Development of a novel beta-glucan supplemented hydrogel spray formulation and wound healing efficacy in a db/db diabetic mouse model.

To relieve the severe economic and social burdens and patient suffering caused by the increasing incidence of chronic wounds, more effective treatments are urgently needed. In this study, we focused on developing a novel sprayable wound dressing with the active ingredient ß-1,3/1,6-glucan (ßG). Since ßG is already available as the active ingredient in a commercial wound healing product provided as a hydrogel in a tube (ßG-Gel), the sprayable format should bring clinical benefit by being easily sprayed onto wounds; whilst retaining ßG-Gel's physical stability, biological safety and wound healing efficacy. Potentially sprayable ßG hydrogels were therefore formulated, based on an experimental design setup. One spray formulation, named ßG-Spray, was selected for further investigation, as it showed favorable rheological and spraying properties. The ßG-Spray was furthermore found to be stable at room temperature for more than a year, retaining its rheological properties and sprayability. The cytotoxicity of ßG-Spray in keratinocytes in vitro, was shown to be promising even at the highest tested concentration of 100 µg/ml. The ßG-Spray also displayed favorable fluid affinity characteristics, with a capacity to both donate and absorb close to 10% fluid relative to its own weight. Finally, the ßG-Spray was proven comparably effective to the commercial product, ßG-Gel, and superior to both the water and the carrier controls (NoßG-Spray), in terms of its ability to promote wound healing in healing-impaired animals. Contraction was found to be the main wound closure mechanism responsible for the improvement seen in the ßG-treatment groups (ßG-Spray and ßG-Gel). In conclusion, the novel sprayable ßG formulation, confirmed its potential to expand the clinical use of ßG as wound dressing.

Molecular Structure of Copper and µ-Oxodiiron Octafluorocorrole Derivatives: Insights into Ligand Noninnocence.

Single-crystal X-ray structures were obtained for the copper and µ-oxodiiron complexes of 2,3,7,8,12,13,17,18-octafluoro-5,10,15-triphenylcorrole, hereafter denoted as Cu[F8TPC] and {Fe[F8TPC]}2O. A comparison with the crystal structures of other undecasubstituted Cu corroles, including those with H, Ar, Br, I, and CF3 as ß-substituents, showed that the degree of saddling increases in the order: H ≲ F < Ar ≲ Br ≲ I < CF3. In other words, Cu[F8TPC] is marginally more saddled than ß-unsubstituted Cu triarylcorroles, but substantially less saddled than Cu undecaarylcorroles, ß-octabromo-meso-triarylcorroles, and ß-octaiodo-meso-triarylcorroles, and far less saddled than Cu ß-octakis(trifluoromethyl)-meso-triarylcorroles. As for {Fe[F8TPC]}2O, the moderate quality of the structure did not allow us to draw firm conclusions in regard to bond length alternations in the corrole skeleton and hence also the question of ligand noninnocence. The Fe-O bond distances, 1.712(8) and 1.724(8), however, are essentially identical to those observed for {Fe[TPFPC]}2O, where TPFPC3- is the trianion of 5,10,15-tris(pentafluorophenyl)corrole, suggesting that a partially noninnocent electronic structural description may be applicable for both compounds.

Mimicking regional and fasted/fed state conditions in the intestine with the mucus-PVPA in vitro model: The impact of pH and simulated intestinal fluids on drug permeability.

Intestinal drug absorption following oral administration can be influenced by regional conditions (absorbing surface area, bacterial flora, motility, pH, mucus thickness) and food intake, all of which affect drug solubility and permeability. Therefore, it is crucial to assess the impact of these conditions on the drugability of drugs and formulations. In this study, the ability of the liposome-based mucus-PVPA in vitro permeability model to handle relevant intestinal pH conditions was evaluated, together with the investigation on the pH-dependent solubility and permeability profiles of five model drugs. This study additionally evaluated the impact of all commercially available versions of the fasted and fed state simulated intestinal fluids (SIFs) on the integrity of the barriers, and the permeabilities of one hydrophilic and one lipophilic compound were examined under these conditions. The model was found to be well-functioning in all tested pH conditions, and a pH-dependent trend was found for both solubility and permeability profiles for acidic and basic compounds, according to their degree of ionization. Moreover, the mucus layer and its pH-dependent viscosity particularly influenced the permeation of more lipophilic compounds. The PVPA barriers primarily maintained their functionality in the presence of the fed state SIFs, and the permeability of the two tested compounds showed to be influenced by their hydrophilicity/lipophilicity, their degree of interaction with mucus and by the bile salts and phospholipids content in the SIFs. Overall, the obtained results highlight the relevance of studying the effect that pH, mucus and SIFs have on intestinal drug absorption, and suggest the suitability of the mucus-PVPA model for such investigations.

Beta-octafluorocorroles.

