Use of photoacoustic imaging for monitoring vascular disrupting cancer treatments

Abstract

Vascular disrupting agents disrupt tumor vessels, blocking the nutritional and oxygen supply tumors need to thrive. This is achieved by damaging the endothelium lining of blood vessels, resulting in red blood cells (RBCs) entering the tumor parenchyma. RBCs present in the extracellular matrix are exposed to external stressors resulting in biochemical and physiological changes. The detection of these changes can be used to monitor the efficacy of cancer treatments. Spectroscopic photoacoustic (PA) imaging is an ideal candidate for probing RBCs due to their high optical absorption relative to surrounding tissue. The goal of this work is to use PA imaging to monitor the efficacy of the vascular disrupting agent 5,6‐Dimethylxanthenone‐4‐acetic acid (DMXAA) through quantitative analysis. Then, 4T1 breast cancer cells were injected subcutaneously into the left hind leg of eight BALB/c mice. After 10 days, half of the mice were treated with 15 mg/kg of DMXAA and the other half were injected with saline. All mice were imaged using the VevoLAZR X PA system before treatment, 24 and 72 hours after treatment. The imaging was done at six wavelengths and linear spectral unmixing was applied to the PA images to quantify three forms of hemoglobin (oxy, deoxy and met‐hemoglobin). After imaging, tumors were histologically processed and H&E and TUNEL staining were used to detect the tissue damage induced by the DMXAA treatment. The total hemoglobin concentration remained unchanged after treatment for the saline treated mice. For DMXAA treated mice, a 10% increase of deoxyhemoglobin concentration was detected 24 hours after treatment and a 22.6% decrease in total hemoglobin concentration was observed by 72 hours. A decrease in the PA spectral slope parameters was measured 24 hours after treatment. This suggests that DMXAA induces vascular damage, causing red blood cells to extravasate. Furthermore, H&E staining of the tumor showed areas of bleeding with erythrocyte deposition. These observations are further supported by the increase in TUNEL staining in DMXAA treated tumors, revealing increased cell death due to vascular disruption. This study demonstrates the capability of PA imaging to monitor tumor vessel disruption by the vascular disrupting agent DMXAA.

Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment

“…Lower doses are attractive, but ultimately it is the therapeutic window which is most important. Vascular disrupting agents have also been tested in syngeneic tumors generally examining the extremely aggressive 4T1 breast cancer in the BALB/c mouse [ 33 , 49 , 50 , 51 ].…”

Photoacoustic graphic equalization and application in characterization of red blood cell aggregates

“…Compared to data acquired from a blood clot formed in a vessel with a 0.30 mm inner lumen diameter, mean PAGE image intensity measurements were found to increase by 21.6% and 29.7% when imaging the 0.51 and 0.64 mm vessels, respectively. Future work may explore the use of the PAGE approach for detecting physical changes in the tumor microvascular network (morphology) during both cancer growth and drug treatment [13] , [33] . A spectrogram of PA signals also reveals unique molecular and chemical components for specific tissue types along with corresponding histological microfeatures.…”

“…Given PA spectral parameters are related to the chromophore microstructure, they can be used to estimate the size and shape of the optical absorbers [11] . PA signal-derived spectral parameters were then shown helpful for the detection of tumor changes after administration of a vascular-disrupting agent [12] , [13] . In simulations, Rayleigh and Nakagami distribution parameters from the power spectrum were found to differentiate normal and intratumoral vascular structures [14] .…”

Combined Fluorescence and Optoacoustic Imaging for Monitoring Treatments against CT26 Tumors with Photoactivatable Liposomes

“…When the therapeutic agents are administered in nanoconstructs to target multiple pathways, the agents need to be delivered at the same place at the same time to increase the chance of synergy and thereby, disease control [ 53 ]. In addition to a combination of therapeutics, simultaneous monitoring of changes in tumor biology to predict treatment outcomes especially at early stages is very valuable [ 24 , 84 ]. Improvements in the design of multi-modal nanoformulations have facilitated the specific delivery of theranostics in vitro and in vivo, while improvement in optical imaging techniques has enabled monitoring of drug uptake and dynamic changes in tumor vasculature.…”