Developing a Microbubble-based Contrast Agent for X-ray Phase Contrast Imaging to Detect Neovasculature in Breast Cancer

X-ray phase contrast imaging (XPC) generates contrast from refraction and scattering of X-rays, unlike absorption in conventional radiology. This technique greatly improves the sharpness of boundaries and reveals micro-structured tissues that are not easily detected by conventional absorption-based X-rays. XPC can be performed at high energy, so the absorbed radiation is reduced. Ultrasound microbubbles (MBs) with biocompatible composition and gas content can maximize the X-ray refraction and scattering. Multiple studies have investigated MBs and XPC, but they share a common feature: no uniform parameters in MBs, leading to the inconsistent findings on the efficacy of MBs. Our primary goal was to develop a contrast agent for XPC by assessing which MB characteristics affect contrast the most. Gas-filled MBs were constructed with two shell materials: phospholipid and polyvinyl-alcohol (PVA). Polydisperse lipid-MBs were size separated using centrifugation. Two populations of PVA-MBs were generated by different homogenizers: 2-3 μm and 3-4 μm. A subset of PVA-MBs 3-4 μm were either coated or integrated with superparamagnetic iron oxide nanoparticles (SPIONs). MBs were then immobilized in agar at three concentrations: 5×10⁷ (high), 5×10⁶ (moderate), and 5×10⁵ MBs/ml (low). MBs were imaged by synchrotron at the Canadian Light Source with In-line phase contrast imaging (PCI) and Multiple-image Radiography (MIR). The refraction contrast in PCI was measured by detecting phase object numbers and comparing the mean pixel values (MPV: 0/255) of MBs to agar in minimum intensity projections (MIN) and maximum intensity projections (MAX). Lipid-MBs 6-10 μm, lipid-MBs 4-6 μm and 4-layer SPION-coated PVA-MBs were significantly different (p < 0.05) at three concentrations. In MAX, the contrast was observed with lipid-MBs 6-10 μm and lipid MBs 4-6 μm, whereas only lipid-MBs 6-10 μm showed a significant increase in MPV at the moderate concentration. In MIN, a significant decrease in MPV was observed from lipid MBs 6-10 μm and lipid-MBs 4-6 μm at the high concentration. With MIR, the contrast intensity was measured by comparing the MPV of MBs to agar in the absorption, refraction and ultra-small-angle X-ray scattering (USAXS) images. We only observed a significant increase in MPV in lipid-MBs 6-10 μm (p = 0.02) in the USAXS at the high concentration. These data suggest that lipid-MBs greater than 4 μm are a promising contrast agent for PCI, where 5×10⁶ MB/ml is possibly the lowest detectable concentration in tissues. With MIR, lipid-MBs 6-10 μm are a potential contrast medium for USAXS, and the minimum concentration in tissues may be 5×10⁷ MB/ml.
\nMagnetic resonance imaging (MRI) is a non-ionizing radiation imaging approach that is excellent at visualizing soft tissues. This modality often makes use of gadolinium-based contrast agents to visualize vasculature and blood flow. However, there is controversy about gadolinium’s toxicity, so we aimed to develop a vascular-restricted contrast agent for MRI based on MBs and SPIONs, a known T2 contrast agent. There are two methods to bind SPIONs to polymer-shell MBs: SPION-coated and SPION-integrated MBs. My goal was to compare these methods and determine which approach results in optimal MB detection in T2-weighted MRI. Multiple concentrations of MBs were immobilized with agar in 1.5 ml tubes and then imaged in 3 Tesla Siemens MRI scanner. The signal intensity was identified in 70 mm² circular ROI and measured MPV in 8-bit grayscale (0-255). We imaged SPION-coated MBs and SPION-integrated MBs at two different concentrations and found that all tested MBs generated T2 contrast. For both types of SPION-coated MBs, the differences among the concentrations ranging from 25 μl - 200 μl were not detectable. No change in the signal was seen from the SPION-integrated MBs compared to the agar and plain PVA-MBs except for the highest concentration. Both MBs coated with one and three layers of SPIONs generated a high T2 contrast. Based on these data, I performed a dosage study to determine the lowest detectable concentration of single layer SPION-coated MBs, which was determined to be 5 × 10⁵ MBs/ml.

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