Photooxidation Chemistry and Photodynamic Therapy: Pointsource Delivery of Singlet Oxygen, Sensitizer and Nitrosamine Drugs

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