Population Pharmacokinetic Analysis of Valsartan in Healthy Chinese Subjects.

The study was conducted to establish a population pharmacokinetic (PPK) model of valsartan in Chinese healthy subjects and investigate potential covariate impacts on the pharmacokinetics (PK) parameters. Data from a bioequivalence study with 78 Chinese healthy subjects were retrospectively analyzed to develop a PPK model of valsartan. Phoenix NLME 8.1 was used to build a PPK model and quantify the effects of covariates, such as demographic data and biochemical, on the PK parameters of valsartan. For the healthy Chinese population, valsartan conformed to the two-compartment model with an absorption lag time. In the final PPK model, food affected the absorption rate constant, while aspartate aminotransferase, alanine aminotransferase, and creatinine affected the clearance of the central compartment. The final PPK model was verified to be reproducible, and it can be used to evaluate the PK parameters. This is the first research describing the PPK profile of valsartan in healthy Chinese subjects, and it is expected to provide relevant PK parameters for further study of valsartan.

Thioguanine restoration through type I photosensitization-superoxide oxidation-glutathione reduction cycles.

UVA-induced deleterious effect of thiopurine prodrugs including azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) increases the risk of cancer development due to the incorporation of 6-TG in patients' DNA. The catalytic mechanism by which thiobases act as a sustained oxidant producer has yet to be explored, especially through the Type I electron transfer pathway that produces superoxide radicals (O2˙-). Under Fenton-like conditions O2˙- radicals convert to extremely reactive hydroxyl radicals (˙OH), thus carrying even higher risk of biological damage than that induced by the well-studied type II reaction. By monitoring 6-TG/UVA-induced photochemistry in mass spectra and superoxide radicals (O2˙-) via nitro blue tetrazolium (NBT) reduction, this work provides two new findings: (1) in the presence of reduced glutathione (GSH), the production of O2˙-via the type I reaction is enhanced 10-fold. 6-TG thiyl radicals are identified as the primary intermediate formed in the reaction of 6-TG with O2˙-. The restoration of 6-TG and concurrent generation of O2˙- occur via a 3-step-cycle: 6-TG type I photosensitization, O2˙- oxidation and GSH reduction. (2) In the absence of GSH, 6-TG thiyl radicals undergo oxygen addition and sulfur dioxide removal to form carbon radicals (C6) which further convert to thioether by reacting with 6-TG molecules. These findings help explain not only thiol-regulation in a biological system but chemoprevention of cancer.

Selective Adsorption of C6, C8, and C10 Linear α-Olefins from Binary Liquid-Phase Olefin/Paraffin Mixtures Using Zeolite Adsorbents: Experiment and Simulations.

The adsorption separation of gaseous olefin/paraffin using porous materials has been extensively studied from both experimental and molecular simulation perspectives, while the adsorption separation of liquid-phase olefin/paraffin has been much less studied. One of the most important reasons for this is that it is difficult to measure the actual adsorption capacity of liquid-phase adsorption separation directly through experiments, and the simulation results of most studies are compared to gas-phase measurements. In this paper, the selective adsorption of linear α-olefins from three binary liquid-phase olefin/paraffin mixtures, 1-hexene/n-hexane (C6), 1-octene/n-octane (C8), and 1-decene/n-decane (C10), by zeolite adsorbents was systematically investigated using batch adsorption experiments and configurational-bias grand canonical Monte Carlo (CB-GCMC) simulations. In the batch experiments, based on the liquid-phase measurement method of the actual adsorption capacity that we developed, a modified commercial 5A zeolite with a relatively large pore volume and surface area was used for adsorption. The results showed that the modified 5A zeolite had larger actual adsorption capacities for C6 and C8 linear α-olefins, which increased by 51% and 56%, respectively, than the standard 5A zeolite that was used in our previous work. The adsorption isotherms of C6, C8, and C10 in the 5A and 13X zeolites were calculated by CB-GCMC simulations. The visualized results of density profiles showed that the olefin molecules were densely distributed at the edge of the zeolite cages and that there were cases where a single molecule was adsorbed over two adjacent cages. The good agreement between the experimental and simulated data proves the completeness of the liquid-phase measurement method that we developed and the reliability of the simulation prediction.

Comparing a thioglycosylated chlorin and phthalocyanine as potential theranostic agents.

