Characterization of Anti-Angiogenic Chemo-Sensitization via Longitudinal Ultrasound Localization Microscopy in Colorectal Carcinoma Tumor Xenografts

Objective: Super-resolution ultrasound localization microscopy (ULM) has unprecedented vascular resolution at clinically relevant imaging penetration depths. This technology can potentially screen for the transient microvascular changes that are thought to be critical to the synergistic effect(s) of combined chemotherapy-antiangiogenic agent regimens for cancer. Methods: In this paper, we apply this technology to a high-throughput colorectal carcinoma xenograft model treated with either the antiangiogenic agent sorafenib, FOLFOX-6 chemotherapy, a combination of the two treatments, or vehicle control. Results: Longitudinal ULM demonstrated morphological changes in the antiangiogenic treated cohorts, and evidence of vascular disruption caused by chemotherapy. Gold-standard histological measurements revealed reduced levels of hypoxia in the sorafenib treated cohort for both of the human cell lines tested (HCT-116 and HT-29). Therapy resistance was associated with an increase in tumor vascular fractal dimension as measured by a box-counting technique on ULM images. Conclusion: These results imply that the morphological changes evident on ULM signify a functional change in the tumor microvasculature, which may be indicative of chemo-sensitivity. Significance: ULM provides additional utility for tumor therapy response evaluation by offering a myriad of morphological and functional quantitative indices for gauging treatment effect(s).