High‐Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis

Systemic delivery of therapeutic nucleic acids to target cells and tissues outside of the liver remains a major challenge. A biomimetic high‐density lipoprotein nanoparticle (HDL NP) is synthesized for delivery of a cholesteryl‐modified therapeutic nucleic acid to vascular endothelial cells (ECs), a cell type naturally targeted by HDL. HDL NPs adsorb cholesteryl‐modified oligonucleotides and protect them from nuclease degradation. As proof of principle, we deliver RNAi targeting vascular endothelial growth factor receptor 2 (VEGFR2) to ECs to effectively silence target mRNA and protein expression in vitro. In addition, data show that treatment strongly attenuates in vivo neovascularization measured using a standard angiogenesis assay and in hypervascular tumor allografts where a striking reduction in tumor growth is observed. For effective delivery, HDL NPs require the expression of the cell surface protein scavenger receptor type‐B1 (SR‐B1). No toxicity of HDL NPs is measured in vitro or after in vivo administration. Thus, by using a biomimetic approach to nucleic acid delivery, data demonstrate that systemically administered RNAi–HDL NPs target SR‐B1 expressing ECs to deliver functional anti‐angiogenic RNAi as a potential treatment of cancer and other neovascular diseases.     

Tuning azolium azolate ionic liquids to promote surface interactions with titanium nanoparticles leading to increased passivation and colloidal stability

The passivation and stability of suspensions of titanium nanoparticles in azolium azolate ionic liquids can be tuned by introducing metal specific binding sites in the azolate anion.     

Live cell imaging of lysosomal pH changes with pH responsive ratiometric lanthanide probes

Europium and terbium complexes of two structurally related ligands have been evaluated as optical probes to monitor changes in lysosomal pH; calibration using ionophores and fluorescent probes allows monitoring of the time dependence of lysosomal pH change, examining the green/red intensity ratio from internalised Tb-Eu complexes.     

Atmospheric pressure plasma induced grafting of poly(ethylene glycol) onto silicone elastomers for controlling biological response

This study investigates the role that surface functionalisation of silicone elastomer (SE) by atmospheric pressure plasma induced graft immobilisation of poly(ethylene glycol) methyl ether methacrylate (PEGMA) plays in the attendant biological response. SE is used in modern ophthalmic medical devices and samples of the material were initially plasma treated using a dielectric barrier discharge reactor (DBD) to introduce reactive oxygen functionalities, prior to in situ grafting of two molecular weights of PEGMA (MW 1000 Da: PEGMA(1000), MW 2000 Da: PEGMA(2000)). The variously processed surfaces were characterised by water contact angle analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry and atomic force microscopy. Lens epithelial cells were then cultured on the PEGMA grafted SE surfaces. It was found that cells on the pristine surface were not well spread and had shrunken morphology. On the DBD pre-treated surfaces, the cells were well spread. On the PEGMA(1000) surface, the cells displayed evidence of shrinkage and were on the verge of detaching. Remarkably, on the PEGMA(2000) surface, no cell adhesion was detection. Bacterial adhesion to the surfaces was studied using Staphylococcus aureus NTC8325. There was no difference in the number of bacteria adhering to any of the surfaces studied.     

Molecular packing in highly stable glasses of vapor-deposited tris-naphthylbenzene isomers

Physical vapor deposition of organic molecules can produce glasses with high kinetic stability and low enthalpy. Previous experiments utilizing wide-angle x-ray scattering (WAXS) have shown that, relative to the ordinary glasses prepared by cooling the supercooled liquid, such glasses exhibit excess scattering characteristic of anisotropic packing. We have used vapor deposition to prepare glasses of four isomers of tris-naphthylbenzene (TNB), and measured both the WAXS patterns and the kinetic stability. While vapor-deposited glasses of all four TNB isomers exhibit high and nearly uniform kinetic stability, the level of excess scattering varies significantly. In addition, for α,α,β-TNB, glasses of essentially identical kinetic stability can have excess scattering levels that vary by a factor of two. These results indicate that anisotropic packing is not the source of kinetic stability in vapor-deposited glasses but rather a secondary feature that depends upon the chemical structure of the glass-forming molecules. We also show that the time required for these stable vapor-deposited glasses to transform into the supercooled liquid greatly exceeds the structural relaxation time τ(α) of the liquid and scales approximately as τ(α) (0.6). The kinetic stability of the vapor-deposited TNB glasses matches that expected for ordinary glasses that have been aged for 10(2) to 10(7) years.     

The reaction of protonated dimethyl ether with dimethyl ether: temperature and isotope effects on the methyl cation transfer reaction forming trimethyloxonium cation and methanol.

Fourier transform ion cyclotron resonance mass spectrometry has been used to study the temperature and deuterium isotope effects on the methyl cation transfer reaction between protonated dimethyl ether and dimethyl ether to produce trimethyloxonium cation and methanol. From the temperature dependence of this bimolecular reaction it was possible to obtain thermodynamic information concerning the energy barrier for methyl cation transfer for the first time. From the slope of an Arrhenius plot, a value for DeltaH(++) of -1.1 +/- 1.2 kJ mol(-1) was obtained, while from the intercept a value for DeltaS(++) of -116 +/- 15 J K(-1) mol(-1) was derived. This yields a DeltaG(++)(298) value of 33.7 +/- 2.1 kJ mol(-1). All thermodynamic values were in good agreement with ab initio calculations. Rate constant ratios for the unimolecular dissociation forming trimethyloxonium cation and the dissociation re-forming reactants were extracted from the apparent bimolecular rate constant. Attempts at modeling the temperature dependence and isotope effects of the unimolecular dissociation forming trimethyloxonium cation were also made.     

Thermochemical ladders: scaling the ramparts of gaseous ion energetics

The use of multiple overlapping gaseous ion–molecule equilibrium measurements to construct thermochemical ladders is reviewed. The types of relative thermochemical data, which may be obtained, are summarized and the types of measurements required to convert the relative equilibrium affinity scales to absolute thermochemical quantities are discussed. The important thermochemical scales produced include proton affinities, gas phase acidities, ionization energies, electron affinities, carbocation stabilities, hydrogen bond energies, Lewis acidities, and metal cation affinities.     

Quasi-static intergranular brittle fracture: Dynamic embrittlement

A mode of brittle fracture is described which is fundamentally different from the rapid transgranular cleavage or intergranular decohesion that is usually associated with that term. It involves stress-induced diffusion of surface-adsorbed embrittling elements along grain boundaries, and it occurs by slow, step-wise crack growth, the rate of which can, in principle, be calculated from the knowledge of the relevant intergranular diffusion coefficient, the stress profile at the crack tip and the dependence of the stress for grain-boundary decohesion on the concentration of the embrittling element. This mode of fracture is postulated to be possible in any high-strength alloy with a low-melting-point element adsorbed on the surface if the applied stress is high enough. Known examples include the brittle type of stress-relief cracking in steels, tin-induced cracking of Cu-Sn alloys, oxygen-induced cracking of iron-, copper-, and nickel-based alloys, and the group of phenomena known as liquid-metal embrittlement and solid-metal embrittlement.The paper is dedicated to Dr. Frantiek Kroupa in honour of his 70^th birthday.This work is supported by National Science Foundation Grant CMS 95-03980.