Herein we describe the design, efficient synthesis, and photophysical properties of two macrocycle dyes for cancer theranostics. This study compares a glycosylated chlorin with a glycosylated phthalocyanine designed to specifically target cancer, wherein the photophysical properties enable both fluorescence imaging and the sensitization of the formation of reactive oxygen species (ROS) for photodynamic therapy. Both the compounds show low darktoxicity (IC50 > 100 µM). The glycosylated phthalocyanine showed low phototoxicity (IC50 > 100 µM) while glycosylated chlorin showed high phototoxicity (IC50 = 1-2 µM). ZnPcGlc8 has low solubility and also form aggregates in aqueous media, thus resulting in minimal uptake in two different human breast cancer cell lines: MDA-MB-231 and MCF-7. The glycosylated chlorin however was efficiently taken up by these two cell lines, thus allows fluorescence imaging in cells and in xenograft tumor model in mice. In this study, we find that the chlorin conjugate is the more promising theranostic agent.

Nanocomposite liposomes for pH-controlled porphyrin release into human prostate cancer cells.

It is both challenging and desirable to have drug sensitizers released at acidic tumor pH for photodynamic therapy in cancer treatment. A pH-responsive carrier was prepared, in which fumed silica-attached 5,10,15,20-tetrakis(4-trimethylammoniophenyl)porphyrin (TTMAPP) was encapsulated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanocomposite liposomes. The sizes of agglomerates were determined by dynamic light scattering to be 115 nm for silica and 295 nm for silica-TTMAPP-DOPC liposomes. Morphological changes were also found in TEM images, showing liposome formation at pH 8.5 but collapse upon silanol protonation. TTMAPP release is enhanced from 13% at pH 7.5 to 80% at pH 2.3, as determined spectrophotometrically through dialysis membranes. Fluorescence emission of TTMAPP encapsulated in the dry film of liposomes was reduced to half at pH 8.6 when compared to that at pH 5.4, while the production of singlet oxygen was quintupled at pH 5.0 compared to pH 7.6. Upon treatment of human prostate cancer cells with liposomes containing 6.7 µM, 13 µM, 17 µM and 20 µM TTMAPP, the cell viabilities were determined to be 60%, 18%, 20% and 5% at pH 5.4; 58%, 30%, 25% and 10% at pH 6.3; and 90%, 82%, 68% and 35% at pH 7.4, respectively. Light-induced apoptosis in cancerous cells was only observed in the presence of liposomes at pH 6.3 and pH 5.4 but not at pH 7.4, as indicated by chromatin condensation.

Distorted Phthalocyanines by Click Chemistry: Photoacoustic, Photothermal, and Surface-Enhanced Resonance Raman Studies.

Distortion of nominally planar phthalocyanine macrocycles affects the excited state dynamics in that most of the excited-state energy decays through internal conversion. A click-type annulation reaction on a perfluorophthalocyanine platform appending a seven-membered ring to the ß-positions on one or more of the isoindoles distorts the macrocycle and modulates solubility. The distorted derivative enables photoacoustic imaging, photothermal effects, and strong surface-enhanced resonance Raman signals.

Synthesis and cell phototoxicity of a triply bridged fused diporphyrin appended with six thioglucose units.

A triply bridged fused diporphyrin appended with six thioglucose units is reported. This new, chemically and photochemically stable amphiphilic compound is taken up by breast cancer cells and causes cell death upon light exposure. Photophysical studies reveal absorption bands in the near IR region, and photosensitized formation of singlet oxygen in high quantum yields.

Effects of light energy and reducing agents on C60-mediated photosensitizing reactions.

Many biomolecules contain photoactive reducing agents, such as reduced nicotinamide adenine dinucleotide (NADH) and 6-thioguanine (6-TG) incorporated into DNA through drug metabolism. These reducing agents may produce reactive oxygen species under UVA irradiation or act as electron donors in various media. The interactions of C60 fullerenes with biological reductants and light energy, especially via the Type-I electron-transfer mechanism, are not fully understood although these factors are often involved in toxicity assessments. The two reductants employed in this work were NADH for aqueous solutions and 6-TG for organic solvents. Using steady-state photolysis and electrochemical techniques, we showed that under visible light irradiation, the presence of reducing agents enhanced C60 -mediated Type-I reactions that generate superoxide anion (O2(.-)) at the expense of singlet oxygen ((1)O2) production. The quantum yield of O2(.-) production upon visible light irradiation of C60 is estimated below 0.2 in dipolar aprotic media, indicating that the majority of triplet C60 deactivate via Type-II pathway. Upon UVA irradiation, however, both C60 and NADH undergo photochemical reactions to produce O2(.-), which could lead to a possible synergistic toxicity effects. C60 photosensitization via Type-I pathway is not observed in the absence of reducing agents.

