A Novel Antimicrobial Hydrogel for the Management of Periodontal Diseases.

OBJECTIVES: This study aimed to synthesise a drug-delivery system based on a porous polymer hydrogel, with antimicrobial properties against Porphyromonas gingivalis and potential to be used in tissue regeneration. MATERIAL AND METHODS: 2-Hydroxyethyl methacrylate monomers were polymerised using thermal and photoactivation in the presence of silver nitrate (AgNO3) and/or chlorhexidine digluconate. Poly-2-hydroxyethyl methacrylate (pHEMA) hydrogels containing silver nanoparticles (AgNPs) and/or 0.12% chlorhexidine (CHX) were produced and characterised using cryo-SEM and confocal microscopy. Hydrogel degradation and leaching of AgNP were tested for 1.5 months. The antimicrobial properties were tested against P. gingivalis using broth culture system and disk diffusion tests. RESULTS: Our methodology manufactured porous polymeric hydrogels doped with AgNPs and CHX. Hydrogels showed a successful delivery of CHX and sustainable release of AgNPs in a steady hydrogel degradation rate determined based on the weight loss of samples. Hydrogels with AgNPs or CHX had a significant antimicrobial effect against P. gingivalis, with CHX-hydrogels exhibiting a stronger effect than AgNP-hydrogels in the short-term assessment. AgNP-CHX hydrogels showed a compounded antimicrobial effect, whereas control hydrogels containing neither AgNPs nor CHX had no influence on bacterial growth (P < .05). CONCLUSIONS: The dual-cured pHEMA hydrogel loaded with antimicrobial agents proved to be an efficient drug-delivery system against periodontopathogens, with the potential to be used as a scaffold for tissue regeneration.

Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model.

Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced.

Ca2+ detection utilising AlGaN/GaN transistors with ion-selective polymer membranes.

We demonstrate highly selective and sensitive potentiometric ion sensors for calcium ion detection, operated without the use of a reference electrode. The sensors consist of AlGaN/GaN heterostructure-based transistor devices with chemical functionalisation of the gate area using poly (vinylchloride)-based (PVC) membranes having high selectivity towards calcium ions, Ca2+. The sensors exhibited stable and rapid responses when introduced to various concentrations of Ca2+. In both 0.01 M KCl and 0.01 M NaCl ionic strength buffer solutions, the sensors exhibited near Nernstian responses with detection limits of less than 10-7 M, and a linear response range between 10-7-10-2 M. Also, detection limits of less than 10-6 M were achieved for the sensors in both 0.01 M MgCl2 and 0.01 M LiCl buffer solutions. AlGaN/GaN-based devices for Ca2+ detection demonstrate excellent selectivity and response range for a wide variety of applications. This work represents an important step towards multi-ion sensing using arrays of ion-selective field effect transistor (ISFET) devices.

Stable AuIII complexes with four N-heterocyclic carbene groups can be prepared in high yield directly from KAuCl4.

Gold(iii) N-heterocyclic carbene (NHC) complexes of form [Au(NHC)4Cl2]Cl were synthesized by reaction of KAuCl4 with bis- and tetrakis(imidazolium) salts in the presence of a mild base. Treatment of these complexes with KPF6 afforded four-coordinate AuIII complexes of form [Au(NHC)4](PF6)3. X-Ray crystallography showed the [AuIII(NHC)4]3+ cations in the hexafluorophosphate salts to have a square planar Au(NHC)4 moiety [AuCNHC 2.024(4)-2.082(7) Å]. In the [AuIII(NHC)4Cl2]+ cations in the chloride salts, coordination about Au was tetragonally-distorted octahedral, the axial Au-Cl bonds being substantially longer [AuCl 3.148(2)-3.693(1) Å] than the equatorial Au-CNHC bonds [AuC 2.024(4)-2.082(7) Å]. NMR and conductance studies suggested that the structures of the complexes seen in the solid state persisted in DMSO solution, except in one case where a chlorido ligand dissociated from [AuIII(NHC)4Cl2]+ to form [AuIII(NHC)4Cl]2+. The AuIII(NHC)4 unit was surprisingly robust. An AuIII complex was found to undergo H/D exchange reactions in D2O solution at 100 °C with no signs of decomposition detectable by 1H NMR spectroscopy. 1H NMR studies showed that various complexes containing AuIII(NHC)4 moieties underwent little or no decomposition when heated at 120 °C in DMSO-d6 for extended periods.

