Dynamics of therapeutic ultrasound contrast agents

Novel therapeutic contrast agents offer great potential for localized drug delivery. Localized delivery should significantly improve the efficacy of drug delivery and reduce any toxic exposure to the healthy tissue. This work describes a preliminary theoretical description of agents, such as those developed by the ImaRx Corporation, enclosed by a relatively thick fluid shell. A theoretical extension is made to a generalized Rayleigh-Plesset formulation that allows it to be solved for an encapsulating liquid shell of arbitrary thickness and density. The equation is used to investigate the role of shell thickness, density and viscosity on the radial dynamics and velocity of the inner and outer radii. Comparisons are made with experimental measurements of the maximum radial expansions for agents with triacetin shells. For a seven-cycle driving acoustic pulse with a center frequency of 1.5 MHz and peak amplitude of 1.6 MPa, the equation predicts maximum expansions from 5.5 to 1.3 times the initial radius for agents 1 to 10 microm, respectively, in initial radius with a 500-nm (28.0 cP) encapsulating shell. These predictions have reasonable agreement with the maximum radial expansions obtained from optical experimental data of fragmenting and intact agents. Approximate agreement between theory and experiment for a similar range of agent sizes is also demonstrated for a pulse with the same pressure amplitude at 2.5 MHz. At 2.5 MHz, smaller radial expansion amplitudes from 1.1 to 4.1 times the initial radius were found for agents 1 to 10 microm in initial radius, respectively. Discrepancies are attributed to shape instabilities and their associated fragmentation effects not incorporated in the equation. A significant difference in the inner and outer wall velocities is predicted for agents with a 500-nm triacetin shell. A 2.5 microm initial radius agent driven with a seven-cycle pulse at 2.5 MHz and 1.6 MPa achieves a maximum negative inner wall velocity of 364 m/s and outer wall velocity of 63 m/s. For parameters that correspond to large differences between the inner and outer wall velocities, fragmentation is typically observed experimentally.