Title

Diffuse Fluorescence Tomography for Mapping Tumor Vasculature and Hypoxia

Date of Completion

January 2010

Keywords

Engineering, Biomedical|Engineering, Electronics and Electrical|Health Sciences, Radiology

Degree

Ph.D.

Abstract

Near-infrared diffuse optical tomography is an emerging cost-effective modality to probe molecular changes associated with tumor proliferation, growth, vasculature, angiogenesis, and hypoxia. The technique targets tissue intrinsic chromophores such as oxy- and deoxy- hemoglobin and the uptake of exogenous contrast agents. A quantitative measurement of the chromophores provides an access for tumor imaging, diagnosis and screening. In this dissertation, techniques and applications using diffuse photons for mapping tumor vasculature and hypoxia are presented. ^ A high sensitive, low background noise, Frequency-domain near infrared fluorescence imaging system is built and calibrated with tissue mimicking phantoms. The optical-only imaging technique separately estimates the target depth and this information is used to reconstruct the functional information such as fluorophore concentration. Fluorescence targets with concentrations as low as sub-25 nanomolars are well reconstructed at depths up to 2 cm in both homogeneous and heterogeneous media. The technique is further validated using animal models injected with an angiogenesis tracer, vascular endothelial growth factor conjugated with a near infrared dye Cyanine 7 (VEGF/Cy7).^ Second part of the research is on tumor hypoxia imaging. A novel 2-nitroimidazole bis-carboxylic acid indocyanine dye conjugate has been developed for tumor-targeted hypoxia fluorescence imaging. The hypoxia probe has been evaluated in-vitro using 4T1 tumor cell lines and in-vivo tumor targeting in animal models. Significant differences in fluorescence emission and dye wash out half-life between the hypoxia probe and unconjugated indocyanine dye were observed from tumors. The in-vitro cell studies were performed to assess fluorescence labeling comparing hypoxia to normoxia conditions. ^ Hypoxia mapping is also achieved using endogenous chromophores such as oxy- and deoxyhemoglobin in the tissue. The approach employs ultrasound structural information as a-prior knowledge for diffuse optical imaging. Because oxy- and deoxyhemoglobin respond differently at different wavelengths, four different laser diodes of wavelengths 740 nm, 780 nm, 808 nm and 830 nm are used for mapping tumor hypoxia by diffuse optical imaging. Hypoxia model experiments are performed using phantoms at different oxygenation conditions and targets of different sizes mimicking different development stages of breast tumors. A strong correlation is found between phantom experiments and observations seen from advanced breast cancers. ^