Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.     

Effect of the implantation dose and annealing time on the luminescence properties of (113) defects in silicon implanted by oxygen ions

Physics of the Solid State - The photoluminescence properties of (113) defects formed in a silicon structure after the implantation by oxygen ions with an energy of 350 keV and doses of 1.7 ×...     

The temperature dependence of the interaction of oxygen with Pd(111); A study by photoemission and auger spectroscopy

The temperature dependence of the different binding states of oxygen on Pd(111) has been studied using photoemission spectroscopy and Auger spectroscopy. By examining the oxygen 2s binding energies, three distinct states are observed, which are identified as surface chemisorbed oxygen, oxygen incorporated into the first Pd layer, and subsurface oxygen. Changes in the relative oxygen Auger peak heights for 1000 K exposure temperature are explained if the oxygen is assumed to become more negatively charged as it penetrates the Pd surface. A model for the interaction of oxygen with the Pd(111) surface is proposed.     

CO chemisorption on PtCu surfaces I. CO on (1 × 3) Pt0.98Cu0.02(110)

Thermal desorption and photoemission spectroscopy (PES) have been used to investigate the chemisorption of CO on an annealed Pt_0.98Cu_0.02(110) surface. The clean surface shows 9.1 ± 2.6% Cu within the top 4 Å, and is (1 × 3) reconstructed. Thermal desorption of CO has revealed the existence of various adsorption states with these respective heats of adsorption: (α) 35.2 to 37.8 kcal/mol and (β) 24.5 to 26.3 kcal/mol on Pt sites, (γ) 16.0 to 17.2 kcal/mol on PtCu “mixed” sited, and (δ) 12.9 to 13.9 kcal/mol on Cu sites. PES observation of Cu 3d-derived states (using hv = 150 eV) and the $\text{Cu 2p}{}_{\mathrm{<mtext>3</mtext><mtext>2</mtext>}}$ core levels (using Mg Kα radiation) shows that the electronic structure of the Cu constituent is changed only when CO adsorbs on the Pt-Cu “mixed” sites or the Cu sites. Furthermore, the CO states associated with Pt sites reflect the structural difference between the (1 × 3) alloy surface and the (1 × 2) pure Pt(110) surface: α-CO on the alloy surface desorbs at a temperature 17 to 21 K. higher than the maximum desorption temperature of CO from pure Pt(110), and the ratio of β-CO to α-CO desorption from the alloy surface is larger than the ratio of low temperature to high temperature peaks in the desorption of CO from pure Pt(110).     

Extended Defects in O+-Implanted Si Layers and Their Luminescence

Crystallography Reports - The structure and luminescence properties of Czochralski-grown n-Si samples implanted with oxygen ions have been comprehensively analyzed using photoluminescence and...     

Al-induced crystallization of amorphous ge and formation of fractal ge micro-/nanoclusters

Results on Al-induced crystallization of amorphous Ge (a-Ge) deposited by vacuum thermal evaporation techniques under thermal annealing in N(2) atmosphere are presented in detail. The a-Ge crystallization and fractal Ge pattern formation on the free surface of annealed Al/Ge bilayer films deposited on single-crystal Si (100) substrates were investigated by using scanning electron microscopy (SEM), X-ray diffraction (XRD), atomic force microscopy (AFM), energy dispersive X-ray spectrometry (EDS), and Raman spectra. It is found that the temperature field effects play an extremely crucial role in a-Ge crystallization and fractal Ge formation process. The open branched structure of fractal Ge clusters in Al/Ge bilayer films was effectively prepared by Al-induced crystallization when they were annealed at 400 °C for 60 min. These films with fractal Ge clusters exhibit charming noninteger dimensional nanostructures, which differ from those of conventional integer dimensional materials such as one-dimensional nanowires/nanorods, nanotubes, nanobelts/nanoribbons, two-dimensional heterojunctions, thin films, and zero-dimensional nanoparticles. The SEM image shows that a big Al grain was found located near the center of a fractal Ge cluster after the films were annealed at 400 and 500 °C for 60 min. This suggests that the grain boundaries of polycrystalline Al films are the initial nucleation sites of a-Ge. It also validates the preferred nucleation theory of a-Ge at triple-point grain boundaries of polycrystalline Al at the interface. This discovery may be explained by the metal-induced nucleation (MIN) mechanism.     

Cyclometalated Iridium(III)–Polyamine Complexes with Intense and Long‐Lived Multicolor Phosphorescence: Synthesis,Crystal Structure,Photophysical Behavior,Cellular Uptake,and Transfection Properties