Dinuclear Au(i) N-heterocyclic carbene complexes derived from unsymmetrical azolium cyclophane salts: potential probes for live cell imaging applications.

We have synthesized a new series of azolium cyclophanes and used them as precursors of inherently luminescent dinuclear Au(i)-N-heterocyclic carbene (NHC) complexes. The azolium cyclophanes contained two azolium groups (either imidazolium or benzimidazolium), an o-xylyl group, and an alkyl linker chain (either C2, C3 or C4). All of the azolium cyclophanes were characterised by X-ray diffraction studies and VT NMR studies, and all were fluxional in solution on the NMR timescale. The C3- and C4-linked azolium cyclophanes served as precursors of Au2L2(2+) complexes (L is a cyclophane bis(NHC) ligand). Due to the unsymmetrical nature of the azolium cyclophanes, the Au2L2(2+) complexes each existed as cis and trans isomers. X-ray diffraction studies showed that the Au2L2(2+) complexes had short intramolecular AuAu distances, in the range 2.9-3.3 Å, suggestive of an aurophilic attraction, presumably as a consequence of the geometrical constraints imposed by the cyclophane bis(NHC) ligands. The complexes having the shortest AuAu distances (i.e., those based on C3-linked cyclophanes) exhibited intense luminescence in solution. The uptake of one of the dinuclear Au-NHC complexes by tumorigenic cells, and its subsequent distribution and toxicity in the cells, was monitored by luminescence microscopy over 6 h and proliferation measurements, respectively.

Pore size dynamics in interpenetrated metal organic frameworks for selective sensing of aromatic compounds.

The two-fold interpenetrated metal-organic framework, [Zn2(bdc)2(dpNDI)]n (bdc=1,4-benzenedicarboxylate, dpNDI=N'N'-di(4-pyridyl)-1,4,5,8-naphthalenediimide) can undergo structural re-arrangement upon adsorption of chemical species changing its pore structure. For a competitive binding process with multiple analytes of different sizes and geometries, the interpenetrated framework will adopt a conformation to maximize the overall binding interactions. In this study, we show for binary mixtures that there is a high selectivity for the larger methylated aromatic compounds, toluene and p-xylene, over the small non-methylated benzene. The dpNDI moiety within [Zn2(bdc)2(dpNDI)]n forms an exciplex with these aromatic compounds. The emission wavelength is dependent on the strength of the host-guest CT interaction allowing these compounds to be distinguished. We show that the sorption selectivity characteristics can have a significant impact on the fluorescence sensor response of [Zn2(bdc)2(dpNDI)]n towards environmentally important hydrocarbons based contaminants (i.e., BTEX, PAH).

Improving the cellular invasion into PHEMA sponges by incorporation of the RGD peptide ligand: the use of copolymerization as a means to functionalize PHEMA sponges.

A monomer that contained the RGD ligand motif was synthesized and copolymerized with 2-hydroxyethyl methacrylate using polymerization-induced phase separation methods to form poly(2-hydroxyethyl methacrylate)-based hydrogel sponges. The sponges had morphologies of aggregated polymer droplets and interconnected pores, the pores having dimensions in the order of 10 µm typical of PHEMA sponges. RGD-containing moieties appeared to be evenly distributed through the polymer droplets. Compared to PHEMA sponges that were not functionalized with RGD, the new sponges containing RGD allowed greater invasion by human corneal epithelial cells, by advancing the attachment of cells to the surface of the polymer droplets.

