Mammary Window Chamber Model: A Platform For Multi-Modality Cancer Imaging And Dynamic Oxygenation Assessment

Abstract

Window chamber models have served as a tool for optically visualizing a tissue environment over time. Their use throughout the years has furthered the study of cancer. However, optical imaging techniques utilized with the model are limited in the depth from which light can penetrate and signal can be received. Further, ectopic placement of a xenograft in a model animal may modify the relevancy of findings by altering the normal environmental conditions. In the first section of the dissertation, improvements on the traditional window chamber model are described in the context of enabling multiple imaging modalities (optical, MR and nuclear) to be complementarily applied. The developed model, specifically geared toward breast cancer, is orthotopic and supports uninhibited tumor growth into the body of the animal. The three main imaging modalities applied provide unique strengths in obtaining information from the model system. Optical imaging allows for use of targeted fluorescent contrast agents, as well as sufficient resolution to visualize individual cells and capillaries. Magnetic resonance imaging provides the possibility of acquiring quantitative information about tumor morphology as well as a variety of physiological processes. This can be accomplished over the entire 3D volume of the tumor. Nuclear imaging provides functional and/or metabolic information using radiolabeled agents. The MWC model provides a platform for more specifically focused cancer imaging approaches to be applied and tested. The presence of hypoxia in tumors has a broad impact on cancer development and treatment. Current oxygenation assessment methods for longitudinally following spatially resolved oxygen changes over time are lacking. The development and testing of an oxygen sensitive porphyrin coating used in conjunction with the mammary window chamber model is detailed in the second section of the dissertation. Three different modulations were applied to induce physiologic oxygenation changes. All were capable of being detected over time utilizing a phosphorescence lifetime approach. An assessment of the stability of the coating found the coating remained suitable for a minimum of one week. The oxygen dependent phosphorescence lifetime of the coating was determined to be worthwhile for temporally and spatially monitoring oxygen changes of the tissue in contact with the surface of the coating. The third section of this dissertation work utilized the developed window chamber and oxygen measurement technique to investigate a novel oxygen modulator. The effectiveness of radiation therapy is reduced in tumors with low oxygen. The drug, NVX-108, is under investigation as a means to increase oxygenation prior to radiation treatment. NVX-108 is given while the patient breaths carbogen and has not been thoroughly tested when the patient is breathing oxygen or air. The study described herein focused on measuring the increase in oxygenation when NVX-108 was delivered while an anesthetized mouse breathed carbogen, oxygen or air. A similar average increase was measured under carbogen and oxygen breathing at two dosage levels of NVX-108. The increase was higher than with air breathing conditions. Additional animal experiments are needed in order to obtain a statistically significant finding.