Photoacoustic Imaging for Monitoring Vascular Disrupting Agents

Abstract

<p>The tumour vasculature supplies the tumour with oxygen and nutrition that are vital for the survival and growth of cancer cells. Vascular disrupting agents (VDAs) are a category of cancer therapeutic drugs that target the endothelial cells lining the vessels and damage tumour vasculature. Photoacoustic (PA) imaging has high sensitivity in detecting vascular changes due to the high optical absorption of hemoglobin. PA quantitative analysis can be used to further extract structural and biochemical changes of hemoglobin through ultrasound spectral analysis and multi-spectral PA imaging. I proposed the use of simulations, in-vitro, and in-vivo PA imaging to assess the efficacy of VDAs in cancer therapy.</p> <p>PA signals acquired from single and a collection of red blood cells (RBCs) were examined before and after acid sphingomyelinase exposure (SMase is a signaling molecule excreted due to endothelial cells damage) to investigate changes at the cellular level. Bleeding of tumour vasculature was simulated using a fractal-based model of bifurcating cylinders and the diffusion of blood to the tumour interstitium. Wavelength selection and fluence matching approaches were proposed to improve chromophore quantification in real time for PA imaging. In-vivo experiments were conducted to examine how PA imaging can be used to monitor the effect of the VDA 5,6-dimethylxanthenone-4-acetic acid (DMXAA). PA ultrasound frequency analysis and multi-spectral PA imaging were used to detect structural and biochemical changes to the tumour vasculature.</p> <p>PA quantitative analysis of the in-vivo data demonstrates a decrease in the total hemoglobin 72 hrs post DMXAA injection and an increase in Hb 24 hrs post DMXAA injection. The changes in the chromophores’ composition are due to changes in the environment as the RBCs extravasate to the surrounding tissues as seen from the in-vitro experiments. A decrease in the average spectral slope at 24 hrs post injection was measured. The decrease in the spectral slope was correlated to an increase in the effective vessel size due to bleeding, which was also supported by the vascular tree simulations. The combination of simulations, in-vitro and in-vivo studies demonstrate the capability of PA signal analysis in monitoring VDA at early time points.</p>