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ABSTRACT: A portable "fiber optic-based sensitizer delivery" device has been developed and studied. Before there might be success in photodynamic therapy (PDT) and anti-bacterial ambitions, an understanding of basic factors on device performance were 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 pheophorebide 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 fluorosiliane tip by virtue of its Teflon-like property compared to a conventional glass tip (greater sensitizer quantities photoreleased and laterally diffused, and greater amounts of ovarian OVCAR-5 cancer cell killing). 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. © 2013 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2013 The American Society of Photobiology.
Photochemistry and Photobiology 03/2013; · 2.41 Impact Factor
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ABSTRACT: Pegylated chlorin e(6) photosensitizers were synthesized with triethylene glycol attached at the ester bond(s) for a 1:1 conjugate at the 17(3)-position, a 2:1 conjugate at the 15(3)- and 17(3)-positions, and a 3:1 conjugate at the 13(1)-, 15(2)-, and 17(3)-positions. These chlorin sensitizers were studied for hydrolytic stability, solubility, as well as ovarian OVCAR-5 cancer cell uptake, localization, and phototoxicity. Increasing numbers of the PEG groups in the mono-, di-, and tri-PEG chlorin conjugates increased the water solubility and sensitivity to hydrolysis and uptake into the ovarian cancer cells. The PEG chlorin conjugates accumulated in the cytoplasm and mitrochondria, but not in lysosomes. Higher phototoxicity was roughly correlated with higher numbers of PEG groups, with the tri-PEG chlorin conjugate showing the best overall ovarian cancer cell photokilling of the series. Singlet oxygen lifetimes, solvent deuteration, and the effects of additives azide ion and D-mannitol were examined to help clarify the photokilling mechanisms. A Type-II (singlet oxygen) photosensitized mechanism is suggested for the di- and tri-PEG chlorin conjugates, however, a more complicated process based in part on a Type-I (radicals or radical ions) mechanism is suggested for the parent chlorin e(6) and the mono-PEG chlorin conjugate.
The Journal of Organic Chemistry 11/2012; · 4.45 Impact Factor
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ABSTRACT: A microphotoreactor device was developed to generate bubbles (sized: 1.4 mm diameter, 90 µL) containing singlet oxygen at levels toxic to bacteria and fungus. As singlet oxygen decays rapidly to triplet oxygen, the bubbles leave behind no waste or by-products other than O(2). From a comparative study in deaerated, air saturated, and oxygenated solutions, it was reasoned that the singlet oxygen bubbles inactivate Escherichia coli and Aspergillus fumigatus, mainly by an oxygen gradient inside and outside of the bubble such that singlet oxygen is solvated and diffuses through the aqueous solution until it reacts with the target organism. Thus, singlet oxygen bubble toxicity was inversely proportional to the amount of dissolved oxygen in solution. In a second mechanism, singlet oxygen interacts directly with E. coli that accumulate at the gas-liquid interface although this mechanism operates at a rate approximately 10 times slower. Due to encapsulation in the gaseous core of the bubble and a 0.98 ms lifetime, the bubbles can traverse relatively long 0.39 mm distances carrying (1)O(2) far into the solution; by comparison the diffusion distance of (1)O(2) fully solvated in H(2)O is much shorter (~150 nm). Bubbles that reached the outer air/water interface contained no (1)O(2). The mechanism by which (1)O(2) deactivated organisms was explored through the addition of detergent molecules and Ca(2+) ions. Results indicate that the preferential accumulation of E. coli at the air-water interface of the bubble leads to enhanced toxicity of bubbles containing (1)O(2). The singlet oxygen device offers intriguing possibilities for creating new types of disinfection strategies based on photodynamic ((1)O(2)) bubble carriers.
Environmental Science & Technology 10/2012; · 4.80 Impact Factor
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ABSTRACT: The usefulness of a fiber optic technique for generating singlet oxygen and releasing the pheophorbide photosensitizer has been increased by the fluorination of the porous Vycor glass tip. Singlet oxygen emerges through the fiber tip with 669-nm light and oxygen, releasing the sensitizer molecules upon a [2 + 2] addition of singlet oxygen with the ethene spacer and scission of a dioxetane intermediate. Switching from a nonfluorinated to a fluorinated glass tip led to a clear reduction of the adsorbtive affinity of the departing sensitizer with improved release into homogeneous toluene solution and bovine tissue, but no difference was found in water since the sensitizer was insoluble. High surface coverage of the nonafluorohexylsilane enhanced the cleavage efficiency by 15% at the ethene site. The fluorosilane groups also caused crowding and seemed to reduce access of (1)O(2) to the ethene site, which attenuated the total quenching rate constant k(T), although there was less wasted (1)O(2) (from surface physical quenching) at the fluorosilane-coated than the native SiOH silica. The observations support a quenching mechanism that the replacement of the SiOH groups for the fluorosilane C-H and C-F groups enhanced the (1)O(2) lifetime at the fiber tip interface due to less efficient electronic-to-vibronic energy transfer.
