Synthesis, characterization, and preliminary application of new biocompatible nanogels useful as anticancer drug delivery systems

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Assessment of naproxen adsorption on bone char in aqueous solutions using batch and fixed-bed processes

An integrated analysis of naproxen adsorption on bone char in batch and packed-bed column conditions has been performed. Kinetic, thermodynamic and breakthrough parameters have been calculated using adsorption models and artificial neural networks. Results show that naproxen removal using bone char in batch conditions is a feasible and effective process, which could involve electrostatic and non-electrostatic interactions depending mainly on pH conditions. However, the application of packed-bed column for naproxen adsorption on bone char is not effective for the treatment of diluted solutions due to the low degree of adsorbent utilization (below 4%) at tested operating conditions. The proposed mechanism for naproxen removal using bone char could include a complexation process via phosphate and naproxen, hydrogen bonding and the possibility of hydrophobic interactions via π–π electron. This study highlights the relevance of performing an integrated analysis of adsorbent effectiveness in batch and dynamic conditions to establish the best process configuration for the removal of emerging water pollutants such as pharmaceuticals.

Dissolution rate enhancement of repaglinide by solid dispersion

Purpose: To enhance the solubility and dissolution rate of the antidiabetic drug repaglinide by solid dispersion (SD) technique Method: The solid dispersion of repaglinide was prepared by solvent evaporation method using the hydrophilic carrier, polyethylene glycol 4000 (PEG 4000) in three drug:PEG 4000 ratios (1:1, 1:3, 1:5). For comparison, physical mixtures of repaglinide and PEG 4000 in the same ratios were also prepared. The formulations were characterized by Fourier transformed infrared spectroscopy (FTIR), x-ray diffractometry (XRD) and differential scanning colorimetry (DSC). Phase solubility study of pure repaglinide, physical mixture and solid dispersion was performed in distilled water. Dissolution studies were carried out in pH 7.4 phosphate buffer. Results: DSC and XRD results indicate that repaglinide exists in amorphous form in solid dispersion. FT-IR analysis demonstrated the presence of intermolecular hydrogen bonding between repaglinide and PEG 4000 in the solid dispersion. The solubility of pure repaglinide was enhanced from 22.5± 5.0 to 235.5± 5.0 µg/mL in distilled water at 37 0C. Rapid burst release (80 - 86 %) from the solid dispersion formulations was observed within 15 min. Conclusion: The solubility and dissolution rate of repaglinide are enhanced by formulating SDs of repaglinide with PEG 4000. This will likely lead to increase in bioavailability which would be beneficial for better glucose control in diabetic patients.

Development of measurement and modeling techniques to quantify atmospheric deposition of persistent, bioaccumulative and toxic chemicals in the Great Lakes

Measurement and modeling techniques were developed to improve over-water gaseous air-water exchange measurements for persistent bioaccumulative and toxic chemicals (PBTs). Analytical methods were applied to atmospheric measurements of hexachlorobenzene (HCB), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Additionally, the sampling and analytical methods are well suited to study semivolatile organic compounds (SOCs) in air with applications related to secondary organic aerosol formation, urban, and indoor air quality. A novel gas-phase cleanup method is described for use with thermal desorption methods for analysis of atmospheric SOCs using multicapillary denuders. The cleanup selectively removed hydrogen-bonding chemicals from samples, including much of the background matrix of oxidized organic compounds in ambient air, and thereby improved precision and method detection limits for nonpolar analytes. A model is presented that predicts gas collection efficiency and particle collection artifact for SOCs in multicapillary denuders using polydimethylsiloxane (PDMS) sorbent. An approach is presented to estimate the equilibrium PDMS-gas partition coefficient (Kpdms) from an Abraham solvation parameter model for any SOC. A high flow rate (300 L min-1) multicapillary denuder was designed for measurement of trace atmospheric SOCs. Overall method precision and detection limits were determined using field duplicates and compared to the conventional high-volume sampler method. The high-flow denuder is an alternative to high-volume or passive samplers when separation of gas and particle-associated SOCs upstream of a filter and short sample collection time are advantageous. A Lagrangian internal boundary layer transport exchange (IBLTE) Model is described. The model predicts the near-surface variation in several quantities with fetch in coastal, offshore flow: 1) modification in potential temperature and gas mixing ratio, 2) surface fluxes of sensible heat, water vapor, and trace gases using the NOAA COARE Bulk Algorithm and Gas Transfer Model, 3) vertical gradients in potential temperature and mixing ratio. The model was applied to interpret micrometeorological measurements of air-water exchange flux of HCB and several PCB congeners in Lake Superior. The IBLTE Model can be applied to any scalar, including water vapor, carbon dioxide, dimethyl sulfide, and other scalar quantities of interest with respect to hydrology, climate, and ecosystem science.