A new class of phosphorescent cyclometalated iridium(III)–polyamine complexes [{Ir(N^C)₂}_n(bPEI)](PF₆)_n (bPEI=branched poly(ethyleneimine), average M_w=25 kDa, n=15.6–27.4; HN^C=2‐phenylpyridine Hppy ( 1 a ), 2‐((1,1′‐biphenyl)‐4‐yl)pyridine Hpppy ( 2 a ), 2‐phenylquinoline Hpq ( 3 a ), 2‐phenylbenzothiazole Hbt ( 4 a ), 2‐(1‐naphthyl)benzothiazole Hbsn ( 5 a )) and [Ir(N^C)₂(en)](PF₆) (en=ethylenediamine; HN^C=Hppy ( 1 b ), Hpppy ( 2 b ), Hpq ( 3 b ), Hbt ( 4 b ), Hbsn ( 5 b )) have been synthesized and characterized. The X‐ray crystal structure of complex 5 b was also determined. All of these complexes showed a reversible iridium(IV/III) oxidation couple at +1.01 to +1.26 V and a quasi‐reversible ligand‐based reduction couple at ?1.54 to ?2.08 V (versus SCE). Upon photoexcitation, the complexes displayed intense and long‐lived green to orange–red emission in fluid solutions at room temperature and in low‐temperature glass. Lipophilicity measurements indicated that bPEI played a dominant role in the polar nature of complexes 1 a – 5 a , thus rendering them very soluble in aqueous solutions. Inductively coupled plasma–mass spectrometry (ICP‐MS) and confocal laser scanning microscopy (CLSM) data indicated that an energy‐requiring process, such as endocytosis, was involved in the cellular uptake of all of the complexes. In addition, the cytotoxicity of the complexes toward human cervix epithelioid carcinoma (HeLa) and human embryonic kidney 293T (HEK293T) cell‐lines has been evaluated by the 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The DNA‐binding properties of complex 5 a have been investigated by gel‐retardation assays and the polyplexes that were formed from this complex with plasmid DNA (pDNA) were studied by zeta‐potential measurements and particle‐size estimation. Furthermore, complex 5 a was grafted with poly(ethylene glycol) (PEG, average M_w=2 kDa) to different extents, thereby yielding the phosphorescent copolymers PEG_12.3‐g‐5 a , PEG_25.4‐g‐5 a , and PEG_62.1‐g‐5 a . Interestingly, these copolymers showed enhanced transfection activity, as revealed by in vitro transfection experiments with tissue‐culture‐based luciferase assays.     

Fractal Germanium Patterns: Annealing Strategies and Perspectives of Metal-Induced Crystallization

Semiconductor germanium (Ge) in contact with some metals, such as Al, Pd, and Au, etc., is a class of distinctive materials with non-integer dimensions (D) that differ from integer dimensional materials, such as nanoparticles (0D), nanowires/nanorods//nanotubes/nanoribbons (1D), and thin films (2D). In this article, we describe our efforts toward understanding the annealing strategies and perspectives of metal-induced crystallization for the amorphous Ge embedded in Al, Pd, and Au matrices prepared by high vacuum thermal evaporation techniques, highlighting contributions from our laboratory. First, we present the Al-induced crystallization of amorphous Ge and formation processes of fractal Ge patterns. In addition, the fractal Ge patterns induced by Pd nanoparticles with solid-state reactions will be summarized in detail. Temperature-dependent properties of resistance and fractal dimension in Pd/Ge bilayer films will be expounded. In particular, the nonlinear optical properties are discussed in detail. Finally, we will emphasize the in situ observations by transmission electron microscopy and multi-fractal analysis for the fractal Ge patterns induced by Au nanoparticles. Moreover, the polycondensation-type fractal Ge patterns with non-integer dimensions, thick branches and smooth edges, and metastable gamma-Au_0.6Ge_0.4 are further investigated. The computer simulation indicated that the experimental results are good agreement with the simulation patterns, which were carried out by a ripening mechanism of non uniform grains. This review may provide a novel insight to modulate their competent performance and promote rational design of micro/nanodevices.     

Molecular wheels of ruthenium and osmium with bridging chalcogenolate ligands: edge-shared-octahedron structures and metal-ion binding

Inventing new wheels: reaction of [M(3)(CO)(12) ] (M=Ru, Os) with 4-RC(6)H(4)SH afforded [{M(S-4-RC(6)H(4))(2)(CO)(2)}(8)] (R=H; I) or [{M(S-4-RC(6)H(4))(2)(CO)(2)}(6)] (R=Me, iPr; II; see scheme), all of which have been structurally characterized. The octamers I are unique metal molecular wheels featuring skew-edge-shared octahedra with a central planar M(8) octagon. [{Ru(S-4-iPrC(6)H(4))(2)(CO)(2)}(6)] selectively binds a Cu(+) or Ag(+) ion to form [M'{Ru(S(4-iPr-C(6)H(4)))(2)(CO)(2)}(6)](+) (III).     

An analysis of the grain growth kinetics in Mn2O3 nanocrystals

The isothermal grain growth of Mn₂O₃ nanocrystals, prepared by the chemical liquid-phase homogeneous precipitation route, was investigated at various temperatures between 200 and 500 °C for different annealing times. X-ray diffraction patterns and transmission electron micrographs show that the average grain sizes are in the range of 4–50 nm. The grain growth data were analyzed using two different models. The first model, assuming normal grain growth as that in conventional polycrystalline materials, yields large grain growth exponent (n) and extremely low activation energy (Q). Although it can describe the evolution of grain sizes, it fails to give satisfactory physical interpretation of n and Q, both beyond the theoretical predictions. The second model is based on the structural relaxation of the interface component in nanocrystalline materials. In this case, the ordering of distorted interfaces by structural relaxation proceeds with grain growth. This structure relaxation model not only describes the evolutions of grain growth well, but also makes reasonable attribution of the low activation energy to the short-range rearrangement of atoms in the interface region as well. PACS 63.50.+x; 78.30.-j; 81.20.-n