Functional ultrasound imaging quantifying angiogenesis and enhancing vascular permeability for drug delivery

In cancer therapy, successful treatment of the patient is dependent on early detection, monitoring of disease progression, and delivery of therapeutic agents in sufficient concentration to the target site to reliably kill cancer cells. Angiogenesis has been shown to be crucial in tumor growth and metastasis; however there are very few practical techniques for quantifying angiogenesis noninvasively. Most of the current approaches used to estimate angiogenesis require tissue core biopsy. The aims of this thesis were to evaluate the potential of contrast ultrasound for quantifying angiogenesis and for targeted drug delivery by enhancing vascular wall permeability.;The effect of low-frequency contrast enhanced ultrasound on the vascular endothelium and the parameters required to deliver a therapeutic agent were evaluated using the chorioallantoic membrane (CAM) model. The threshold at which vascular permeability increased was evaluated by incrementally increasing insonation pressure or decreasing insonation frequency. Enhanced drug transport across the vascular wall without causing overt injury to the vessel wall was achieved using low frequency (1 or 2.25 MHz) and low stress (mechanical index MI<1.3) contrast ultrasound. Capillaries and small vessels up to a diameter of 55 microns were most affected by directed insonation.;The Matrigel angiogenesis and the CAM model haves been proven to be useful models in contrast ultrasound research. Contrast enhanced ultrasound has demonstrated potential quantifying angiogenesis and therefore for monitoring angiogenesis during disease processes. Furthermore, directed contrast ultrasound enhanced the vascular wall permeability and led to transfer of intravascular pharmaceuticals across the vascular wall to a target site.;Imaging and quantification of angiogenesis were demonstrated using non-targeted or targeted (echistatin-bearing) lipid-shelled microbubbles with two different contrast ultrasound imaging techniques, a destructive power Doppler and a non-destructive low-power multipulse imaging sequence, Cadence(TM) contrast pulse sequencing (CPS) using a Matrigel angiogenesis model in rats. The ultrasound examinations were followed by histology and the results were compared with each other. With power Doppler imaging, a significant correlation between microvessel density and the ultrasound enhanced area (r=0.65, p<0.05) were observed. Using CPS the acoustic intensity received from targeted contrast agents in angiogenic regions significantly exceeded the acoustic intensity from non-targeted agents (p<0.001).