Asymmetric Syntheses of Analogs of Kainic Acid

Kainic acid has been used for nearly 50 years as a tool in neuroscience due to its pronounced neuroexcitatory properties. However, the significant price increase of kainic acid resulting from the disruption in the supply from its natural source, the alga Digenea Simplex, as well as inefficient synthesis of kainic acid, call for the exploration of functional mimics of kainic acid that can be synthesized in a simpler way. Aza kainoids analog could be one of them. The unsubstituted aza analog of kainoids has demonstrates its ability as an ionotropic glutamate receptor agonist and showed affinity in the chloride dependent glutamate (GluCl) binding site. This opened a question of the importance of the presence of one nitrogen or both nitrogens in the aza kainoid analogs for binding to glutamate receptors. Therefore, two different pyrrolidine analogs of kainic acid, trans-4-(carboxymethyl)pyrrolidine-3-carboxylic acid and trans-2-carboxy-3-pyrrolidineacetic acid, were synthesized through multi-step sequences. The lack of the affinity of both pyrrolidine analogs in GluCl binding site indicated that both nitrogens in aza kainoid analogs are involved in hydrogen bonding with receptors, significantly enhancing their affinity in GluCl binding site. Another potential functional mimic of kainic acid is isoxazolidine analogs of kainoids whose skeleton can be constituted directly via a 1, 3 dipolar cycloaddition as the key step. The difficulty in synthesizing N-unsubstituted isoxazolidines when applying such common protecting groups as alkyl, phenyl and benzyl groups, and the requirement of a desired enantioselectivity due to the three chiral ceneters in kainic acid, pose great challenges. Hence, several different protected nitrones were studied to establish that diphenylmethine nitrone may be a good candidate as the dipole in that the generated isoxazolidines can be deprotected in mild conditions with high yields. Our investigations also indicated that the exo/endo selectivity of the 1, 3 dipolar cycloaddition can be controlled by Lewis acids, and that the application of a directing group in dipolarophiles can accomplish a satisfied enantioselectivity. Those results demonstrated the synthesis of isoxazoldines analogs of kainic acid is very promising.

Pressure Induced Structural Changes and Gas Diffusion Pathways in Monomeric Fluorescent Proteins

Fluorescent proteins (FPs) are extremely valuable biochemical markers which have found a wide range of applications in cellular and molecular biology research. The monomeric variants of red fluorescent proteins (RFPs), known as mFruits, have been especially valuable for in vivo applications in mammalian cell imaging. Fluorescent proteins consist of a chromophore caged in the beta-barrel protein scaffold. The photophysical properties of an FP is determined by its chromophore structure and its interactions with the protein barrel. Application of hydrostatic pressure on FPs results in the modification of the chromophore environment which allows a systematic study of the role of the protein-chromophore interactions on photophysical properties of FPs. Using Molecular Dynamics (MD) computer simulations, I investigated the pressure induced structural changes in the monomeric variants mCherry, mStrawberry, and Citrine. The results explain the molecular basis for experimentally observed pressure responses among FP variants. It is found that the barrel flexibility, hydrogen bonding interactions and chromophore planarity of the FPs can be correlated to their contrasting photophysical properties at vaious pressures. I also investigated the oxygen diffusion pathways in mOrange and mOrange2 which exhibit marked differences in oxygen sensitivities as well as photostability. Such computational identifications of structural changes and oxygen diffusion pathways are important in guiding mutagenesis efforts to design fluorescent proteins with improved photophysical properties.

