Reducing protein corona formation and enhancing colloidal stability of gold nanoparticles by capping with silica monolayers

A study demonstrated the reducing of protein corona (PC) formation and enhancing colloidal stability of gold nanoparticles (Au NP) by capping with silica monolayers. Au NP surface was needed to achieve silica monolayer formation. In a first attempt to have a high density ligand coverage around NS-1, an excess of 3-mercaptopropyltrimethoxysilane (MPTMS) was directly added to a Au NP hydrosol, but this resulted in immediate aggregation. The resulting trimethoxysilane moiety covering the surface of NS-3 was subsequently hydrolyzed by addition of 5 mM NaOH in a 2:1 methanol/water mixture, yielding a polymeric monolayer

Reversible control of protein corona formation on gold nanoparticles using host-guest interactions

When nanoparticles (NPs) are exposed to biological media, proteins are adsorbed, forming a so-called protein corona (PC). This cloud of protein aggregates hampers the targeting and transport capabilities of the NPs, thereby compromising their biomedical applications. Therefore, there is a high interest in the development of technologies that allow control over PC formation, as this would provide a handle to manipulate NPs in biological fluids. We present a strategy that enables the reversible disruption of the PC using external stimuli, thereby allowing a precise regulation of NP cellular uptake. The approach, demonstrated for gold nanoparticles (AuNPs), is based on a biorthogonal, supramolecular host-guest interactions between an anionic dye bound to the AuNP surface and a positively charged macromolecular cage. This supramolecular complex effectively behaves as a zwitterionic NP ligand, which is able not only to prevent PC formation but also to disrupt a previously formed hard corona. With this supramolecular stimulus, the cellular internalization of AuNPs can be enhanced by up to 30-fold in some cases, and even NP cellular uptake in phagocytic cells can be regulated. Additionally, we demonstrate that the conditional cell uptake of purposely designed gold nanorods can be used to selectively enhance photothermal cell death

Biocompatible, Multiresponsive Nanogel Composites for Codelivery of Antiangiogenic and Chemotherapeutic Agents

Single therapy approaches are usually insufficient to treat certain diseases, due to genetic differences between patients or disease resistance. Therefore, such approaches are gradually replaced by combination therapies comprising two or more drugs. In oncology, these include BRAF inhibitors and cytotoxic, antiangiogenic, or immunomodulatory agents, among others. We propose herein the use of multiresponsive nanogel composites for the codelivery of a DNA intercalator (doxorubicin) and an antiangiogenic and immunomodulatory agent (pomalidomide). We introduce a surfactant-free synthetic protocol to decorate biocompatible poly(ethylene glycol)methacrylate nanogels (PEGMA) with evenly distributed gold nanoparticles and explore their ability to deliver drugs upon stimulation by various triggers such as heat, light, and reducing agents present in the intracellular environment. We further demonstrate that an additional polymer coating on the nanogel surface can decrease uncontrolled drug leakage and modulate cellular uptake and the drug release profile

Properties of Cosmic Shock Waves in Large Scale Structure Formation

We have examined the properties of shock waves in simulations of large scale structure formation for two cosmological scenarios (a SCDM and a LCDM with Omega =1). Large-scale shocks result from accretion onto sheets, filaments and Galaxy Clusters (GCs) on a scale of circa 5 Mpc/h in both cases. Energetic motions, both residual of past accretion history and due to current asymmetric inflow along filaments, generate additional, common shocks on a scale of about 1 Mpc/h, which penetrate deep inside GCs. Also collisions between substructures inside GCs form merger shocks. Consequently, the topology of the shocks is very complex and highly connected. During cosmic evolution the comoving shock surface density decreases, reflecting the ongoing structure merger process in both scenarios. Accretion shocks have very high Mach numbers (10-10^3), when photo-heating of the pre-shock gas is not included. The typical shock speed is of order v_{sh}(z) =H(z)lambda_{NL}(z), with lambda_{NL}(z) the wavelength scale of the nonlinear perturbation at the given epoch. However, the Mach number for shocks occuring within clusters is usually smaller (3-10), due to the fact that the intracluster gas is already hot. Statistical fits of shock speed around GCs as a function of GCs temperature give power-law's in accord with 1-D predictions. However, a very different result is obtained for fits of the shock radius, reflecting the very complex shock structures forming in 3-D simulations. The in-flowing kinetic energy across such shocks, giving the power available for cosmic-ray acceleration, is comparable to the cluster X-ray luminosity emitted from a central region of radius 0.5 Mpc/h. Considering their large size and long lifetimes, those shocks are potentially interesting sites for cosmic-ray acceleration, if modest magnetic fields exist within them.Comment: 20 Pages, 11 figures, ApJ in press. Complete set of full resolution figures available at http://www.msi.umn.edu:80/Projects/twj/figures.tar.g

