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Project Description:

Theranostic agents contain both image contrast enhancing and therapeutic components and they have recently become the topic of an NIH Challenge Area within the National Institute of Biomedical Imaging and Bioengineering.  Using ultrasound contrast agents, which are microbubbles that are typically composed of an inert gas surrounded by a lipid or polymer shell, ultrasound can monitor and diagnose various disease states, including cancerous tumors.  These contrast agents may be targeted to specific cell surface receptors by incorporating targeting ligands to the surface of the microbubble, which aids in binding for both imaging and delivery purposes.  This effectively enhances ultrasound as an anatomical imaging modality to one that also includes molecular imaging capabilities.  There has been limited success in delivering a substance associated with the microbubble to target cells due to the fact that there is little room for drug payload in this hollow vehicle.   In addition, efforts to modify microbubbles are restricted due to their metastable nature. This pilot project aims to incorporate potent hydrophobic chemotherapeutics into microbubbles and liposomes by chemically conjugating the drug molecule to a lipid tail for self-assembly into lipid based vehicles that can be used in conjunction with ultrasound to deliver and monitor therapy.  This chemical design is hypothesized to advance the current potential of microbubble drug delivery with ultrasound, as lipid conjugation may addresses barriers in this field: 1) achieving enough drug incorporation in the microbubble, 2) non-uniform distribution of the drug into a population of microbubbles, and 3) uptake upon release of  drug from microbubbles. Specific ultrasound sequences to both bring the microbubble in contact with the vascular enodthelium and disrupt the vehicle such that microubble shell fragments containing drug could be internalized. Specific aims include the preparation, characterization, and in vitro performance assessment of this delivery scheme. Cell viability assays will assess efficiacy and  be used to demonstrate successful intracellular.  Imaging techniques, such as optical and electron microscopy, will be utilized to characterize the agents and to assess resulting particles after ultrasound exposure.