Role of the Tryptophan Residues in the Specific interaction of the Sea Anemone Stichodacty la helianthus’s Actinoporin Sticholysin II with Biological Membranes

Actinoporins are pore-forming toxins from sea anemones. Upon interaction with sphingomyelin-containing bilayers, they become integral oligomeric membrane structures that form a pore. Sticholysin II from Stichodactyla helianthus contains five tryptophans located at strategic positions; its role has now been studied using different mutants. Results show that W43 and W115 play a eterminant role in maintaining the high thermostability of the protein, while W146 provides specific interactions for protomer−protomer assembly. W110 and W114 sustain the hydrophobic effect, which is one of the major driving forces for membrane binding in the presence of Chol. However, in its absence, additional interactions with sphingomyelin are required. These conclusions were confirmed with two sphingomyelin analogues, one of which had impaired hydrogen bonding properties. The results obtained support actinoporins’ Trp residues playing a major role in membrane recognition and binding, but their residues have an only minor influence on the diffusion and oligomerization steps needed to assemble a functional pore.

Transfert ultrarapide d’électron et transfert modéré d’énergie au sein d’assemblages supramoléculaires de colorants et d’un cluster de palladium

Résumé : Les transferts d’électrons photo-induits et d’énergie jouent un rôle primordial dans un grand nombre de processus photochimiques et photobiologiques, comme la respiration ou la photosynthèse. Une très grande quantité de systèmes à liaisons covalentes ont été conçus pour copier ces processus de transferts. Cependant, les progrès sont, en grande partie, limités par les difficultés rencontrées dans la synthèse de nouveaux couples de types donneurs-accepteurs. Récemment, des espèces utilisant des liaisons non-covalentes, comme les liaisons hydrogènes, les interactions [pi]-[pi], les liaisons de coordination métal-ligands ou encore les interactions électrostatiques sont le centre d’un nouvel intérêt du fait qu’ils soient plus faciles à synthétiser et à gérer pour obtenir des comportements de transferts d’électrons ou d’énergie plus flexibles et sélectifs. C’est dans cette optique que le travail de cette thèse a été mené, i.e. de concevoir des composés auto-assemblés avec des porphyrines et un cluster de palladium pour l’étude des transferts d’électrons photo-induits et d’énergie. Cette thèse se divise en quatre parties principales. Dans la première section, le chapitre 3, deux colorants porphyriniques, soit le 5-(4-carboxylphényl)-10, 15, 20-tristolyl(porphyrinato)zinc(II) (MCP, avec Na+ comme contre-ion) et 5, 15-bis(4-carboxylphényl)-15, 20-bistolyl(porphyrinato)zinc(II) (DCP, avec Na+ comme contre-ion) ont été utilisés comme donneurs d’électrons, et le [Pd3(dppm)3(CO)]2+ ([Pd32+], dppm = (Ph2P)2CH2, PF6‾ est le contre-ion) a été choisi comme accepteur d’électrons. La structure de l’assemblage [Pd32+]•••porphyrine a été élucidée par l’optimisation des géométries à l’aide de calculs DFT. La spectroscopie d’absorption transitoire (TAS) montre la vitesse de transferts d’électrons la plus rapide (< 85 fs, temps inférieurs à la limite de détection) jamais enregistrée pour ce type de système (porphyrine-accepteur auto-assemblés). Généralement, ces processus sont de l’ordre de l’échelle de la ps-ns. Cette vitesse est comparable aux plus rapides transferts d’électrons rapportés dans le cas de systèmes covalents de type porphyrine-accepteur rapide (< 85 fs, temps inférieurs à la limite de détection). Ce transfert d’électrons ultra-rapide (ket > 1.2 × 1013 s-1) se produit à l’état énergétique S1 des colorants dans une structure liée directement par des interactions ioniques, ce qui indique qu’il n’est pas nécessaire d’avoir de forts liens ou une géométrie courbée entre le donneur et l’accepteur. Dans une deuxième section, au chapitre 4, nous avons étudié en profondeur l’effet de l’utilisation de porphyrines à systèmes π-étendus sur le comportement des transferts d’électrons. Le colorant 9, 18, 27, 