Compartmentalized Encapsulation of Two Antibiotics in Porous Nanoparticles: an Efficient Strategy to Treat Intracellular Infections

Combinatorial drug therapies emerge among the most promising strategies to treat complex pathologies such as cancer and severe infections. Biocompatible nanoparticles of mesoporous iron carboxylate metal–organic framework (nanoMOFs) are used here to address the challenging aspects related to the coincorporation of two antibiotics. Amoxicillin and potassium clavulanate, a typical example of drugs used in tandem, are efficiently coincorporated with payloads up to 36 wt%. Due to the occurrence of two distinct pore sizes/apertures within the MOF architecture, each drug is able to infiltrate the porous framework and localize within separate compartments. Molecular simulations predict drug loadings and locations consistent with experimental findings. Drug loaded nanoMOFs that are internalized by Staphylococcus aureus infected macrophages are able to colocalize with the pathogen, which in turn leads to an alleviation of bacterial infection. The data also reveal potential antibacterial properties of nanoMOFs alone as well as their ability to deliver a high payload of drugs to fight intracellular bacteria. These results pave the way toward the design of engineered “all‐in‐one” nanocarriers in which both the loaded drugs and their carrier play a role in fighting intracellular infections.     

Comparison of δ81Br and δ37Cl composition of volatiles,salt precipitates,and associated water in terrestrial evaporative saline lake systems

This study provides the first characterization of the variability of bromine and chlorine stable isotopic composition in evaporites, associated residual brines, and shoreline gases in terrestrial evaporative saline lakes. The lakes investigated here are groundwater discharge locations, and include both potash-rich alkaline lakes and sodic-dominated neutral pH lakes at a variety of salinities and evaporative stages. The chlorine and bromine isotope systems behave consistently different during evaporative salt precipitation, with ³⁷Cl more enriched in the salt than in the fluid, but ⁸¹Br more enriched in the fluid compared with the precipitated salt. The ⁸¹Br concentration of shore off-gassing was even smaller than mineral precipitate compositions. The trends observed for bromine isotopes are surprising compared with published laboratory studies, indicating that a process besides inorganic mineral precipitation is affecting δ⁸¹Br. Additional processes explored include diffusion, salt deflation, microbial and photolytic conversion to the gas phase, and oxidative bromination of organic matter.

Dedicated to Professor Peter Fritz on the occasion of his 80th birthday     

Asymmetric synthesis of (−)- and (+)-neodichroine/hydrachine A from (+)- and (−)-febrifugine

A new asymmetric approach to both enantiomers of the quinazolinone-containing natural product febrifugine is reported. Utilising a proline-mediated aminooxylation-Horner-Wadsworth-Emmons sequence provides the key optically active 2,3-disubstituted piperidine intermediate 7 in high enantioselectivity but poor overall yield (7 steps, 3%, 98% ee). This intermediate has been used to prepare both naturally occurring (+)-febrifugine (1) and its (?)-enantiomer. In turn, each were then used to synthesise, for the first time, both enantiomers of the claimed natural product neodichroine/hydrachine A. Spectroscopic data for the synthetic compound matched the claimed structure. However, the specific rotation differed in both magnitude and sign from the isolation work.     

Anisotropic effective core potentials

We present a convenient method for accounting for the anisotropy of partially filled d shells that are incorporated in effective core potentials by including the leading anisotropy term of the d-type electron density, which is the quadrupole moment, as an electrostatic potential energy operator in the model Hamiltonian. We present sample calculations on the cobalt hydride and dicobalt systems. We find the quadrupole anisotropy to have a very large effect in the distance regime of CoH. In the dicobalt system, which has a relatively long internuclear distance, the quadrupole anisotropy shifts the equilibrium bond length by nearly 0.02 bohr.     