The Journal of Organic Chemistry 04/2012; 77(10):4557-65. · 4.45 Impact Factor
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ABSTRACT: Laser-coupled microphotoreactors were developed to bubble singlet oxygen [(1)O(2) ((1)Δ(g))] into an aqueous solution containing an oxidizable compound. The reactors consisted of custom-modified SMA fiberoptic receptacles loaded with 150 μm silicon phthalocyanine glass sensitizer particles, where the particles were isolated from direct contact with water by a membrane adhesively bonded to the bottom of each device. A tube fed O(2) gas to the reactor chambers. In the presence of O(2), singlet oxygen was generated by illuminating the sensitizer particles with 669 nm light from an optical fiber coupled to the top of the reactor. The generated (1)O(2) was transported through the membrane by the O(2) stream and formed bubbles in solution. In solution, singlet oxygen reacted with probe compounds (9,10-anthracene dipropionate dianion, trans-2-methyl-2-pentanoate anion, N-benzoyl-D,L-methionine, or N-acetyl-D,L-methionine) to give oxidized products in two stages. The early stage was rapid and showed that (1)O(2) transfer occurred via bubbles mainly in the bulk water solution. The later stage was slow; it arose only from (1)O(2)-probe molecule contact at the gas/liquid interface. A mechanism is proposed that involves (1)O(2) mass transfer and solvation, where smaller bubbles provide better penetration of (1)O(2) into the flowing stream due to higher surface-to-volume contact between the probe molecules and (1)O(2).
Langmuir 02/2012; 28(5):3053-60. · 4.19 Impact Factor
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ABSTRACT: Nanotubes are a class of host cavities increasingly used to encapsulate unstable molecules, yet none have been exploited to host reactive sulfur species, such as thiozone (S(3)). In this paper, density functional theory and (ONIOM) calculations were used to compute single-walled carbon nanotube (SWNT)-thiozone combinations for the inclusion of S(3) into the hollow nanotube space and to rationalize when 1,2,3-thiozonide formation can take place. Nanotube diameter selectivity for the isomerization of the C(2v) form of S(3) to the D(3h) form proved to be elusive. Acyclic C(2v) S(3) was ~6 kcal/mol more stable than cyclic D(3h) S(3) whether it was free or encapsulated within an SWNT. 1,2,3-Thiozonide formation took place on the convex side of nanotubes of low tube radii, such as the armchair (4,4) and (5,5) SWNTs. In terms of the reaction mode of C(2v) S(3), the 1,3-dipolar addition reaction was preferred compared with the [2 + 2] cycloaddition and chelotrope paths.
Journal of Physical Organic Chemistry 01/2012; 25(1):42-49. · 1.96 Impact Factor
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Alexander Greer
Chemistry & Biodiversity 11/2011; 8(11):2158-61. · 1.80 Impact Factor
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ABSTRACT: This review of Photochemistry and Photobiology summarizes articles published in 2010, and highlights progress in the area of photosensitization. The synthesis of conjugated photosensitizers is an area of interest where increasing water solubility has been a goal. Targeting infrared sensitizer absorption has been another goal, and relates to the practical need of deep tissue absorption of light. Photodynamic techniques for inactivating microbes and destroying tumors have been particularly successful. Biologically, singlet oxygen [(1)O(2)((1)Δ(g))] is an integral species in many of these reactions, although photosensitized oxidations tuned to electron and hydrogen transfer (Type I) give rise to other reactive species, such as superoxide and hydrogen peroxide. How photoprotection against yellowing, oxygenation and degradation occurs was also an area of topical interest.
Photochemistry and Photobiology 08/2011; 87(6):1204-13. · 2.41 Impact Factor
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ABSTRACT: 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.