Enhanced Photodynamic Selectivity of Nano-Silica-Attached Porphyrins Against Breast Cancer Cells.

The synthesis and characterization of bare silica (4 nm in diameter) nanoparticle-attached meso-tetra(N-methyl-4-pyridyl)porphine (SiO(2)-TMPyP, 6 nm in diameter) are described for pH-controllable photosensitization. Distinguished from organosilanes, SiO(2) nanoparticles were functionalized as a potential quencher of triplet TMPyP and/or singlet oxygen ((1)O(2)) at alkaline pH, thereby turning off sensitizer photoactivity. In weak acidic solutions, TMPyP was released from SiO(2) surface for efficient production of (1)O(2). By monitoring (1)O(2) luminescence at 1270 nm, quantum yields of (1)O(2) production were found to be pH-dependent, dropping from ~ 0.45 in a pH range of 3-6 to 0.08 at pH 8-9, which is consistent with pH-dependent adsorption behavior of TMPyP on SiO(2) surface. These features make bare SiO(2)-attached cationic porphyrin a promising candidate for use in PDT for cancer treatment in which efficient (1)O(2) production at acidic pH and sensitizer deactivation at physiological pH are desirable. The enhanced therapeutic selectivity was confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests and trypan blue exclusion tests of cell viability in breast cancer cell lines. Bimolecular quenching rate constants of (1)O(2) by free TMPyP, SiO(2) and SiO(2)-TMPyP nanoparticles were also determined.

Quantification of Thiopurine/UVA-Induced Singlet Oxygen Production.

Thiopurines were examined for their ability to produce singlet oxygen ((1)O(2)) with UVA light. The target compounds were three thiopurine prodrugs, azathioprine (Aza), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), and their S-methylated derivatives of 6-methylmercaptopurine (me6-MP) and 6-methylthioguanine (me6-TG). Our results showed that these thiopurines were efficient (1)O(2) sensitizers under UVA irradiation but rapidly lost their photoactivities for (1)O(2) production over time by a self-sensitized photooxidation of sulfur atoms in the presence of oxygen and UVA light. The initial quantum yields of (1)O(2) production were determined to be in the range of 0.30-0.6 in aqueous solutions. Substitution of a hydrogen atom with a nitroimidazole or methyl group at S decreased the efficacy of photosensitized (1)O(2) production as found for Aza, me6-MP and me6-TG. (1)O(2)-induced formation of 8-oxo-7,8-dihydro-2'-dexyguanosine (8-oxodGuo) was assessed by incubation of 6-methylthiopurine/UVA-treated calf thymus DNA with human repair enzyme 8-oxodGuo DNA glycosylase (hOGG1), followed by apurinic (AP) site determination. Because more 8-oxodGuo was formed in Tris D(2)O than in Tris H(2)O, (1)O(2) is implicated as a key species in the reaction. These findings provided quantitative information on the photosensitization efficacy of thiopurines and to some extent revealed the correlations between photoactivity and phototoxicity.

Synthesis and photophysics of an octathioglycosylated zinc(II) phthalocyanine.

A water soluble zinc(II) phthalocyanine symmetrically appended with eight thioglucose units was synthesized from commercially available hexadecafluorophthalocyaninatozinc(II) by controlled nucleophilic substitution of the peripheral fluoro groups. The photophysical properties and cancer cell uptake studies of this nonhydrolyzable thioglycosylated phthalocyanine are reported. The new compound has amphiphilic character, is chemically stable, and can potentially be used as a photosensitizer in photodynamic therapy.

Imidazole-modified porphyrin as a pH-responsive sensitizer for cancer photodynamic therapy.

5,10,15,20-Tetrakis(N-(2-(1H-imidazol-4-yl)ethyl)benzamide)porphyrin produced twice as many singlet oxygen ((1)O(2)) molecules at pH 5.0 (quantum yield 0.53 ± 0.01) than at pH 7.4, whereas the (1)O(2) quenching rate was reduced by a factor of 2.5 for a pH change from 7.4 to 5.0.