Enhanced deep-blue emission from Pt(II) complexes bound to 2-pyridyltetrazolate and an ortho-xylene-linked bis(NHC)cyclophane.

The coordination of 2-pyridyltetrazolate and ortho-xylene-linked bis(NHC)cyclophane to Pt(II) yielded a novel complex characterised by enhanced pure deep-blue emission, whose intensity can be modulated via methylation of the tetrazole ring.

Biodegradation of poly(2-hydroxyethyl methacrylate) (PHEMA) and poly{(2-hydroxyethyl methacrylate)-co-[poly(ethylene glycol) methyl ether methacrylate]} hydrogels containing peptide-based cross-linking agents.

PHEMA-peptide and P[HEMA-co-(MeO-PEGMA)]-peptide conjugate hydrogels [where PHEMA = poly(2-hydroxyethyl methacrylate; PEGMA = poly(ethylene glycol) methacrylate] were readily prepared via photoinitiated free-radical polymerization in water. The PHEMA-peptide hydrogels were opaque and had a heterogeneous morphology of interconnected polymer droplets, characteristic of polymers that separate from the aqueous phase during the polymerization experiment. The P[HEMA-co-(MeO-PEGMA)]-peptide conjugates were transparent gels with a homogeneous morphology when formed in water, but when formed in aqueous NaCl solutions the P[HEMA-co-(MeO-PEGMA)]-peptide conjugates were also opaque and exhibited the heterogeneous morphology of interconnected polymer droplets. When incubated in solutions containing activated papain, P[HEMA-co-(MeO-PEGMA)]-peptide conjugates underwent degradation that was characterized by macroscopic changes to sample shape and size, sample weight, and microscopic structure. PHEMA-peptide conjugates did not undergo any significant degradation when incubated with papain, although ninhydrin-staining experiments suggested that some peptide cross-linker groups were cleaved during the incubation. The difference in degradation behavior of PHEMA-peptide and P[HEMA-co-(MeO-PEGMA)]-peptide conjugates is attributed to differences in aqueous solubility of PHEMA and P[HEMA-co-(MeO-PEGMA)].

A new binding geometry for an ortho-xylylene-linked bis(NHC)cyclophane: a ruthenium(II) complex with a chelating (eta(1)-NHC)2:eta(6)-arene ligand.

Using two different reaction procedures, a Ru(II) complex has been isolated that contains an ortho-xylylene-linked bis(NHC)cyclophane (NHC = N-heterocyclic carbene) that binds to the Ru centre through two carbene carbons and one of the arene rings in an eta(6)-mode.

Octapi interactions: self-assembly of a Pd-based [2]catenane driven by eightfold pi interactions.

An unprecedented 2.5 nm array of pi interactions between eight aromatic rings drives the formation of a [2]catenane. Disruption of this array through the use of longer ligands results in the formation of only single, uncatenated rings. The catenated complex is shown to persist in solution alongside its constituent metallomacrocycles.

Palladium complexes of o-xylyl-linked alkoxybenzimidazolin-2-ylidenes: interesting structural conformations and application as pre-catalysts.

New PdBr(2)-bis(N-heterocyclic carbene) complexes derived from 4,7-dibutoxybenzimidazole and 5,6-dibutoxybenzimidazole have been synthesized and structurally and spectroscopically characterized. The complexes show much greater solubility compared to the parent complex derived from benzimidazole, and interesting structural characteristics dependent on the position of the butoxy substituents. The complexes display high activities in the coupling of aryl iodides in the Mizoroki-Heck reaction and moderate activities in the Suzuki-Miyaura coupling of inactivated aryl bromides at low catalyst loadings, although activity differences between pre-catalysts has been observed. Structural studies suggest electronic effects within the complexes to be strongly affected by steric interactions between the hydrogen atoms of the o-xylyl bridges and the benzimidazole components and their substituents.