Photochemistry and Photobiology 07/2011; 87(6):1330-7. · 2.41 Impact Factor
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ABSTRACT: An optical fiber has been developed with a maneuverable mini-probe tip that sparges O(2) 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-d(8) (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.
Journal of the American Chemical Society 05/2011; 133(20):7882-91. · 9.91 Impact Factor
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ABSTRACT: We present an experimental and computational study of the reaction of aryl substituted benzyl 1-alkynyl sulfides with potassium alkoxide in acetonitrile, which produces 2-aryl 2,3-dihydrothiophenes in poor to good yields. The cyclization is most efficient with electron withdrawing groups on the aromatic ring. Evidence indicates there is rapid exchange of protons and tautomerism of the alkynyl unit prior to cyclization. Theoretical calculations were also conducted to help rationalize the base induced 5-endo cyclization of benzyl 1-propynyl sulfide (1a). The potential energy surface was calculated for the formation of 2,3-dihydrothiophene in a reaction of benzyl 1-propynyl sulfide (1a) with potassium methoxide. Geometries were optimized with CAM-B3LYP/6-311+G(d,p) in acetonitrile with the CPCM solvent model. It is significant that the benzyl propa-1,2-dien-1-yl sulfane (6) possessed a lower benzylic proton affinity than the benzyl prop-2-yn-1-yl sulfane (8) thus favoring the base induced reaction of the former. From benzyl(propa-1,2-dien-1-yl sulfane (6), 2,3-dihydrothiophene can be formed via a conjugate base that undergoes 5-endo-trig cyclization followed by a protonation step.
Tetrahedron 02/2011; 67(5):1002-1010. · 3.03 Impact Factor
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09/2010; , ISBN: 9780470682531
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ABSTRACT: Benzopolysulfanes, 4-CH(3)(OCH(2)CH(2))(3)NHC(O)-C(6)H(4)-1,2-S(x) (x = 3-7 and 9) were synthesized with a PEG group attached through an amide bond and examined for water solubility, antitumor activity, and propensity to equilibrate and desulfurate. LCMS and HPLC data show the PEG pentasulfane ring structure predominates, and the tri-, tetra-, hexa-, hepta-, and nonasulfanes were present at very low concentrations. The presence of the PEG group improved water solubility by 50-fold compared to the unsubstituted benzopolysulfanes, C(6)H(4)S(x) (x = 3, 5, and 7), based on intrinsic solubility measurements. Polysulfur linkages in the PEG compounds decomposed in the presence of ethanethiol and hydroxide ion. The PEG pentathiepin desulfurated rapidly, and an S(3) transfer reaction was observed in the presence of norbornene; no S(2) transfer reaction was observed with 2,3-dimethylbutadiene. The antitumor activities of the PEG-substituted benzopolysulfane mixtures were analyzed against four human tumor cell lines PC3 (prostate), DU145 (prostate), MDA-MB-231 (breast), and Jurkat (T-cell leukemia). The PEG-conjugated polysulfanes had IC(50) values 1.2-5.8 times lower than the parent "unsubstituted" benzopolysulfanes. Complete cell killing was observed for the PEG polysulfanes at 4 microM for PC3 and DU145 cells and at 12 muM for MDA-MB-231 cells. The results suggest that solubilization of the polysulfur linkage is a key parameter to the success of these compounds as drug leads.
The Journal of Organic Chemistry 08/2010; 75(16):5549-57. · 4.45 Impact Factor
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ABSTRACT: Traditionally, Type II heterogeneous photo-oxidations produce singlet oxygen via external irradiation of a sensitizer and external supply of ground-state oxygen. A potential improvement is reported here. A hollow-core fiber-optic device was developed with an "internal" supply of light and flowing oxygen, and a porous photosensitizer-end capped configuration. Singlet oxygen was delivered through the fiber tip. The singlet oxygen steady-state concentration in the immediate vicinity of the probe tip was ca 20 fm by N-benzoyl-DL-methionine trapping. The device is portable and the singlet oxygen-generating tip is maneuverable, which opened the door to simple disinfectant studies. Complete Escherichia coli inactivation was observed in 2 h when the singlet oxygen sensitizing probe tip was immersed in 0.1 mL aqueous samples of 0.1-4.4 x 10(7) cells. Photobleaching of the probe tip occurred after ca 12 h of use, requiring baking and sensitizer reloading steps for reuse.