Direct observation and quantitative characterization of singlet oxygen in aqueous solution upon UVA excitation of 6-thioguanines.

The incorporation of 6-thioguanine (6-TG) into DNA increases the risk of (1)O(2)-initiated skin cancer. We herein provide the first report on quantitative characterization of the photoactivity of 6-thioguanines including 6-TG and 6-thioguanosine. Time-resolved singlet oxygen luminescence was observed directly for the first time after UVA irradiation of 6-thioguanines in both CHCN(3) and aqueous solutions. Their photosensitization was characterized by the quantum yield of singlet oxygen production, showing a dramatic decrease over time from the initial 0.49-0.58 to zero. Experiments performed on both 6-TG and 6-thioguanosine did not show any significant difference in the quantum yield of singlet oxygen production, indicating that there was no potential participation of 7H- and 9H-tautomers. Our findings provide a primary basis for a better understanding of molecular events of thiopurine drugs in biological systems.

Synthesis and photophysical properties of thioglycosylated chlorins, isobacteriochlorins, and bacteriochlorins for bioimaging and diagnostics.

The facile synthesis and photophysical properties of three nonhydrolyzable thioglycosylated porphyrinoids are reported. Starting from meso-perfluorophenylporphyrin, the nonhydrolyzable thioglycosylated porphyrin (PGlc4), chlorin (CGlc4), isobacteriochlorin (IGlc4), and bacteriochlorin (BGlc4) can be made in 2-3 steps. The ability to append a wide range of targeting agents onto the perfluorophenyl moieties, the chemical stability, and the ability to fine-tune the photophysical properties of the chromophores make this a suitable platform for development of biochemical tags, diagnostics, or as photodynamic therapeutic agents. Compared to the porphyrin in phosphate buffered saline, CGlc4 has a markedly greater absorbance of red light near 650 nm and a 6-fold increase in fluorescence quantum yield, whereas IGlc4 has broad Q-bands and a 12-fold increase in fluorescence quantum yield. BGlc4 has a similar fluorescence quantum yield to PGlc4 (<10%), but the lowest-energy absorption/emission peaks of BGlc4 are considerably red-shifted to near 730 nm with a nearly 50-fold greater absorbance, which may allow this conjugate to be an effective PDT agent. The uptake of CGlc4, IGlc4, and BGlc4 derivatives into cells such as human breast cancer cells MDA-MB-231 and K:Molv NIH 3T3 mouse fibroblast cells can be observed at nanomolar concentrations. Photobleaching under these conditions is minimal.

Singlet oxygen production upon two-photon excitation of TiO2 in chloroform.

Singlet oxygen ((1)O(2)) signals observed upon illumination at 532 nm are a consequence of TiO(2) excitation in a two-photon process, and at 355 nm in a one-photon pathway. After corrections for light reflectance, the relative quantum yields of (1)O(2) production are 0.23+/-0.01 and 0.22+/-0.02 for 532 and 355 nm excitation, respectively. Total quenching rate constants of (1)O(2) removal by TiO(2) particles are near the diffusion-controlled rate limit. By employing (1)O(2) as a probe, we have established an efficient and simple method to elucidate the nature of TiO(2) photoexcitation.

pH-responsive, TiO2-attached porphyrin for singlet oxygen production in an aqueous solution.

A pH-responsive, TiO2-attached sensitizer was prepared based on the adsorption of 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) onto TiO2 nanoparticles. This colloidally dispersed TiO2-attached TCPP behaves as a single-phase colloidal sensitizer at pH 1.0-3.3 with quantum yields of singlet oxygen production (Phi(Delta)) between 0.20 and 0.25, as a heterogeneous particle sensitizer at pH 3.5-6.0 with Phi(Delta) between 0.25 and 0.50, and as homogeneous free TCPP molecules in alkaline solutions with Phi(Delta) = 0.53. The changes in Phi(Delta) are fully consistent with pH-dependent adsorption of TCPP onto the TiO2 surface. Recovery yields of 99.8% for TCPP and 98.8% for TiO2 were obtained from 1.4 mM TiO2-attached TCPP. We attribute its photosensitization ability to retaining TCPP solubility on the TiO2 surface and, hence, activity. This novel system shows a potential to bridge the gap between easily recoverable and highly efficient sensitizers.

