Establishing a Robust and Reliable Response from a Potent Osmium-Based Photosensitizer Via Lipid Nanoformulation†

Osmium (Os) based photosensitizers (PSs) are a unique class of nontetrapyrrolic metal-containing PSs that absorb red light. We recently reported a highly potent Os(II) PS, rac-[Os(phen)₂(IP-4T)](Cl)₂, referred to as ML18J03 herein, with light EC₅₀ values as low as 20 pm . ML18J03 also exhibits low dark toxicity and submicromolar light EC₅₀ values in hypoxia in some cell lines. However, owing to its longer oligothiophene chain, ML18J03 is not completely water soluble and forms 1–2 μm sized aggregates in PBS containing 1% DMSO. This aggregation causes variability in PDT efficacy between assays and thus unreliable and irreproducible reports of in vitro activity. To that end, we utilized PEG-modified DPPC liposomes (138 nm diameter) and DSPE-mPEG₂₀₀₀ micelles (10.2 nm diameter) as lipid nanoformulation vehicles to mitigate aggregation of ML18J03 and found that the spectroscopic properties important to biological activity were maintained or improved. Importantly, the lipid formulations decreased the interassay variance between the EC₅₀ values by almost 20-fold, with respect to the unformulated ML18J03 when using broadband visible light excitation (P = 0.0276). Herein, lipid formulations are presented as reliable platforms for more accurate in vitro photocytotoxicity quantification for PSs prone to aggregation (such as ML18J03) and will be useful for assessing their in vivo PDT effects.     

Using Biological Photophysics to Map the Excited-State Topology of Molecular Photosensitizers for Photodynamic Therapy

This study employs TLD1433, a Ru^II-based photodynamic therapy (PDT) agent in human clinical trials, as a benchmark to establish protocols for studying the excited-state dynamics of photosensitizers (PSs) in cellulo, in the local environment provided by human cancer cells. Very little is known about the excited-state properties of any PS in live cells, and for TLD1433, it is terra incognita. This contribution targets a general problem in phototherapy, which is how to interrogate the light-triggered, function-determining processes of the PSs in the relevant biological environment, and establishes methodological advances to study the ultrafast photoinduced processes for TLD1433 when taken up by MCF7 cells. We generalize the methodological developments and results in terms of molecular physics by applying them to TLD1433’s analogue TLD1633, making this study a benchmark to investigate the excited-state dynamics of phototoxic compounds in the complex biological environment.     

Aspherical‐Atom Modeling of Coordination Compounds by Single‐Crystal X‐ray Diffraction Allows the Correct Metal Atom To Be Identified

Single‐crystal X‐ray diffraction (XRD) is often considered the gold standard in analytical chemistry, as it allows element identification as well as determination of atom connectivity and the solid‐state structure of completely unknown samples. Element assignment is based on the number of electrons of an atom, so that a distinction of neighboring heavier elements in the periodic table by XRD is often difficult. A computationally efficient procedure for aspherical‐atom least‐squares refinement of conventional diffraction data of organometallic compounds is proposed. The iterative procedure is conceptually similar to Hirshfeld‐atom refinement (Acta Crystallogr. Sect. A­ 2008 , 64, 383–393; IUCrJ. 2014 , 1,61–79), but it relies on tabulated invariom scattering factors (Acta Crystallogr. Sect. B­ 2013 , 69, 91–104) and the Hansen/Coppens multipole model; disordered structures can be handled as well. Five linear‐coordinate 3d metal complexes, for which the wrong element is found if standard independent‐atom model scattering factors are relied upon, are studied, and it is shown that only aspherical‐atom scattering factors allow a reliable assignment. The influence of anomalous dispersion in identifying the correct element is investigated and discussed.     