Photochemistry and Photobiology 05/2010; 86(4):890-4. · 2.41 Impact Factor
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03/2010: pages 353 - 386; , ISBN: 9783527628193
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ABSTRACT: The development of the first photosensitizer/fiber optic device is reported. An oxygen-flowing, fiber-capped configuration is used for the application of heterogeneous, spatially confined singlet oxygen delivery in aqueous media. This is a unique device, unlike other heterogeneous photosensitizers, in which local concentrations of singlet oxygen can be delivered via introduction and withdrawal of the fiber tip.
The Journal of Physical Chemistry B 12/2009; 113(48):15803-6. · 3.70 Impact Factor
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ABSTRACT: beta-Lactam synthetase (beta-LS) is the paradigm of a growing class of enzymes that form the critical beta-lactam ring in the clavam and carbapenem antibiotics. beta-LS catalyzes a two-stage reaction in which N(2)-(2-carboxyethyl)-L-arginine is first adenylated, and then undergoes intramolecular ring closure. It was previously shown that the forward kinetic commitment to beta-lactam formation is high, and that the overall rate of reaction is partially limited to a protein conformational change rather than to the chemical step alone of closing the strained ring. beta-Lactam formation was evaluated on the basis of X-ray crystal structures, site-specific mutation, and kinetic and computational studies. The combined evidence clearly points to a reaction coordinate involving the formation of a tetrahedral transition state/intermediate stabilized by a conserved Lys. The combination of substrate preorganization, a well-stabilized transition state and an excellent leaving group facilitates this acyl substitution to account for the strong forward commitment to catalysis and to lower the barrier of four-membered ring formation to the magnitude of a protein conformational change.
ChemBioChem 10/2009; 10(18):2904-12. · 3.94 Impact Factor
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ABSTRACT: Theoretical calculations have been used to examine singlet oxygen release from a naphthalene endoperoxide which bears a flexible (CH(2))(22) polymethylene "lid". Monte Carlo and ONIOM calculations that incorporated semi-empirical and density functional theory predicted the conformational influence of the polymethylene chain in the cycloreversion of dioxapaddlane, 1,4-diicosa naphthalene-1,4-endoperoxide, to (1)O(2) and 1,4-diicosa naphthalene. This study attempts to build a connection between (1)O(2) generation and "jump rope" dynamics of the dioxapaddlane. The polymethylene chain appears to function as a gatekeeper for the oxygen. Instead of coming full circle, a semi-circle rotation of the polymethylene bridge protected the peroxide group, limiting the dissociation of (1)O(2) from the naphthalene site.
Structural Chemistry 06/2009; 20(3):399-407. · 1.85 Impact Factor
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ABSTRACT: Insight into the O2 quenching mechanism of a photosensitizer (static or dynamic) would be useful for the design of heterogeneous systems to control the mode of generation of 1O2 in water. Here, we describe the use of a photosensitizer, meso-tetra(N-methyl-4-pyridyl)porphine (1), which was adsorbed onto porous Vycor glass (PVG). A maximum loading of 1.1 x 10(-6) mol 1 per g PVG was achieved. Less than 1% of the PVG surface was covered with photosensitizer 1, and the penetration of 1 reaches a depth of 0.32 mm along all faces of the glass. Time-resolved measurements showed that the lifetime of triplet 1*-ads was 57 microseconds in water. Triplet O2 quenched the transient absorption of triplet 1*-ads; for samples containing 0.9 x 10(-6)-0.9 x 10(-8) mol 1 adsorbed per g PVG, the Stern-Volmer constant, K(D), ranged from 23,700 to 32,100 M(-1). The adduct formation constant, Ks, ranged from 1310 to 510 M(-1). The amplitude of the absorption at 470 nm decreased slightly (by about 0.1) with increased O2 concentrations. Thus, the quenching behavior of triplet 1*-ads by O2 was proposed to be strongly dependent on dynamic quenching. Only approximately 10% of the quenching was attributed to the static quenching mechanism. The quenching of triplet 1*-ads was similar to that observed for photosensitizers in homogeneous solution which are often quenched dynamically by O2.
The Journal of Physical Chemistry B 01/2009; 112(49):15646-50. · 3.70 Impact Factor
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ABSTRACT: The enthalpy of oxidative cleavage of azo compounds (diazenes) is discussed and compared with that of symmetric olefins. The
roles of substituents and of electronegativity are explicitly discussed.
Structural Chemistry 09/2008; 19(5):817-818. · 1.85 Impact Factor