Photosensitized Singlet Oxygen Production upon Two-Photon Excitation of Single-Walled Carbon Nanotubes and Their Functionalized Analogs.

Single-walled carbon nanotubes (SWNTs) functionalized with -COOH (along with some sulphonation and nitration), and/or modified with chitosan were prepared and tested for their singlet oxygen ((1)O(2)) production. The emission from (1)O(2) observed upon SWNT irradiation at 532 nm was due to a two-photon process, while (1)O(2) production via excitation at 355 nm occurred through a conventional one-photon pathway. The relative quantum yield of (1)O(2) production at excitation wavelength of 532 nm was found to be 0.00, 0.07-0.13 and 0.24-0.54 for highly-functionalized, partially-functionalized and non-functionalized SWNT samples respectively. The nanotube-mediated generation of (1)O(2) may find applications in both targeted destruction of tumor cells and selective degradation of drug molecules. Our research provides a practical approach to modulate the production of reactive oxygen species from SWNTs via surface functionalization/modification.

Singlet oxygen chemistry in water: a porous vycor glass-supported photosensitizer.

Singlet molecular oxygen [1O2 (1Deltag)] is generated cleanly in aqueous solution upon irradiation of a heterogeneous complex, meso-tetra(N-methyl-4-pyridyl)porphine (1) adsorbed onto porous Vycor glass (PVG). The cationic photosensitizer 1 tightly binds onto PVG and gives a stable material, which does not dissociate 1 into the surrounding aqueous phase. The production of 1O2 was measured by monitoring the time-resolved 1O2 (1Deltag) phosphorescence at 1270 nm. Indirect analysis of 1O2 generation was also carried out with the photooxidation of trans-2-methyl-2-pentenoate anion, which afforded the corresponding hydroperoxide. Sensitizer-1-impregnated PVG gives rise to a new singlet oxygen generator but more importantly provides a heterogeneous system for use in water.

Cyclometalated iridium and platinum complexes as singlet oxygen photosensitizers: quantum yields, quenching rates and correlation with electronic structures.

Photophysical properties are reported for a series of cyclometalated platinum and iridium complexes that can serve as photosensitizers for singlet oxygen. The complexes have the formula (C;N)(2)Ir(O;O) or (C;N)Pt(O;O) where C;N is a monoanionic cyclometalating ligand such as 2-(phenyl)pyridyl and 2-(phenyl)quinolyl, and O;O is the ancillary ligand acetylacetonate (acac) or dipivaloylmethane (dpm). Also examined were a series of (N;N)PtMe(2) complexes where N;N is a diimine such as 2,2'-bipyridyl. In general, the cyclometalated complexes are excellent photosensitizers for the production of singlet oxygen, while the (N;N)PtMe(2) complexes were ineffective at this reaction. Quantum yields of singlet oxygen production range from 0.9-1.0 for the cyclometalated Pt complexes and 0.5-0.9 for Ir complexes. Luminescence quenching and singlet oxygen formation of the Ir complexes occurs from a combination of electron and energy transfer processes, whereas the Pt complexes only react by energy transfer. For Ir complexes with low emission energy, physical deactivation of the triplet excited state becomes competitive with energy transfer to ground state dioxygen. The rates of singlet oxygen quenching for the complexes presented here are in the range 6 x 10(6)-2 x 10(7) M(-1) s(-1) for Pt complexes and 2 x 10(5)-2 x 10(7) M(-1) s(-1) for Ir complexes, respectively. Differences in the efficiency of both forming and quenching singlet oxygen between the Ir and Pt cyclometalates are believed to come about from the more exposed coordination geometry in the latter species.

Intramolecular arene epoxidation by phosphadioxiranes.

Singlet oxygen reacts with binaphthyl phosphine derivatives such as 1,1'-binaphthyl di-tert-butyl phosphine to form the corresponding binaphthyl-2-oxide phosphine oxides. This new intramolecular arene epoxidation reaction proceeds with complete retention of stereochemistry. The binaphthyl-2-oxide di-tert-butyl phosphine oxide undergoes a slow "NIH-rearrangement" to form the corresponding hydroxylated product. A transient phosphadioxirane intermediate has been directly observed by low-temperature NMR. Kinetic analyses show that all of the phosphadioxirane intermediate is converted to product. [reaction: see text]