Date of Degree

6-2016

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Alexander Greer

Committee Members

Wayne W. Harding

David R. Mootoo

Subject Categories

Organic Chemistry

Keywords

singlet oxygen, photooxidation, photodynamic therapy, nitrosamines

Abstract

Eradication of residual tumor cells that are directly adjacent to vital tissue is a daunting challenge to surgeons. Because the field needs advances in intraoperative settings and a means for high-precision delivery of singlet oxygen for photodynamic therapy (PDT) of cancers, this dissertation outlines the development and application of a “pointsource” fiber optic device. The device offers highly localized and simultaneous delivery of sensitizer drug, light, and oxygen (components necessary for PDT) for cancer cell eradication in-vitro and in-vivo. The following chapters describe (a) the photokilling activity and precision of pointsource PDT in monolayer ovarian and brain cancer cells in-vitro by creating a halo of singlet oxygen, (b) minimal biomaterial fouling on the pace of sensitizer drug photorelease into in-vivo tumors of the head and neck cancer, and (c) synthesis of PEGylated pheophorbide sensitizers to enhance their bio-availability and uptake in cancer cells. (d) With the view of delivering nitrosamine drugs alongside singlet oxygen for dual chemo-photodynamic therapy, the photooxidation mechanism in N-nitrosamines was studied. 18O-isotopic labelling, photochemistry, tandem mass spectrometry and DFT calculations were utilized and an 18O label scrambling into aromatic but not aliphatic N-nitrosamine drugs from molecular 18O2, was discovered. The oxygen atom exchange mechanism was proposed to occur by nitrosoperoxy intermediates and might provide a clue to new factors significant in nitrosamine phototoxicity. (e) Lastly, a review of the literature is presented on using singlet oxygen (1O2) to synthesize natural products and drugs that intends to draw a logical link between flow and batch reactions in the current state of 1O2 in synthesis.

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