Chemical exchange magnetic resonance imaging (CHEMI)

Systems investigated with NMR spectroscopy are sometimes heterogeneous with respect to chemical composition, rates of chemical exchange, and other properties influencing magnetic resonance parameters. A method was developed to spatially encode reaction kinetic information and produce NMR images sensitive to chemical exchange. A modified spin-echo pulse sequence was used to allow chemical shift-selective imaging and chemical exchange encoding. 1H and 31P images with microscopic resolution were obtained which yielded chemical exchange as a function of position. Chemical exchange images of the base-catalyzed proton exchange of acetylacetone and of the enzyme-catalyzed 31P transfer between PCr and ATP were obtained at 8.4 T in phantoms at 360 and 146 MHz, respectively. These images demonstrate a means of investigating kinetic heterogeneity and compartmentalization of reactions that are important in the study of both living and non-living systems.     

Effect of incident shock wave strength on the decay of Richtmyer–Meshkov instability-introduced perturbations in the refracted shock wave

The effect of incident shock wave strength on the decay of interface introduced perturbations in the refracted shock wave was studied by performing 20 different simulations with varying incident shock wave Mach numbers (M ~ 1.1? 3.5). The analysis showed that the amplitude decay can be represented as a power law model shown in Eq.7, where A is the average amplitude of perturbations (cm), B is the base constant (cm^?(E?1), S is the distance travelled by the refracted shockwave (cm), and E is the power constant. The proposed model fits the data well for low incident Mach numbers, while at higher mach numbers the presence of large and irregular late time oscillations of the perturbation amplitude makes it hard for the power law to fit as effectively. When the coefficients from the power law decay model are plotted versus Mach number, a distinct transition region can be seen. This region is likely to result from the transition of the post-shock heavy gas velocity from subsonic to supersonic range in the lab frame. This region separates the data into a high and low Mach number region. Correlations for the power law coefficients to the incident shock Mach number are reported for the high and low Mach number regions. It is shown that perturbations in the refracted shock wave persist even at late times for high incident Mach numbers.     

High‐Throughput Synthesis and Screening of Combinatorial Heterogeneous Catalyst Libraries

In less than one minute the catalytic activity and selectivity of a single catalyst was measured in combinatorial libraries of ternary Rh‐Pd‐Pt‐Cu alloys. Only slightly more than two hours were needed to complete a library with 136 elements. The elements of the libraries (ca. 2–4 μg of material) are contained in a two‐dimensional array synthesized by a thin‐film technique. The analysis was performed by a scanning mass spectrometer (see picture).     

Wavelet-bounded empirical mode decomposition for vibro-impact analysis

Nonlinear Dynamics - We consider the response of a single-degree-of-freedom, linear oscillator (LO) coupled to a vibro-impact (VI) nonlinear energy sink (NES), and subject to an impulsive load. A...     

Synthesis and Characterization of Ru(II) Complexes with π-Expansive Imidazophen Ligands for the Photokilling of Human Melanoma Cells

Ru(II) complexes were synthesized with π-expanding (phenyl, fluorenyl, phenanthrenyl, naphthalen-1-yl, naphthalene-2-yl, anthryl and pyrenyl groups) attached at a 1H-imidazo[4,5-f][1,10]phenanthroline ligand and 4,4′-dimethyl-2,2′-bipyridine (4,4′-dmb) coligands. These Ru(II) complexes were characterized by 1D and 2D NMR, and mass spectroscopy, and studied for visible light and dark toxicity to human malignant melanoma SK-MEL-28 cells. In the SK-MEL-28 cells, the Ru(II) complexes are highly phototoxic (EC₅₀ = 0.2–0.5 µm ) and have low dark toxicity (EC₅₀ = 58–230 µm ). The highest phototherapeutic index (PI) of the series was found with the Ru(II) complex bearing the 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline ligand. This high PI is in part attributed to the π-rich character added by the pyrenyl group, and a possible low-lying and longer-lived ³IL state due to equilibration with the ³MLCT state. While this pyrenyl Ru(II) complex possessed a relatively high quantum yield for singlet oxygen formation (Φ_∆ = 0.84), contributions from type-I processes (oxygen radicals and radical ions) are competitive with the type-II (¹O₂) process based on effects of added sodium azide and solvent deuteration.