Damping oscillatory integrals

Research supported by the Australian Research Council and the Italian Ministero della Pubblica Istruzione     

Poly(arylene sulfides) with pendant cyano groups as high-temperature laminating resins

Poly(phenylene sulfides) were synthesized from m-benzenedithiol and aromatic dibromides in a basic medium of potassium carbonate in dimethylformamide or dimethylacetamide. The products obtained were slightly off-white with relatively low melting ranges and had inherent viscosities in the 0.2–0.4 dl/g range in hexamethylphosphoric triamide. Similar poly(phenylene sulfides) containing pendant cyano groups along the polymer chains were obtained by the use of 5 mole-% of either 2,4-dichlorobenzonitrile or 3,5-dichlorobenzonitrile. The products were similar to the pure polyphenylene sulfides, except that they showed lower melting ranges and gave insoluble products when heated alone or in the presence of zinc chloride.     

Comment and evaluation concerning some partial wave electron scattering factors frequently used in gas electron diffraction

An evaluation is presented of some recently published partial wave electron scattering factors for neutral atoms which are frequently used in structural studies by gas electron diffraction. Significant corrections are given for 3 of the 75 elements which were treated.     

Variation of oxo-transfer reactivity of (nitro)cobalt picket fence porphyrin with oxygen-donating ligands

Derivatives of (nitro)cobalt picket fence porphyrin with oxygen-donating ligands have been prepared in solution and in the solid state. Crystal structures of two of these derivatives, (H2O)CoTpivPP(NO2) and (CH3OH)CoTpivPP(NO2), have been determined. The ethanol complex (C2H5OH)Co(TPP)(NO2) has been obtained and spectrally characterized using sublimed layers methodology. The formation constant and the DeltaH degrees value of the association reaction with ethanol have been determined by FTIR measurements in CCl4 solution. Catalytic oxygen activation and oxo-transfer reactions of these derivatives have been assessed in solution. Correlations between the oxo-transfer reactivity, thermodynamics, and characteristics of the nitro ligand show that although calculated and observed ONO vibrational spectra and bond lengths suggest activation of the NO2 ligand and enhanced oxo-transfer reactions as seen in the analogous five-coordinate complexes, density functional theory calculations support that thermodynamics limits oxo-atom transfer reactions in these six-coordinate systems.     

Orientational order and finite strain in nematic elastomers

Nematic elastomers exhibit large, spontaneous shape changes at the transition from the high-temperature isotropic phase to the low-temperature nematic phase. These finite deformations are studied here in the context of a nonlinear, properly invariant, variational theory that couples the orientational order and elastic deformation. The theory is based on the minimization of a free-energy functional that consists of two contributions: a nematic one due to the interaction of the mesogenic units and an elastic one arising from the stretching of the cross-linked polymer chains. Suitable choices for these two contributions allow for large, reversible, spontaneous shape changes in which the elastic deformation can affect the isotropic-nematic transition temperature. The change in transition temperature as well as the magnitude of the resulting spontaneous deformation is illustrated for various parameter values. The theory includes soft elasticity as a special case but is not restricted to it.     

ROLE OF THE TRYPTOPHAN FLUORESCENT STATE IN THE ULTRAVIOLET-INDUCED INACTIVATION OF β-TRYPSIN*

Abstract— Stern-Volmer quenching constants for β-trypsin at pH 3 were determined for fluorescence quenching by histidine, acrylamide, and nitrate ion. A modified Stern-Volmer plot (Lehrer, 1971) was employed to show that all of the fluorescent tryptophanyl residues of β-trypsin were equally susceptible to quenching by acrylamide at pH 3 when the enzyme was either in its native conformation or denatured in 6 M guanidine hydrochloride (GuHCl). Fluorescence lifetime measurements indicated that acrylamide quenched β-trypsin fluorescence by a purely collisional mechanism. Solvation of tryptophanyl residues of the protein was maximal at 2.5 M GuHCl, as monitored by fluorescence emission wavelength.
Investigations of the ultraviolet-induced inactivation of β-trypsin at 295 nm were performed in the presence of acrylamide at pH 3. The quantum yields for enzyme inactivation and indole destruction (determined using the PDAB reagent) were unchanged upon depopulation of the fluorescent state by 65 per cent, whether the enzyme was in its native conformation or denatured by 6 M GuHCl. It is concluded that the fluorescent state of tryptophanyl residues of β-trypsin is not involved in enzyme inactivation or tryptophan destruction.