Date of Completion

5-13-2014

Embargo Period

5-13-2014

Keywords

Indocyanine dyes, Tumor hypoxia

Major Advisor

Dr. Michael B. Smith

Associate Advisor

Dr. Christian Brueckner

Associate Advisor

Dr. Quing Zhu

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs and fluorescence optical tomography has tremendous potential to provide clinically useful functional information by targeting tumor hypoxia. The current techniques to detect hypoxia involve invasive and non-invasive probes, for example MRI, PET (non-invasive) and polarographic needle electrodes (invasive). The polarographic needle electrode technique is limited to superficial tumors, such as cervix, neck, and head. Non-invasive techniques such as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) are expensive for routine clinical use and these techniques suffers from low spatial resolution, high back ground counts, needs an injection of radioactive tracer. Therefore there is a need for a cheap and non-invasive and safe technique for imaging hypoxia in tumors which would improve the cancer therapy outcomes. The aim of this dissertation is to design a cheap and non-invasive method to image hypoxia in tumor cells. In this dissertation, synthesis, photophysical characterization and hypoxia evaluation of a series of 2-nitroimidazole coupled indocyanine green dyes (first, second and third generation) is presented. In the first generation, 2-nitroimidazoles were coupled to indocyanine gree (ICG) via ethanolamine linker and in the second generation ethanolamine was replaced with a piperazine unit. The third generation has the same piperazine linker but linked to a rigid dye (pentamethine dye). Among the three generations, the third generation dyes are effective in providing a strong fluorescence signal and stayed much longer (up to 24h) in the hypoxic regions of tumor cells.

We have observed that incorporation of a methyl group distal to a terminal long-chain alkyne leads to an increased rate of isomerization to the corresponding internal alkyne upon treatment with a strong base, in DMSO. When compared to a long-straight chain terminal alkyne, the isobranch analog isomerizes about three times faster under identical conditions. In both cases, equilibration to a 95-97:5-3 mixture of internal:terminal alkyne follows isomerization. The difference in rate may be due to conformational effects that involve folding of the alkyne, bringing the distal substituent close to the alkyne moiety. The isobranch may provide steric hindrance that disrupts such folding, making the propargylic proton or the terminal alkyne proton more available for reaction with base.

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