The aim of this project is to evaluate the usefulness of a novel drug delivery technology for cancer treatment, based on intravenously injectable emulsions of superheated perfluorocarbon droplets loaded with a therapeutic agent. The micron-size droplets dispersed in the emulsions are superheated, i.e., they are kept above their boiling point. In this thermodynamically metastable state, they can be vaporized by exposure to diagnostic levels of ultrasound, which permits the spatially and temporally controlled release of their drug content into a target region. The droplets are encapsulated with surfactants allowing them to withstand the mechanical stresses arising from inoculation and circulation in the bloodstream. Therefore they do not vaporize spontaneously, but only when triggered externally. The use of ultrasound as a triggering modality enables the integration of targeted delivery and imaging. The project is a collaboration between Yale University, where the superheated emulsion technology was invented and drug delivery applications were proposed, and the University of Michigan, where the use of superheated emulsions has been proposed and proven in vivo for occlusion therapy. The two groups, with complementary interests and expertise, propose to demonstrate the capabilities of the technology in a biologically relevant setting, i.e., the transport and release in vivo of paclitaxel, a highly cytotoxic chemotherapy agent virtually insoluble in water. The project will comprise investigations in various animal models available at our institutes to clarify different aspects of the delivery technology, as well as the utilization of various imaging techniques to confirm and quantify the occurrence and location of droplet activation.
Specific aims of the project are: 1. To manufacture drug-loaded superheated emulsions and determine in-vitro and in-vivo, in dogs and rabbits, their viability for ultrasound-controlled drug-delivery; 2. To examine the acute effects on rats and evaluate the specificity of drug release and biodistribution in comparison with intravenous administration; 3. To use nuclear magnetic resonance techniques to measure and depict the distribution of bubbles in rats, and intravital microscopy techniques to observe directly the biophysical properties of blood-borne particles in the microcirculation of hamsters. ? ?
