Methods for ultrasound imaging of targeted agents are progressing rapidly;we show that with our methods the tumor image intensity from targeted agents is more than 250 times that of the agent in the surrounding tissue and more than 32 times that of a scrambled agent. Our overall goals in the renewal are to create safe and effective targeted imaging strategies for a range of vascular receptors and to incorporate targeted imaging in cancer diagnostics and therapies. Phase III radiology trials of non-targeted agents are underway in the US and targeted agents, such as BR55, are likely to enter the clinic very soon. Contrast ultrasound imaging is a compelling imaging technique, as it is widely-used, inexpensive, portable, and permits real-time anatomical and molecular imaging. Within the past five years, we have created new imaging methods, evaluated the physics and bioeffects of microbubble contrast agents and developed new synthesis strategies. We developed a spectral approach to quantify bound agents and here will determine the sensitivity and accuracy of this strategy. This new method is insensitive to system gain and does not require the use of high mechanical index pulses. We apply these methods to evaluate the avidity of ligands for a set of receptors that are up-regulated in angiogenesis, focusing on breast, prostate and bladder cancer. Further, we will investigate the use of our targeted ultrasound imaging methods to guide and augment cancer therapy. Guiding ultrasound therapy with the targeted ultrasound image is an efficient, cost-effective strategy. In addition, assessment of the safety of targeted ultrasound contrast is essential and will be addressed here. We have previously mapped the range of insonation parameters under which non-targeted microbubble imaging can be performed safely and have demonstrated jetting of bound agents into the endothelium. Now, we demonstrate that in vivo insonation of targeted microbubbles creates biological effects using parameters that were previously found to be safe with a non-targeted agent;in particular, we observe reduced blood flow after high mechanical index insonation of targeted agents. We seek to fully define the mechanism, to define the range of parameters under which such effects occur and to validate the new safe range for targeted agents. Finally, the FDA has previously expressed concerns about complement mediated-anaphylaxis resulting from non-targeted agents but data are very limited for targeted agents. We will assess complement activation in vitro and in vivo, with a goal of estimating the risk of classes of ligands defined by length, charge, cyclization and arginine content.
Currently, one in 4 deaths in the United States is due to cancer. New techniques for the detection and staging of cancer based on a unique molecular signature are under development. In addition, methods for image guidance of cancer nanotherapy show great promise. Ultrasound is an inexpensive and powerful method to accomplish such guidance and to enhance therapy. Here, we describe the development of targeted ultrasound agents and methods to enable their near-term application in cancer imaging and treatment.
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