36-tétrakis-meso-(4-carboxyphényl)tétrabenzoporphyrinatozinc(II) (TCPBP, avec Na+ comme contre-ion) a été sélectionné comme candidat, et le 5, 10, 15, 20-tétrakis-meso-(4-carboxyphényl)porphyrineatozinc(II) (TCPP, avec Na+ comme contre-ion) a aussi été utilisé à des fins de comparaisons. TCPBP et TCPP ont, tous deux, été utilisés comme donneurs d’électrons pour fabriquer des assemblages supramoléculaires avec le cluster [Pd32+] comme accepteur d’électrons. Les calculs DFT ont été réalisés pour expliquer les structures de ces assemblages. Dans les conditions expérimentales, ces assemblages sont composés principalement d’une porphyrine avec 4 équivalents de clusters. Ces systèmes ont aussi été investigués par des mesures de quenching (perte de luminescence), par électrochimie et par d’autres techniques. Les transferts d’électrons (< 85 fs; temps inférieurs à la limite de détection) étaient aussi observés, de façon similaire aux assemblages MCP•••[Pd32+] et [Pd32+]•••DCP•••[Pd32+]. Les résultats nous indiquent que la modification de la structure de la porphyrine vers la tétrabenzoporphyrine ne semble pas influencer le comportement des cinétiques de transferts d’électrons (aller ou retour). Dans la troisième section, le chapitre 5, nous avons synthétisé la porphyrine hautement [pi]-conjuguée: 9, 18, 27, 36-tétra-(4-carboxyphényléthynyl)tétrabenzoporphyrinatozinc(II) (TCPEBP, avec Na+ comme contre-ion) par des fonctionnalisations en positions meso- et β, β-, qui présente un déplacement vers le rouge de la bande de Soret et des bandes Q. TCPEBP était utilisé comme donneur d’électrons pour fabriquer des motifs supramoléculaires avec le [Pd32+] comme accepteur d’électrons. Des expériences en parallèle ont été menées en utilisant la 5, 10, 15, 20-tétra-(4-carboxyphényl)éthynylporphyrinatozinc(II) (TCPEP, avec Na+ comme contre-ion). Des calculs DFT et TDDFT ont été réalisés pour de nouveau déterminer de façon théorique les structures de ces systèmes. Les constantes d’association pour les assemblages TCPEBP•••[Pd32+]x sont les plus élevées parmi tous les assemblages entre des porphyrines et le cluster de palladium rencontrés dans la littérature. La TAS a montré, encore une fois, des processus de transferts d’électrons dans des échelles de l’ordre de 75-110 fs. Cependant, les transferts de retour d’électrons sont aussi très rapides (< 1 ps), ce qui est un obstacle potentiel pour des applications en cellules solaires à pigment photosensible (DSSCs). Dans la quatrième section, le chapitre 6, les transferts d’énergie triplets (TET) ont été étudiés pour les assemblages MCP•••[Pd32+] et [Pd32+]•••DCP•••[Pd32+]. Les analyses spectrales des états transitoires dans l’échelle de temps de la ns-[mu]s démontrent de façon évidente les TETs; ceux-ci présentent des transferts d’énergie lents et/ou des vitesses moyennes pour des transferts d’énergie T1-T1 (3dye*•••[Pd32+] → dye•••3[Pd32+]*) opérant à travers exclusivement le mécanisme de Förster avec des valeurs de kET autour de ~ 1 × 105 s-1 selon les mesures d’absorption transitoires à 298 K. Des forces motrices non-favorables rendent ces types de processus non-opérants ou très lents dans les états T1. L’état T1 de [Pd32+] (~8190 cm-1) a été qualitativement déterminé par DFT et par la mise en évidence de l’émission S0 ← Tn retardée à 680-700 nm provenant de l’annihilation T1-T1, ce qui fait que ce cluster peut potentiellement agir comme un donneur à partir de ses états Tn, et accepteur à partir de T1 à l’intérieur de ces assemblages. Des pertes d’intensités de types statiques pour la phosphorescence dans le proche-IR sont observées à 785 nm. Ce travail démontre une efficacité modérée des colorants à base de porphyrines pour être impliquée dans des TETs avec des fragments organométalliques, et ce, même attachées grâce à des interactions ioniques. En conclusion, les assemblages ioniques à base de porphyrines et de clusters de palladium présentent des propriétés de transferts d’électrons S1 ultra-rapides, et des transferts d’énergie T1 de vitesses modérées, ce qui est utile pour de possibles applications comme outils optoélectroniques. D’autres études, plus en profondeur, sont présentement en progrès.

