Rachel Schafer Abstract
Rachel Schafer
Ph.D. Candidate
Biomedical Engineering GIDP
SPIE Photonics West (BIOS)
San Francisco, California
February 7-12, 2015
ABSTRACT
Technical Abstract submitted to Photonics West, BiOS Conference BO400: Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XIII
Measuring oxygen tension modulation, induced by a new pre-radiotherapy therapeutic, in a mammary window chamber mouse model
Authors: Rachel Schafer1,3, Arthur F. Gmitro2,3
1Department of Biomedical Engineering, The University of Arizona, 1657 E. Helen Street, Tucson, AZ 85721
2College of Optical Sciences, The University of Arizona, 1630 E University Blvd, Tucson, AZ USA 85721;
3Department of Medical Imaging, The University of Arizona, 1609 N Warren Ave, Tucson, AZ USA 85724
Abstract:
Tumor regions under hypoxic or low oxygen conditions respond less effectively to many treatment regimens, including radiation therapy. A novel investigational therapeutic, NVX-108 (NuvOx Pharma), has been developed to increase delivery of oxygen through the use of a nano-emulsion of dodecofluoropentane. By raising pO2 levels prior to delivering radiation, treatment effectiveness may be improved. To aid in evaluating the novel drug, oxygen tension was quantitatively measured, spatially and temporally, to record the effect of administrating NVX-108 in an orthotopic mammary window chamber mouse model of breast cancer. The oxygen tension was measured through the use of an oxygen-sensitive coating, comprised of phosphorescent platinum porphyrin dye embedded in a polystyrene matrix. The coating, applied to the surface of the coverslip of the window chamber through spin coating, is placed in contact with the mammary fat pad to record the oxygenation status of the surface tissue layer. Prior to implantation of the window chamber, a tumor is grown in the SCID mouse model by injection of MDA-MB-231 cells into the mammary fat pad. Two-dimensional spatial distributions of the pO2 levels were obtained through conversion of measured maps of phosphorescent lifetime. The resulting information on the spatial and temporal variation of the induced oxygen modulation will provide insight into the optimal timing between administration of NVX-108 and radiation treatment to provide the most effective treatment outcome.
Tumor regions under hypoxic conditions respond less effectively to many treatment regimens, including radiation therapy. A novel investigational therapeutic, NVX-108, has been developed to increase delivery of oxygen through the use of a nano-emulsion of dodecofluoropentane. To evaluate the effect of NVX-108, we utilized a mammary window chamber mouse model with a platinum porphyrin coating on the coverslip that has a variable phosphorescent lifetime dependent on local oxygen concentration. Using the oxygen-sensitive coating and window chamber model, we spatially measured the magnitude and temporal behavior of the induced oxygen modulation of NVX-108 under both air and oxygen breathing conditions.
Keywords: Window Chamber; Phosphorescent Lifetime; Oxygen Sensing; Cancer microenvironment
Abstract (for Lay Audience):
In the realm of cancer, poorly oxygenated or hypoxic tumors are known to respond less effectively to radiation treatment. The ineffective treatment prevents eradication of the complete tumor. A novel drug developed by NuvOx Pharmaceutical, NVX-108, is intended to increase delivery of oxygen to the tissue and tumor to change the hypoxic status of the tumor. The intention is to then administer radiation treatment while the tumor is well-oxygenated. Under the well-oxygenated condition, the treatment should be more effective at eradicating the tumor. In order to better inform the testing of the drug in human clinical trials, testing of the drug in a pre-clinical model is being performed to provide insight into the pharmacokinetics of the drug.
Using a preclinical model, we can investigate the timing from administration to peak increase in oxygenation in the tumor tissue. Additionally, we can investigate the effect of the gas the subject is breathing has on the magnitude of the increase in oxygenation. In the current clinical trial protocol, the subjects are asked to breathe carbogen gas, which contains 95% oxygen and 5% carbon dioxide. Some subjects have experienced difficulty breathing the carbogen gas as the presence of carbon dioxide creates the sensation of not obtaining enough oxygen. The difficulty of subjects to breathe the gas could negatively impact the ability of subjects to participate in the clinical trial. Even if the drug successfully passes all phases of the clinical trial, the necessity for breathing carbogen could hinder the implementation of the approach clinically and reduce the number of patients who could benefit from more effective radiation treatment. If testing in a pre-clinical model indicated the drug was equally or comparably effective in raising the oxygenation in the tissue when the subject was breathing oxygen as when breathing carbogen, this could be used as rationale for switching to administering the drug while breathing oxygen in future clinical testing.
I previously developed a pre-clinical breast cancer research model, the mammary window chamber model compatible with a variety of imaging modalities for investigating breast cancer. Optical imaging methods can be utilized with the model because the skin above the mammary tumor is removed and replaced with a transparent glass coverslip. I have applied a phosphorescent lifetime oxygen-sensitive coating to the surface of the coverslip on the model. Analogous to fluorescent imaging, the phosphorescent dye is excited with a particular wavelength of light and results in a longer wavelength being observed. The phosphorescent lifetime is a measure of the time it takes for the excited molecule to return to the ground state. The phosphorescent lifetime becomes shorter when more oxygen is present and interacting with the dye. By measuring the phosphorescent lifetime signal, the partial pressure of oxygen can be quantified across the surface of the window chamber. The measurement approach can be acquired multiple times to dynamically monitor changes and variations in the oxygenation of the underlying tissue over time.
The oxygen sensitive coating is being used in this study to measure the effect of NVX-108 for up to two hours after i.v. administration of the drug. The consistency in the amount of time required to reach a substantial increase in oxygenation is being evaluated. Additionally, the effect of three different breathing gases on the amount of change in the partial pressure of oxygen is being evaluated. This will test the hypothesis that administration of NVX-108 while the subject breaths oxygen will be equally effective to breathing carbogen in causing a statistically significant increase in partial pressure of oxygen compared to the increase resulting while the subject breaths air. The work being tested will serve to inform the most appropriate future directions for the clinical trials involving NVX-108 and ideally aid in successful navigation of the drug through the clinical trials in a manner that will expand the utility and impact of the drug in the cancer patient population.