Phase-Change Contrast Agents for Ultrasound Detection of Breast Cancer

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DESCRIPTION (provided by applicant): Microbubble contrast agents used in conjunction with ultrasound are currently approved by the FDA and other global agencies as vascular agents for enhancing echocardiographic and hepatic imaging. They are also used in the research arena as molecular imaging agents for detection of angiogenesis, inflammation, and vulnerable plaque to name but a few. In addition, they have been translated to the clinic as ultrasound-mediated thrombolytic agents as well (i.e. Sonothrombolysis). Yet despite their utility, they are also restricted primarily to the vasculature due to their relatively large size (1 - 5 microns) and inability to extravasate into the tissue space. Recently, our laboratory has developed new phase-change contrast agents (PCCAs) that are comprised of a 100 nm, ultrasound-activatable, lipid-coated, perfluorocarbon-filled droplet designed for extravascular distribution followed by conversion to microbbubbles for ultrasound tissue imaging. These PCCAs consist of very low boiling liquid perfluorocarbons (decafluorobutane, bp = -1.1¿C, octafluoropropane, bp = -36.7¿C), stable at physiologic temperatures (37¿C) and activatable into imagable microbubbles with low ultrasound energy outputs (FDA approved mechanical indices). Furthermore, conversion to microbubbles is acheivable using standard clinical ultrasound machines. Studies are ongoing with respect to their ability to extravasate into tissue and are the focus of a previou grant. Currently, we are measuring levels of PCCA extravasation as an indication of enhanced permeability and retention effect (EPR). In the focus of this new proposal, we wish to now study methodology for intracellular delivery of these PCCAs for activation inside the cellular milieu of breast cancer cells in vitro and in vivo for the purposes of selective breast tumor cell imaging. I addition, we wish to embark on in vitro studies to determine if intracellular cavitation of the resultant microbubbles can promote tumor cell destruction. As a medium for targeting, we will use the human epidermal growth factor receptor (hEGFR) as a biomarker for more precise delivery and intracellular uptake. Thus, the goal of this proposal is to formulate EGFR-targeted PCCAs for; 1) highly selective intracellular imaging and; 2) initiate monitoring for selective breast tumor cell destruction in vitro via ultrasound-mediated intracellular cavitation of the resultant microbubble. Successful accomplishment of these goals will poise our laboratory for designing the first ultrasound-mediated diagnostic and therapeutic agent for extravascular applications.