Cellulose: A review as natural, modified and activated carbon adsorbent

Cellulose is a biodegradable, renewable, non-meltable polymer which is insoluble in most solvents due to hydrogen bonding and crystallinity. Natural cellulose shows lower adsorption capacity as compared to modified cellulose and its capacity can be enhanced by modification usually by chemicals. This review focuses on the utilization of cellulose as an adsorbent in natural/modified form or as a precursor for activated carbon (AC) for adsorbing substances from water. The literature revealed that cellulose can be a promising precursor for production of activated carbon with appreciable surface area (∼1300 m2 g−1) and total pore volume (∼0.6 cm3 g−1) and the surface area and pore volume varies with the cellulose content. Finally, the purpose of review is to report a few controversies and unresolved questions concerning the preparation/properties of ACs from cellulose and to make aware to readers that there is still considerable scope for future development, characterization and utilization of ACs from cellulose.

Cellulose: A review as natural, modified and activated carbon adsorbent

Cellulose is a biodegradable, renewable, non-meltable polymer which is insoluble in most solvents due to hydrogen bonding and crystallinity. Natural cellulose shows lower adsorption capacity as compared to modified cellulose and its capacity can be enhanced by modification usually by chemicals. This review focuses on the utilization of cellulose as an adsorbent in natural/modified form or as a precursor for activated carbon (AC) for adsorbing substances from water. The literature revealed that cellulose can be a promising precursor for production of activated carbon with appreciable surface area ( 1300 m2 g 1) and total pore volume ( 0.6 cm3 g 1) and the surface area and pore volume varies with the cellulose content. Finally, the purpose of review is to report a few controversies and unresolved questions concerning the preparation/properties of ACs from cellulose and to make aware to readers that there is still considerable scope for future development, characterization and utilization of ACs from cellulose.

Liquid Mixtures Involving Hydrogenated and Fluorinated Alcohols: Thermodynamics, Spectroscopy, and Simulation

This article reports a combined thermodynamic, spectroscopic, and computational study on the interactions and structure of binary mixtures of hydrogenated and fluorinated substances that simultaneously interact through strong hydrogen bonding. Four binary mixtures of hydrogenated and fluorinated alcohols have been studied, namely, (ethanol + 2,2,2-trifluoroethanol (TFE)), (ethanol + 2,2,3,3,4,4,4-heptafluoro-1-butanol), (1-butanol (BuOH) + TFE), and (BuOH + 2,2,3,3,4,4,4-heptafluoro-1-butanol). Excess molar volumes and vibrational spectra of all four binary mixtures have been measured as a function of composition at 298 K, and molecular dynamics simulations have been performed. The systems display a complex behavior when compared with mixtures of hydrogenated alcohols and mixtures of alkanes and perfluoroalkanes. The combined analysis of the results from different approaches indicates that this results from a balance between preferential hydrogen bonding between the hydrogenated and fluorinated alcohols and the unfavorable dispersion forces between the hydrogenated and fluorinated chains. As the chain length increases, the contribution of dispersion increases and overcomes the contribution of H-bonds. In terms of the liquid structure, the simulations suggest the possibility of segregation between the hydrogenated and fluorinated segments, a hypothesis corroborated by the spectroscopic results. Furthermore, a quantitative analysis of the infrared spectra reveals that the presence of fluorinated groups induces conformational changes in the hydrogenated chains from the usually preferred all-trans to more globular arrangements involving gauche conformations. Conformational rearrangements at the CCOH dihedral angle upon mixing are also disclosed by the spectra.