DEVELOPMENT OF A NEW CLASS OF ULTRASOUND CONTRAST AGENTS

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The long term objective of this project is to develop and evaluate new injectable contrast agents for use in diagnostic ultrasound. Towards this aim the research will build upon expertise acquired during the first granting period, where it was shown that ionotropic gelation of alginate can be used to encapsulate air to produce stable microbubbles that are echogenic both in vitro and in vivo. The problem remains to reduce the microbubbles' diameter to below 6 micromoles, to allow unimpeded passage through the pulmonary bed. During the alginate studies an entirely new contrast agent was developed. It consists of surfactant-stabilized microbubbles which are prepared by sonication of aqueous mixtures of particular surfactants. Preliminary studies both in vitro and in vivo indicate that this new agent demonstrates great clinical potential. A key feature of this new agent is that 80% of the bubbles have a diameter of less than 6 micromoles. Contrast agent development will progress along two fronts. The alginate system is still considered to have merit, primarily because a polymer- coated bubble offers advantages of long-term stability and because calcium alginate, being a hydrogel, is highly flexible and deformable, resulting in good resistance to pressures such as those that are encountered in the heart. There have been recent reports of the use of atomizers to produce alginate microcapsules in the micron size range for use as vehicles for in vivo vaccine delivery. Emphasis will be placed on adapting this new technology to include entrapment of a gas in the micron-sized capsules. In addition, the use of a vibrating plate drop generator will be studied for the same purpose. Successful production of micron-sized microbubbles will be followed by extensive in vivo and in vitro characterization of the agent with respect to echogenicity (backscatter and attenuation coefficients), stability (both during storage and after in vivo injection) and biocompatibility. In parallel with these studies, there will be continued development of the surfactant-stabilized microbubbles. The present formulations have been characterized with respect to stability and to attenuation and backscatter coefficients in vitro. Further animal studies are planned to test both in vivo stability, and strength as a contrast agent. Also, it is important to investigate the mechanism of stabilization that is taking place at the surfactant/air interface at the molecular level. This will allow us to define the structural properties required of the surfactant molecule to stabilize air bubbles, which in turn will enable us to broaden the range of molecules available to us for use in this agent. In addition it will allow choice of the optimal molecular structures for maximum agent stability. Physical/chemical studies involving Langmuir trough experiments will be used to probe the molecular interactions of surfactants at air- water interfaces. Development of an effective ultrasound contrast agent would be highly significant to health care. Ultrasound is a relatively inexpensive, safe diagnostic procedure that is not only noninvasive, but also generates real time images of the internal structures of the body.