With the development of new biologically-active therapeutics, many of which are active at nanomolar concentrations and can be complimented by traditional chemotherapy, there is a tremendous opportunity for improvement in therapeutic efficacy. In this project we will address four major outstanding needs for the development of image-guided local delivery of new therapeutics. First, we will develop an entire class of new ultrasound enhanced delivery vehicles. Second, we will improve delivery by exploiting ultrasound-based mechanisms that allow new therapeutics to be concentrated within a tumor, including the local release of a compound, the use of radiation force together with molecular targeting to increase the local capture of delivery vehicles, and a local increase in capillary permeability produced secondary to mechanical disruption of the capillary or local release of a permeability–enhancing compound. Third, we will develop transducers and a 3D ultrasound system that combines imaging with a drug delivery mode, designed to enhance local delivery to a specified region of interest. The system and the new tools will become available to the research community, potentially enabling research in the area of local drug delivery at many research sites, and if successful will become the basis of a new commercial system. New transducers combining different ranges of frequencies (one for local release and one for radiation force) are required to develop the ultrasound-based methods for the clinic. Fourth, we will develop and employ PET tools for the 3D quantitative assessment of the biodistribution of labeled drugs and vehicles. Using these three sets of methods, we will conduct quantitative studies of the delivery of a chemotherapeutic to tumor models in a pre-clinical study. Although these drug delivery strategies are explored here for the unique environment of tumors, the techniques should have broad application.