The Umbilical CordAn Ally in Targeted Imaging Research?*
Jonathan R. Lindner, MD*,
Scott Chadderdon, MD
Division of Cardiovascular Medicine, Oregon Health & Science University, Portland, Oregon
Key Words: contrast ultrasound • molecular imaging • microbubbles
The emergence of methods for molecular imaging with contrast-enhanced ultrasound reflects a general broadening of the scope for all forms of medical imaging. The goal of this trend is to evaluate pathophysiology at the molecular level rather than to image the structural or functional consequences of disease. Most commonly this approach relies on the detection of bioengineered targeted contrast probes. There is an important role for molecular imaging in both pre-clinical investigation and in patient care. In the clinical setting, imaging key molecular mediators or markers of disease may allow very early detection of disease or provide more definitive information on the presence and extent of disease. It may also provide a powerful tool for rapidly testing new therapeutic strategies or to select the most optimal therapy based on the active molecular participants or disease phenotype, a form of "individualized medicine." An established example where targeted probes have made a major impact can be found in cancer medicine where radionuclide imaging with 111In-labeled monoclonal antibody against CD20 (ibritumomab) has been used to detect and stage B-cell non-Hodgkin's lymphoma and to select patients who will benefit from anti-CD20 radioimmunotherapy (1).
In cardiovascular medicine, molecular imaging could potentially be used to improve risk assessment in atherosclerotic disease, to increase sensitivity for detecting thrombus, or to create new diagnostic algorithms for detecting ischemia, myocarditis, or transplant rejection. It is probably naïve to believe that any one imaging method (radionuclide, cardiac magnetic resonance, ultrasound, computed tomography imaging) will be the best option for all of these cardiovascular applications. As in the past, imaging technologies will instead be matched to clinical purpose and circumstance. The use of contrast-enhanced ultrasound with targeted microbubble agents will likely be considered when temporal resolution, cost, and availability/portability are important considerations and when the molecular target of interest is amenable to a contrast agent that is confined to the vascular compartment.
Potential uses for ultrasound and microbubbles extend beyond diagnostics. There has been remarkable progress in the field of ultrasound-mediated gene transfer whereby the bioeffects produced by microbubble cavitation in an ultrasound field can be used to increase gene delivery and transfection (2). This effect is enhanced when complementary deoxyribonucleic acid is directly coupled to the surface of albumin or cationic lipid microbubbles (3,4). The ability to focus ultrasound provides an avenue for transfection to a specific tissue of interest. The exact mechanism(s) responsible for enhanced transfection with ultrasound destruction of microbubble vectors is unknown. Some of the putative mechanisms include transient cellular microporation from high-pressure jets (microstreaming), ballistic effects, and stimulation of endocytosis.
The paper by Barreiro et al. (5) in this issue of iJACC describes a series of experiments in which: 1) targeted microbubbles were used to detect expression of intercellular adhesion molecule-1 and CD9 in umbilical cord vessels; and 2) ultrasound-mediated disruption of microbubbles was used to amplify transfection of plasmid complementary deoxyribonucleic acid for a green fluorescent protein reporter gene in an umbilical vessel with static flow. Previous work has already evaluated the in vitro cell-binding kinetics of microbubbles targeted to endothelial cell adhesion molecules such as selectins, intercellular adhesion molecule-1, vascular cell adhesion molecule-1,  v-integrins, among others (6–10). Molecular imaging with these agents has been used to assess inflammatory phenotype in atherosclerotic disease, to detect recent myocardial ischemia and transplant rejection, and to evaluate the molecular mediators of ischemia-mediated angiogenesis (6–10). This study introduces a new model to study microbubble behavior that may be important for future probe development. The field of drug discovery now has a well-established route whereby individual candidate molecules that are selected randomly through combinatorial chemistry are screened with high-throughput robotic biosensor assays. The milestones for the development of novel ultrasound molecular imaging probes follow a somewhat different route (Fig. 1). This process begins with the creation of a single targeted probe with a specific diagnostic purpose in mind. Almost all of the progress in the field thus far has advanced up to step 3, testing in pertinent animal models of disease. The fourth step, engineering of probes suitable for human testing, involves much more than just a switch to an appropriate human targeting ligand. Targeted microbubble agents are multivalent particles. Accordingly, microbubble formulations must be tested to evaluate the relative effects of the myriad of factors that can affect binding such as: 1) the binding kinetics for different ligands (or combination of ligands); 2) ligand surface density; 3) length of molecular spacer arm that projects the ligand from the bubble surface; 4) presence of other polymers (e.g., polyethylene glycol) on the bubble surface; 5) target molecule density; 6) vascular shear force; and 7) pulsatility of flow, to name a few.
High-throughput methods with human tissues are needed for the testing of human-ready microbubble agents. Flow chamber studies with cultured human cells are not the answer because these preparations do not necessarily recapitulate normal or diseased human tissues and are influenced by procedural variables such as passage history and contact inhibition. The study by Barreiro et al. (5) introduces the concept of using intact ex vivo human umbilical vessels to test targeted microbubble contrast agents in the human vascular environment and to evaluate tissue distribution of ultrasound-mediated gene transfer. With regard to the latter, adequate models are also needed to systematically test important variables of ultrasound-mediated transfection (microbubble preparation, acoustic power, ultrasound frequency, pulsing interval) and to optimize the balance between desired and detrimental bioeffects. Although umbilical vessels may not be satisfactory for modeling most human disease conditions, alternative sources of ex vivo diseased vascular tissue, such as human carotid arteries, have also been used to test binding of novel probes (11).
Descriptive studies may provide particularly useful information when they identify a mechanism or generate a hypothesis (12). The paper by Barreiro et al. (5) reminds us that evolutions in methodology also play an important role for promoting progress in a field.
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Acknowledgments
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The authors thank Chad Carr, MD, and Stuart Bunting, PhD, for their helpful comments and thoughts.
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Footnotes
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* Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. Jonathan R. Lindner, Cardiovascular Division UHN-62, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239 (Email: lindnerj{at}ohsu.edu).
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