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

Photosensitizer Drug Delivery via an Optical Fiber

: An optical fiber has been developed with a maneuverable miniprobe tip that sparges O2 gas and photodetaches pheophorbide (sensitizer) molecules. Singlet oxygen is produced at the probe tip surface which reacts with an alkene spacer group releasing sensitizer upon fragmentation of a dioxetane intermediate. Optimal sensitizer photorelease occurred when the probe tip was loaded with 60 nmol sensitizer, where crowding of the pheophorbide molecules and self-quenching were kept to a minimum. The fiber optic tip delivered pheophorbide molecules and singlet oxygen to discrete locations. The 60 nmol sensitizer was delivered into petrolatum; however, sensitizer release was less efficient in toluene-d8 (3.6 nmol) where most had remained adsorbed on the probe tip, even after the covalent alkene spacer bond had been broken. The results open the door to a new area of fiber optic-guided sensitizer delivery for the potential photodynamic therapy of hypoxic structures requiring cytotoxic control

"Pointsource" Delivery of a Photosensitizer Drug and Singlet Oxygen: Eradication of Glioma Cells In Vitro

ABSTRACT We describe a pointsource sensitizer-tipped microoptic device for the eradication of glioma U87 cells. The device has a mesoporous fluorinated silica tip which emits singlet oxygen molecules and small quantities of pheophorbide sensitizer for additional production of singlet oxygen in the immediate vicinity. The results show that the device surges in sensitizer release and photokilling with higher rates about midway through the reaction. This was attributed to a self-amplified autocatalytic reaction where released sensitizer in the extracellular matrix provides positive feedback to assist in the release of additional sensitizer. The photokilling of the glioma cells was analyzed by global toxicity and live/dead assays, where a killing radius around the tip with~0.3 mm precision was achieved. The implication of these results for a new PDT tool of hard-to-resect tumors, e.g. in the brain, is discussed

A fiberoptic (photodynamic therapy type) device with a photosensitizer and singlet oxygen delivery probe tip for ovarian cancer cell killing

ABSTRACT A portable "fiber optic-based sensitizer delivery" (FOSD) device has been developed and studied. Before there might be success in photodynamic therapy (PDT) and antibacterial ambitions, an understanding of basic factors on device performance was needed. Thus, the device was examined for the localized delivery of sensitizer molecules in ovarian cancer cells and production of high concentrations of singlet oxygen for their eradication in vitro. The device tip releases stored pheophorbide by attack of singlet oxygen from sensitized oxygen gas delivered through the hollow fiber using 669 nm laser light. The performance of the device was enhanced when configured with a fluorosilane tip by virtue of its Teflon-like property compared with a conventional glass tip (greater sensitizer quantities were photoreleased and laterally diffused, and greater amounts of ovarian OVCAR-5 cancer cells were killed). No cell damage was observed at 2.2 N of force applied by the probe tip itself, an amount used for many of the experiments described here

REVIEW PAPER ON EFFECT OF ALUMINIUM DROSS ON PROPERTIES OF CONCRETE

The Bhima River is a main river in South India. It flows southeast for 861 kilometers (535 mi) through Maharashtra, Karnataka, and Telangana states, before inflowing the Krishna River. Along the river stretch there are about 7000 industries comprise Large, middling and little scale units according to CPCB. Most of the industry are located in the Maharashtra Industrial enlargement Corporation (MIDC). The river is 70% polluted by industries pollution and 30% by domestic wastewater. The following decision article presents the termination of the work approved out by the researchers in the past on the various River wate

“Ene” Reactions of Singlet Oxygen at the Air–Water Interface

Prenylsurfactants [(CH₃)₂CCH­(CH₂)_<i>n</i>SO₃^– Na⁺ (<i>n</i> = 4, 6, or 8)] were designed to probe the “ene” reaction mechanism of singlet oxygen at the air–water interface. Increasing the number of carbon atoms in the hydrophobic chain caused an increase in the regioselectivity for a secondary rather than tertiary surfactant hydroperoxide, arguing for an orthogonal alkene on water. The use of water, deuterium oxide, and H₂O/D₂O mixtures helped to distinguish mechanistic alternatives to homogeneous solution conditions that include dewetting of the π bond and an unsymmetrical perepoxide transition state in the hydroperoxide-forming step. The prenylsurfactants and a photoreactor technique allowed a certain degree of interfacial control of the hydroperoxidation reaction on a liquid support, where the oxidant (airborne ¹O₂) is delivered as a gas

A Hand-held Fiber-optic Implement for the Site-specific Delivery of Photosensitizer and Singlet Oxygen

We have constructed a fiber optic device that internally flows triplet oxygen and externally produces singlet oxygen, causing a reaction at the (Z)-1,2-dialkoxyethene spacer group, freeing a pheophorbide sensitizer upon the fragmentation of a reactive dioxetane intermediate. The device can be operated and sensitizer photorelease observed using absorption and fluorescence spectroscopy. We demonstrate the preference of sensitizer photorelease when the probe tip is in contact with octanol or lipophilic media. A first-order photocleavage rate constant of 1.13 h−1 was measured in octanol where dye desorption was not accompanied by readsorption. When the probe tip contacts aqueous solution, the photorelease was inefficient because most of the dye adsorbed on the probe tip, even after the covalent ethene spacer bonds have been broken. The observed stability of the free sensitizer in lipophilic media is reasonable even though it is a pyropheophorbide-a derivative that carries a p-formylbenzylic alcohol substituent at the carboxylic acid group. In octanol or lipid systems, we found that the dye was not susceptible to hydrolysis to pyropheophorbide-a, otherwise a pH effect was observed in a binary methanol-water system (9:1) at pH below 2 or above 8