Azolium-linked cyclophanes: effects of structure, solvent, and counteranions on solution conformation behavior.

This paper describes the synthesis, structural characterization, and solution behavior of some xylyl-linked imidazolium and benzimidazolium cyclophanes decorated with alkyl or alkoxy groups. The addition of alkyl/alkoxy chains to the cyclophanes allows for studies in chlorinated solvents, whereas previous solution studies of azolium cyclophanes have generally required highly polar solvents. The azolium cyclophanes may exist in a syn/syn conformation (azolium rings mutually syn, arene rings mutually syn) or a syn/anti conformation (azolium rings mutually syn, arene rings mutually anti). The preferred conformation is significantly affected by (i) binding of bromide (ion pairing) to the protons on the imidazolium or benzimidazolium rings, which occurs in solutions of bromide salts of the cyclophanes in chlorinated solvents, and (ii) the addition of alkoxy groups to the benzimidazolium cyclophanes. These structural modifications have also led to cyclophanes that adopt conformations not previously identified for similar azolium cyclophane analogues. Detailed (1)H NMR studies for one cyclophane identified binding of bromide at two independent sites within the cyclophane.

Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols.

A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single molecule. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiological pH the rate constants for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compound is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.

Bioenergetic differences selectively sensitize tumorigenic liver progenitor cells to a new gold(I) compound.

A hallmark of cancer cells is their ability to evade apoptosis and mitochondria play a critical role in this process. Delineating mitochondrial differences between normal and cancer cells has proven challenging due to the lack of matched cell lines. Here, we compare two matched liver progenitor cell (LPC) lines, one non-tumorigenic [p53-immortalized liver (PIL) 4] and the other tumorigenic (PIL2). Analysis of these cell lines and a p53 wild-type non-tumorigenic cell line [bipotential murine oval liver (BMOL)] revealed an increase in expression of genes encoding the antiapoptotic proteins cellular inhibitor of apoptosis protein (cIAP) 1 and yes associate protein in the PIL2 cells, which resulted in an increase in the protein encoded by these genes. PIL2 cells have higher mitochondrial membrane potential (Deltapsi(m)) compared with PIL4 and BMOL and had greater levels of reactive oxygen species, despite the fact that the mitochondrial antioxidant enzyme, manganese superoxide disumutase, was elevated at transcript and protein levels. Taken together, these results may account for the observed resistance of PIL2 cells to apoptotic stimuli compared with PIL4. We tested a new gold compound to show that hyperpolarized Deltapsi(m) led to its increased accumulation in mitochondria of PIL2 cells. This compound selectively induces apoptosis in PIL2 cells but not in PIL4 or BMOL. The gold compound depolarized the Deltapsi(m), depleted the adenosine triphosphate pool and activated caspase-3 and caspase-9, suggesting that apoptosis was mediated via mitochondria. This investigation shows that the non-tumorigenic and tumorigenic LPCs are useful models to delineate the role of mitochondrial dysfunction in tumorigenesis and for the future development of mitochondria-targeted chemotherapeutics that selectively target tumor cells.

Cationic, linear Au(I) N-heterocyclic carbene complexes: synthesis, structure and anti-mitochondrial activity.