The one-pot corrole synthesis first reported by the Gross and Paolesse groups appears to have evolved into a remarkably general and predictable self-assembly based synthetic reaction. Gross's solvent-free procedure (refs 8 and 9) has proven particularly effective in our hands and, in fact, more general than originally claimed. In earlier work (ref 17), we showed that the reaction works for a variety of aromatic aldehyde starting materials and was not limited to relatively electron-deficient aldehydes, as reported by Gross and co-workers. Here, we show that the pyrrole component is also variable in that 3,4-difluoropyrrole undergoes oxidative condensation with four different p-X-substituted benzaldehydes to yield the corresponding beta-octafluoro-meso-tris(para-X-phenyl)corroles (X = CF3, H, CH3, and OCH3). Further, we have prepared the Cu and FeCl derivatives of the beta-octafluorocorrole ligands. The XPS nitrogen 1s ionization potentials of these fluorinated ligands are some 0.7 eV higher than those of the corresponding beta-unfluorinated ligands. The oxidation half-wave potentials of the Cu and FeCl complexes of the fluorinated corroles are also positively shifted by 300-400 mV relative to their beta-unsubstituted analogues, demonstrating the strongly electron-deficient character of the fluorinated ligands. 1H NMR spectroscopy suggests that like their beta-unfluorinated counterparts, the new beta-octafluorinated triarylcorroles act as substantially noninnocent ligands, i.e., exhibit corrole pi-cation radical character, in the FeCl complexes. Quantitatively, however, NMR spectroscopy and DFT calculations indicate that the beta-octafluorinated corroles are somewhat less noninnocent (i.e., carry less radical character) than their beta-unfluorinated counterparts in the FeCl complexes. Temperature-dependent 19F NMR spectroscopy suggests that the Cu octafluorocorroles have a thermally accessible paramagnetic excited state, which we assign as a Cu(II) corrole pi-cation radical. We have previously reported that the electronic absorption spectra, particularly the Soret absorption maxima, of high-valent transition metal triarylcorroles are very sensitive to the nature of the substituents in the meso positions. In contrast, the Soret absorption maxima of free-base triarylcorroles are not particularly sensitive to the nature of the meso substituents. This scenario also holds for the fluorinated corroles described here. Thus, although the four free-base fluorinated triarylcorroles exhibit practically identical Soret absorption maxima, the Soret bands of the Cu derivatives of the same corroles red-shift by approximately 35 nm on going from the p-CF3 to the p-OCH3 derivative.

High-valent transition metal centers versus noninnocent ligands in metallocorroles: insights from electrochemistry and implications for high-valent heme protein intermediates.

For relatively electron-rich corrole ligands, the halfwave potentials for oxidation of Cu(III), Sn(IV)Ph, Fe(IV)Ph, and Fe(IV)-O-Fe(IV) complexes are significantly lower than those of Sn(IV)Cl, Fe(IV)Cl, Mn(IV)Cl, and Cr(V)(O) complexes, suggesting that the corrole ligand is relatively electron-rich or 'innocent' in the former group of complexes and that it is relatively electron-deficient or 'noninnocent' in the latter group. Both the formal charge of the central metal ion and the nature of the axial ligand, if any, appear to be key determinants of the electronic character of the corrole ligand in metallocorrole complexes, a theme that has interesting resonances with recent findings on high-valent heme protein intermediates. However, for very strongly electron-deficient ligands such as meso-tris(pentafluorophenyl)corrole (TPFPC) and beta-octabromo-meso-tris(pentafluorophenyl)corrole (Br(8)TPFPC), which cannot sustain significant radical character, the various metal complexes all exhibit comparable halfwave potentials for oxidation and the ligand may be considered to be relatively innocent.

Resonance Raman spectroscopy and density functional theoretical calculations of manganese corroles. A parallelism between high-valent metallocorroles and metalloporphyrins, relevant to horseradish peroxidase and chloroperoxidase compound I and II intermediates.

Soret-excited resonance Raman (RR) spectra are reported for the Mn(III) and Mn(IV)Cl derivatives of meso-tris(p-(trifluoromethyl)phenyl)corrole, H(3)T(p-CF(3)-P)Cor, and the Mn(III) derivative of beta-octabromo-meso-tris(p-(trifluoromethyl)phenyl)corrole, H(3)Br(8)T(p-CF(3)-P)Cor. Three high-frequency bands in the RR spectrum of Mn(III)[T(p-CF(3)-P)Cor] at 1465, 1524 and 1615 cm(-1) appear to upshift to 1486, 1528 and 1620 cm(-1) for Mn(IV)[T(p-CF(3)-P)Cor]Cl. This suggests that the electronic character of the corrole ligand is significantly different for these two compounds, which is consistent with electrochemical evidence for partial radical character of the corrole ligand for Mn(IV)[T(p-CF(3)-P)Cor]Cl but not for Mn(III)[T(p-CF(3)-P)Cor]. The observed upshifts are also consistent with DFT calculations showing a shortening of some of the relevant bonds in the Mn(IV)Cl derivative relative to the Mn(III) derivative. The results raise the possibility of an extensive parallelism between the electronic structures of high-valent metallocorroles and metalloporphyrins. Three high-frequency bands in the RR spectrum of Mn(III)[T(p-CF(3)-P)Cor] at 1331, 1465 and 1545 cm(-1) appear to downshift to 1320, 1457 and 1537 cm(-1) for Mn(III)[Br(8)T(p-CF(3)-P)Cor]. This is consistent with the suspected longer carbon-carbon bond lengths in the brominated corrole macrocycle.