S,S‐Chiral Linker Induced U Shape with a Syn‐facial Sensitizer and Photocleavable Ethene Group

There is a major need for light-activated materials for the release of sensitizers and drugs. Considering the success of chiral columns for the separation of enantiomer drugs, we synthesized an S,S-chiral linker system covalently attached to silica with a sensitizer ethene near the silica surface. First, the silica surface was modified to be aromatic rich, by replacing 70% of the surface groups with (3-phenoxypropyl)silane. We then synthesized a 3-component conjugate [chlorin sensitizer, S,S-chiral cyclohexane and ethene building blocks] in 5 steps with a 13% yield, and covalently bound the conjugate to the (3-phenoxypropyl)silane-coated silica surface. We hypothesized that the chiral linker would increase exposure of the ethene site for enhanced 1 O2-based sensitizer release. However, the chiral linker caused the sensitizer conjugate to adopt a U shape due to favored 1,2-diaxial substituent orientation; resulting in a reduced efficiency of surface loading. Further accentuating the U shape was p–p stacking between the (3-phenoxypropyl)silane and sensitizer. Semiempirical calculations and singlet oxygen luminescence data provided deeper insight into the sensitizer’s orientation and release. This study has lead to insight on modifications of surfaces for drug photorelease and can help lead to the development of miniaturized photodynamic devices.Fil: Ghosh, Goutam. City University of New York; Estados Unidos. Acadia University; CanadáFil: Belh, Sarah J.. City University of New York; Estados UnidosFil: Chiemezie, Callistus. City University of New York; Estados UnidosFil: Walalawela, Niluksha. City University of New York; Estados UnidosFil: Ghogare, Ashwini A.. City University of New York; Estados UnidosFil: Vignoni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Thomas, Andrés Héctor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: McFarland, Sherri A.. Acadia University; Canadá. University of North Carolina; Estados UnidosFil: Greer, Edyta M.. City University of New York; Estados UnidosFil: Greer, Alexander. City University of New York; Estados Unido

Photoactive Fluoropolymer Surfaces That Release Sensitizer Drug Molecules

We describe a physical–organic study of two fluoropolymers bearing a photoreleasable PEGylated photosensitizer that generates ¹O₂(¹Δ_g) [chlorin e₆ methoxy tri­(ethylene glycol) triester]. The surfaces are Teflon/poly­(vinyl alcohol) (PVA) nanocomposite and fluorinated silica. The relative efficiency of these surfaces to photorelease the PEGylated sensitizer [shown previously to be phototoxic to ovarian cancer cells (Kimani, S. et al. <i>J. Org. Chem</i> <b>2012</b>, <i>77</i>, 10638)] was slightly higher for the nanocomposite. In the presence of red light and O₂, ¹O₂ is formed, which cleaves an ethene linkage to liberate the sensitizer in 68–92% yield. The fluoropolymers were designed to deal with multiple problems. Namely, their success relied not only on high O₂ solubility and drug repellency but also on the C–F bonds, which physically quench little ¹O₂, for singlet oxygen’s productive use away from the surface. The results obtained here indicate that Teflon-like surfaces have potential uses in delivering sensitizer and singlet oxygen for applications in tissue repair and photodynamic therapy (PDT)

Mechanism of Photochemical O‑Atom Exchange in Nitrosamines with Molecular Oxygen

The detection of an oxygen-atom photoexchange process of <i>N-</i>nitrosamines is reported. The photolysis of four nitrosamines (<i>N</i>-nitrosodiphenylamine <b>1</b>, <i>N</i>-nitroso-<i>N</i>-methylaniline <b>2</b>, <i>N</i>-butyl-<i>N</i>-(4-hydroxy­butyl)­nitrosamine <b>3</b>, and <i>N</i>-nitroso­diethylamine <b>4</b>) with ultraviolet light was examined in an ¹⁸O₂-enriched atmosphere in solution. HPLC/MS and HPLC-MS/MS data show that ¹⁸O-labeled nitrosamines were generated for <b>1</b> and <b>2</b>. In contrast, nitrosamines <b>3</b> and <b>4</b> do not exchange the ¹⁸O label and instead decomposed to amines and/or imines under the conditions. For <b>1</b> and <b>2</b>, the ¹⁸O atom was found not to be introduced by moisture or by singlet oxygen [¹⁸(¹O₂ ¹Δ_g)] produced thermally by ¹⁸O–¹⁸O labeled endoperoxide of <i>N,N</i>′-di­(2,3-hydroxy­propyl)-1,4-naphthalene dipropanamide (DHPN¹⁸O₂) or by visible-light sensitization. A density functional theory study of the structures and energetics of peroxy intermediates arising from reaction of nitrosamines with O₂ is also presented. A reversible head-to-tail dimerization of the <i>O-</i>nitrooxide to the 1,2,3,5,6,7-hexaoxa­diazocane (30 kcal/mol barrier) with extrusion of O¹⁸O accounts for exchange of the oxygen atom label. The unimolecular cyclization of <i>O-</i>nitrooxide to 1,2,3,4-trioxazetidine (46 kcal/mol barrier) followed by a retro [2 + 2] reaction is an alternative, but higher energy process. Both pathways would require the photoexcitation of the nitrooxide