Ultrasound Image-Guided Drug Delivery using a Spherically Focused Phased Array Transducer

Abstract

The tumor microenvironment presents a physical barrier for successful drug delivery. Low-intensity pulsed ultrasound (US) in combination with a microbubble (MB) contrast agent has been shown to safely and reversibly increase microvascular permeability. This procedure temporarily allows anticancer drugs to more effectively extravasate to the targeted tumor tissue. Previously, focused US therapies were performed throughout a single two-dimensional plane using either a single or a multiple focused US configuration. This research demonstrated that a multi-focus, multi-repetition approach was superior to a single focus US therapy. The goal of this research was to build upon those findings and introduce a new three-dimensional (3-D) focused US therapeutic system that incorporates US imaging guidance and functionality for user-defined planning in volume space. To evaluate drug delivery, a small molecule infrared (IR) dye was used for in vivo detection in live animals and represents a surrogate anticancer drug. 3-D US therapy was compared to a 2-D approach using breast cancer-bearing mice. Prior to US therapy, each mouse received a bolus injection of MBs (Lantheus Medical Imaging) and IR dye. Both 2-D and 3-D US therapy was performed using a custom US image-guided system (HIFUPlex-06, Verasonics Inc). In vivo optical imaging (Pearl Trilogy, LI-COR Biosciences) was performed at 0, 24, and 48 h. Tumors were then excised for ex vivo optical imaging and analysis. Preliminary results revealed up to a 3-fold increase in dye uptake ( <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$p &lt; 0.03$</tex> ) at both 24 and 48 <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$h$</tex> for tumors treated with the 3-D US therapy. These findings were consistent with ex vivo optical imaging results.