The objective of this proposal is to develop and evaluate several particulate ultrasonic contrast agents which selectively accumulate in normal liver parenchyma but not in most tumors. Ultrasound is frequently employed for liver evaluation in both staging and followup of therapy because of its availability, low cost, and easy patient acceptance. However, neoplastic liver lesions have variable ultrasonographic features which can hinder detection by this modality. Even modest improvements in sensitivity using contrast enhancement would enhance the utility of ultrasound for primary screening and for followup of already demonstrated liver metastases. We propose to thoroughly evaluate iodipamide ethyl ester (IDE) particulate suspensions to develop models for ultrasound-particle and ultrasound-particle-tissue interactions. Preliminary experiments using IDE particles suspended in agar demonstrated that IDE increased ultrasonic backscatter and attenuation coefficients with increased particle diameter and concentration. B-scan images of rabbit livers (in vivo) and rat livers (ex vivo) containing IDE particles showed greater contrast enhancement compared to control livers than was anticipated from studies of agar. The additional mechanisms which act in liver require further investigation. Additional studies of other particulate agents covering a range of mechanical properties (compressibility and density) should indicate the desirable chemical-mechanical properties for optimization of ultrasound contrast enhancement. New particulate ultrasonic contrast agents will be produced using technology already developed for IDE. Ultrasonic evaluation of these new agents, using instrumentation developed at this institution as well as commercial imaging equipment, will start with simple agar suspensions and proceed to more complex experiments involving mice for safety evaluation and normal rats, normal rabbits, and rabbits with liver tumor implants for efficacy evaluation. Screening of each new contrast agent will terminate with the least complex study which demonstrates the agent is not superior to IDE. The investigators have experience with all of the methodology proposed in this application. The proposed studies, combining a unique technology for particulate suspension formulation and unique instrumentation for precise measurement of ultrasonic properties of normal and treated tissues should produce quantitative understanding of ultrasound-particle-tissue interactions and, possibly, a clinically useful ultrasound contrast agent.
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