, Stephen Griffey, Erik Wisner, Katherine Ferrara, Imaging of Angiogenesis Using Cadence Contrast Pulse Sequencing and Targeted Contrast Agents Contrast Media and Molecular Imaging, Jan;3(1):9-18.

E-mail: padayton@email.unc.edu
Telephone: 843-9521
Address: 302 Taylor Hall Chapel Hill, NC 27599

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