? Many promising studies indicate that ultrasound-enhanced delivery vehicles can be used to locally deliver a drug to a region of interest, with ultrasound imaging used to define the region to be treated and to monitor the inflow of the delivery vehicle. We will specifically explore the ultrasound-based mechanisms that allow new therapeutics to be concentrated in a user-specified region of interest within a tumor. These include the use of ultrasonic radiation force to increase the capture of targeted delivery agents, the release of a compound through ultrasound-induced fragmentation of the vehicle, and the use of ultrasound to mechanically or chemically induce an increase in microvascular permeability. Drug delivery vehicles can be engineered to be manipulated by ultrasonic radiation force, where the ultrasound pressure deflects the flow of the agent to the vessel wall. The vehicles can also be coated with a targeting ligand, resulting in adhesion to endothelial cells. In addition, the vehicles can be designed such that ultrasound pressure produces fragmentation of a micron-sized sphere into particles on the order of tens to hundreds of nanometers, which are taken up more readily. UC Davis and Siemens Medical Systems will create an ultrasound system and transducers that can create an image with a typical clinical frequency (2.5-7.5 MHz) and disseminate a drug to a 3D region of interest with a lower center frequency (1 MHz). A full three-dimensional integrated system will be operational in year four of the proposed work, with prototypes available earlier. Although ultrasound-enhanced local delivery has shown great promise in vitro and in preliminary in vivo studies, we believe that a system that can specify a region of interest in three dimensions and monitor the inflow of the drug vehicle must be created in order to produce reproducible and quantitative improvements. UC Davis and ImaRx will cooperate in the development and evaluation of molecularly-targeted drug delivery vehicles, with new vehicles available beginning in the first year. Additionally, in the first two years of the project period, a team of UC Davis investigators will develop PET tools required to assess the biodistribution of the labeled agents with and without insonation, and these tools will be applied throughout this project and disseminated to the imaging community. With the advent of commercially-available systems for small animal imaging with PET, the development of techniques to label drugs and drug carriers should also be of great interest. We will initially develop these drug delivery strategies for the unique environment of tumors, although the techniques should have broad application. ? ?
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