Six linear, two-coordinate cationic Au(I) N-heterocyclic carbene complexes of the form [(R2Im)2Au]+ (R = Me 1, Me, Et 2, i-Pr 3, n-Bu 4, t-Bu 5 and Cy 6) have been prepared by the reaction of two equivalents of the appropriate dialkylimidazol-2-ylidene (R2Im) with (Me2S)AuCl in dmf. Single crystal structural studies for 1.PF6, 2.PF6), 3.Cl and 4-6.PF6 show that for all six complexes the gold(I) centres have quasi-linear C-Au-C coordination, with quasi-parallel pairs of aromatic imidazole planes, except in 5.PF6 where they are quasi-normal; in the latter, Au-C are 2.038(3), 2.033(3) A, cf. (e.g.) 2.027(2) A. Inter-cation Au...Au are close at 3.487(2), 3.525(2) A in 1PF6 and 2.PF6. The structural studies and low temperature NMR experiments provide no supportive evidence for the presence of pi back-bonding within this series of complexes. The lipophilicities of the six compounds, as estimated from the logarithm of the n-octanol-water partition coefficients (log P), varied across the series within the range -1.09 to 1.73. To investigate their potential as possible anti-mitochondrial anti-tumour agents, five of the compounds have been evaluated for their propensities to induce mitochondrial membrane permeabilization (MMP) in isolated rat liver mitochondria. At concentrations between 1-10 microM compounds 1.Br and 3-6.Cl induced dose-dependent, Ca2+-sensitive mitochondrial swelling at rates that increased with the lipophilicities of the complexes, with the most lipophilic compounds inducing the most rapid onset of swelling. The swelling was completely inhibited by cyclosporin A, the specific inhibitor of the mitochondrial permeability transition pore.

Synthetic, structural and spectroscopic studies of (pseudo)halo(1,3-di-tert-butylimidazol-2-ylidine)gold complexes.

A series of (pseudo)halo(1,3-di-tert-butylimidazol-2-ylidine)gold complexes [(But2Im)AuX](X = Cl, Br, I, CN, N3, NCO, SCN, SeCN, ONO2, OCOCH3, CH3) have been synthesized and characterised spectroscopically and structurally. 13C NMR chemical shifts for the carbene carbon vary widely with differing ancillary anion, correlating well with the sigma-donor ability of the latter and with the M-C(carbene) bond distance. These results reinforce the notion that N-heterocyclic carbene ligands are primarily sigma-donor ligands with little pi-acceptor ability.

Azolium-linked cyclophanes: a comprehensive examination of conformations by 1H NMR spectroscopy and structural studies.

The synthesis and characterization of a series of azolium-linked cyclophanes are reported. The cyclophanes consist of two azolium groups (17 examples) or three imidazolium groups (1 example) linked to two benzenoid units (benzene, naphthalene, p-xylene, mesitylene, 1,2,3,4- and 1,2,4,5-tetramethylbenzene, 2,6-pyridine, and p-tert-butylphenol) via methylene groups. Cyclophanes containing ortho-, meta-, and para-substitution patterns in the benzenoid units were examined. The conformations of the cyclophanes were examined in solution by variable-temperature NMR studies and in the solid state by crystallographic studies. The p-cyclophanes and mesitylene-based m- and o/m-cyclophanes are rigid on the NMR time scale, as indicated by sharp (1)H NMR spectra at all accessible temperatures. The non-mesitylene-based m-cyclophanes and the o-cyclophanes are fluxional on the NMR time scale at high temperatures, but in most cases, specific conformations can be "frozen out" at low temperatures. Many structures deduced from solution studies were consistent with those in the solid state.

Dinuclear N-heterocyclic carbene complexes of silver(I), derived from imidazolium-linked cyclophanes.

The synthesis of four new silver complexes of bidentate N-heterocyclic carbenes, derived from imidazolium-linked cyclophanes, has been achieved via a simple complexation reaction of the imidazolium-linked cyclophanes with the basic metal source Ag(2)O. The cyclophane structures contain two imidazolyl links between ortho-, meta- and mixed ortho/meta-substituted aromatic rings. The new silver carbene systems are thermally stable and have been characterised by NMR spectroscopy and X-ray crystallography. Three of the complexes have a dimeric structure of the form [L(2)Ag(2)](2+) in the solid state that is rigid on the NMR timescale in solution. The fourth complex has a neutral structure of the form [L(AgBr)(2)], the NMR studies suggesting some lability of the L-Ag bonding in solution.