Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy.

Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.

A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration-dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH.

Platinum(II) complexes of N

A new family of platinum(II) complexes of the form PtL(n)SR have been prepared, where L(n) represents a cyclometalating, N^C^N-bound tridentate ligand and SR is a monodentate thiolate ligand. The complexes fall into two groups, those of PtL(1)SR where HL(1) = 1,3-bis(2-pyridyl)benzene, and those of PtL(2)SR, where HL(2) = methyl 3,5-bis(2-pyridyl)benzoate. Each group consists of five complexes, where R = CH3, C6H5, p-C6H4-CH3, p-C6H4-OMe, p-C6H4-NO2. These compounds, which are bright red, orange, or yellow solids, are formed readily upon treatment of PtL(n)Cl with the corresponding potassium thiolate KSR in solution at room temperature. The replacement of the chloride by the thiolate ligand is accompanied by profound changes in the photophysical properties. A broad, structureless, low-energy band appears in the absorption spectra, not present in the spectra of PtL(n)Cl. In the photoluminescence spectra, the characteristic, highly structured phosphorescence bands of PtL(n)Cl in the green region are replaced by a broad, structureless emission band in the red region. These new bands are assigned to a πS/dPt → π*N^C^N charge-transfer transition from the thiolate/platinum to the N^C^N ligand. This assignment is supported by electrochemical data and TD-DFT calculations and by the observation that the decreasing energies of the bands correlate with the electron-donating ability of the substituent, as do the increasing nonradiative decay rate constants, in line with the energy-gap law. However, the pair of nitro-substituted complexes do not fit the trends. Their properties, including much longer luminescence lifetimes, indicate that the lowest-energy excited state is localized predominantly on the arenethiolate ligand for these two complexes. Red-emitting thiolate adducts may be relevant to the use of PtL(n)Cl complexes in bioimaging, as revealed by the different distributions of emission intensity within live fibroplast cells doped with the parent complex, according to the region of the spectrum examined.

An unprecedented cyclometallated platinum(II) complex incorporating a phosphinine co-ligand: synthesis and photoluminescence behaviour.

The first luminescent cyclometallated platinum(II) complex bearing phosphinine co-ligands is reported. The long-lived luminescence, which it displays at 77 K, is assigned to a phosphinine-localised triplet excited state on the basis of electrochemical data and TD-DFT calculations.

Phosphorescent, liquid-crystalline complexes of platinum(II): influence of the ß-diketonate co-ligand on mesomorphism and emission properties.

Two series of rod-like ortho-platinated complexes bound to a range of ß-diketonate co-ligands are reported of the form [Pt(N^C)(O^O)]. The liquid crystal and luminescent properties are influenced through the introduction of different ß-diketonates (O^O) as well as through the presence of a fused cyclopentene ring on the N^C-coordinated 2-phenylpyridine ligand. For metal complexes, smectic phases are dominant but no mesomorphism is exhibited when the ß-diketonate is hexafluorinated acetylacetonate (1,1,1-5,5,5-hexafluoro-2,4-pentandione). The introduction of an unsymmetrical trifluoroacetyl acetonate (1,1,1-trifluoro-2,4-pentandione) ligand is particularly interesting due to the discovery of the ß-diketonate as a dynamic system that readily isomerises to a 1:1 ratio under thermal conditions, from an initial ratio of 3:1 formed during the synthesis. As expected, the presence of the 3,5-heptanedionato co-ligand decreases the transition temperatures due to the introduction of a larger lateral substituent. Unfortunately complexes based on 2-phenylpyridine ligands with a fused cyclopentene ring are, with one exception, not mesomorphic. With the exception of the hexafluoroacetyl acetonate complexes, the materials are brightly luminescent and have excited state lifetimes between 13 and 30 µs with emission quantum efficiencies exceeding 0.5, with one as high as 0.7. A time-dependent density functional theory (TD-DFT) study suggests that the lack of emission from the hexafluoroacetyl acetonate complexes may be associated with large structural distortion upon formation of the excited state, as well as to poorer overlap of orbitals leading to a lower radiative rate constant. The same analysis provides an explanation for the apparently quite different emission efficiencies of the two isomers of the trifluoroacetyl acetonate complexes.

Aqueous methods for the preparation of 5'-substituted guanosine derivatives.

We have developed simple, aqueous strategies, that avoid the use of protecting groups and chromatography, for the preparation of a series of 5'-substituted guanosine derivatives.