| Cardiovascular disease (CVD) is the leading cause of death worldwide, and the economic impact of CVD is expected to increase substantially in future decades as disability rates due to ischemic heart disease and stroke rise. More effective diagnostic tools and therapies are necessary to limit the growing burden of CVD, particularly those which manifest in clotting within the arteries of the heart or brain.;Echogenic liposomes (ELIP) are nanoparticle theragnostic agents being developed to target and treat cardiovascular disease. ELIP contain a small amount of gas and can function as an injectable ultrasound contrast agent (UCA) to improve visualization of the heart or diseased arteries. Previous investigations have shown that it is possible to load ELIP with bioactive gases, and that pulsed ultrasound exposure can result in the loss of echogenicity from ELIP. The purpose of this study was to determine if pulsed ultrasound exposure can also be used for controlled release of gas from ELIP. Determining the relationship between microbubble activity and acoustically-induced gas release will help to develop a method utilizing ELIP as therapeutic agents for delivery of gas to tissue.;In Chapters 2 and 3, acoustic methods were used to characterize a series of novel formulations of ELIP with different shell components and gas content. Estimates of the shell properties of ELIP, as well as two commercially available UCAs, DefinityRTM and MicroMarkerRTM, were obtained using a linearized viscoelastic acoustic scattering model. Overall, ELIP are characterized by higher shell elasticity and shell damping coefficient than the commercially available agents. Replacing air with the high molecular weight gas octafluoropropane and addition of polyethylene glycol into the shell formulation resulted in longer stability and improved high-frequency response, making these ELIP formulations particularly suitable for intravascular ultrasound applications. In addition, ELIP encapsulating octafluoropropane and two physiologically active gases, nitric oxide and xenon, were investigated. It was shown that encapsulation of nitric oxide has a strong and prolonged osmotic effect whereas ELIP containing xenon gas were relatively stable in vitro..;In Chapters 4 and 5, an ultra-high-speed optical imaging approach was used to investigate the acoustic response of ELIP to both short-pulse and multiple-cycle tone burst insonations. The acoustic response and viscoelastic shell properties of ELIP were found to be similar to other phospholipid-shelled UCAs. A decrease in shell viscosity was observed with increasing dilatation rate, indicative of shear-thinning behavior. ELIP are stable when exposed to short-pulse insonations similar to those used in echocardiography, and can therefore be used as an echocontrast agent for cardiovascular imaging applications. For tone burst insonations it was shown that the maximum dilatation rate correlates with loss of gas due to acoustically-driven diffusion, and a threshold was identified for loss of gas due to this effect. These studies demonstrated that ELIP can be considered a theragnostic agent, with both stable and unstable dynamics that can be exploited using different ultrasound parameter regimes. The observed phenomena of ultrasound-induced loss of gas could be exploited to optimize ELIP for therapeutic delivery of gas to tissue. |
