Multimodal Imaging of Tumor Microenvironment in Murine Window Chamber Models Using Optical, Magnetic Resonance, and Nuclear Imaging Techniques

Abstract

Pre-clinical study of cancer often involves imaging different aspects of a tumor, ranging from visualizing sub-cellular detail to imaging of the tumor anatomy. Multimodal imaging seeks to combine imaging techniques with complementary strengths and use them to provide a more complete picture of the disease. In this dissertation work, the development of various optical, nuclear and magnetic resonance imaging (MRI) techniques applicable to the study of cancer xenografts in murine window chamber models was carried out. Two types of window chamber models were used in this work: the dorsal skinfold WC (DSFWC) model and the mammary WC (MWC) model. The MWC was specifically used to study breast cancer xenografts. In this work, optical pH imaging with a pH-sensitive fluorescent agent was used to evaluate methods to achieve tumor-specific pH modulation. Temporary tumor acidification was performed by administration of an agent that consists of glucose and meta-iodobenzylguanidine. On the other hand, re-normalization of pHₑ in acidic tumor tissue was achieved by administration of buffer solutions, such as sodium bicarbonate. A broadband reflectance spectral imaging system was developed to perform in vivo imaging of oxygen saturation in the MWC murine model. The imaging system was used to study tissue oxygenation changes in animals that receive chemotherapy. Preliminary results were obtained to evaluate the utility of the MWC murine model in imaging the spatiotemporal changes in oxygen saturation (SaO₂) as an early biomarker of response to neo-adjuvant chemotherapy. To study metabolic activity, nuclear imaging of radiolabeled fluorodeoxyglucose (18F-FDG) was carried out using a beta-imager, as well as a pre-clinical PET system. The 2D nuclear imaging capability of the beta-imager was cross-validated with the 3D PET imaging system. Anatomical and functional MRI was performed on the MWC murine model. Anatomical MRI was used to study tumor growth rates, which aid in the identification of animals that responded to chemotherapy. In addition, diffusion-weighted (DW) MRI, dynamic-contrast-enhancement (DCE) MRI, and perfusion MRI were performed to study various functional aspects of the tumor xenografts. Lastly, work was done to incorporate patient derived xenograft (PDX) tumors into the MWC murine model. As opposed to xenografts grown from cultured cancer cells, PDX tumors better recapitulate characteristics of human tumors. This new cancer model is aimed at improving the translational power of pre-clinical studies employing window chamber models.