Density profiles of dark matter haloes: diversity and dependence on environment

(Abridged) We study the outer density profiles of dark matter haloes predicted by a generalized secondary infall model and observed in a N-body cosmological simulation of a \Lambda CDM model. We find substantial systematic variations in shapes and concentrations of the halo profiles as well as a strong correlation of the profiles with the environment. In the N-body simulation, the average outer slope of the density profiles, \beta (\rho\propto r^{-\beta}), of isolated haloes is \approx 2.9; 68% of these haloes have values of \beta between 2.5 and 3.8. Haloes in dense environments of clusters are more concentrated and exhibit a broad distribution of \beta with values larger than for isolated haloes . Contrary to what one may expect, the haloes contained within groups and galaxy systems are less concentrated and have flatter outer density profiles than the isolated haloes. The concentration decreases with M_h, but its scatter for a given mass is substantial. The mass and circular velocity of the haloes are strongly correlated: M_h \propto V_m^{\alpha} with \alpha ~ 3.3 (isolated) and ~3.5 (haloes in clusters). For M_h=10^12M_sun the rms deviations from these relations are \Delta logM_h=0.12 and 0.18, respectively. Approximately 30% of the haloes are contained within larger haloes or have massive companions (larger than ~0.3 the mass of the current halo) within 3 virial radii. The remaining 70% of the haloes are isolated objects. The distribution of \beta as well as the concentration-mass and M_h-V_m relations for the isolated haloes agree very well with the predictions of our seminumerical approach which is based on a generalization of the secondary infall model and on the extended Press-Schechter formalism.Comment: 14 pages, 11 figures included, uses mn.sty, accepted by MNRAS. Minor modifications, new and updated reference

Gold Nanostar-Coated Polystyrene Beads as Multifunctional Nanoprobes for SERS Bioimaging

Hybrid colloidal nanocomposites comprising polystyrene beads and plasmonic gold nanostars are reported as multifunctional optical nanoprobes. Such self-assembled structures are excellent Raman enhancers for bioapplications as they feature plasmon modes in the near-infrared "first biological transparency window". In this proof of concept study, we used 4-mercaptobenzoic acid as a Raman-active molecule to optimize the density of gold nanostars on polystyrene beads, improving SERS performance and thereby allowing in vitro cell culture imaging. Interestingly, intermediate gold nanostar loadings were found to yield higher SERS response, which was confirmed by electromagnetic modeling. These engineered hybrid nanostructures notably improve the possibilities of using gold nanostars as SERS tags. Additionally, when fluorescently labeled polystyrene beads are used as colloidal carriers, the composite particles can be applied as promising tools for multimodal bioimaging

The Physics of Cluster Mergers

Clusters of galaxies generally form by the gravitational merger of smaller clusters and groups. Major cluster mergers are the most energetic events in the Universe since the Big Bang. Some of the basic physical properties of mergers will be discussed, with an emphasis on simple analytic arguments rather than numerical simulations. Semi-analytic estimates of merger rates are reviewed, and a simple treatment of the kinematics of binary mergers is given. Mergers drive shocks into the intracluster medium, and these shocks heat the gas and should also accelerate nonthermal relativistic particles. X-ray observations of shocks can be used to determine the geometry and kinematics of the merger. Many clusters contain cooling flow cores; the hydrodynamical interactions of these cores with the hotter, less dense gas during mergers are discussed. As a result of particle acceleration in shocks, clusters of galaxies should contain very large populations of relativistic electrons and ions. Electrons with Lorentz factors gamma~300 (energies E = gamma m_e c^2 ~ 150 MeV) are expected to be particularly common. Observations and models for the radio, extreme ultraviolet, hard X-ray, and gamma-ray emission from nonthermal particles accelerated in these mergers are described.Comment: 38 pages with 9 embedded Postscript figures. To appear in Merging Processes in Clusters of Galaxies, edited by L. Feretti, I. M. Gioia, and G. Giovannini (Dordrecht: Kluwer), in press (2001

Directed differentiation of hematopoietic precursors and functional osteoclasts from human ES and iPS cells

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - 2010 by The American Society of HematologyThe directed differentiation of human pluripotent stem cells offers the unique opportunity to generate a broad spectrum of human cell types and tissues for transplantation, drug discovery, and studying disease mechanisms. Here, we report the stepwise generation of bone-resorbing osteoclasts from human embryonic and induced pluripotent stem cells. Generation of a primitive streak-like population in embryoid bodies, followed by specification to hematopoiesis and myelopoiesis by vascular endothelial growth factor and hematopoietic cytokines in serum-free media, yielded a precursor population enriched for cells expressing the monocyte-macrophage lineage markers CD14, CD18, CD11b, and CD115. When plated in monolayer culture in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor-kappa B ligand (RANKL), these precursors formed large, multinucleated osteoclasts that expressed tartrate-resistant acid phosphatase and were capable of resorption. No tartrate-resistant acid phosphatase-positive multinucleated cells or resorption pits were observed in the absence of RANKL. Molecular analyses confirmed the expression of the osteoclast marker genes NFATc1, cathepsin K, and calcitonin receptor in a RANKL-dependent manner, and confocal microscopy demonstrated the coexpression of the alpha v beta 3 integrin, cathepsin K and F-actin rings characteristic of active osteoclasts. Generating hematopoietic and osteoclast populations from human embryonic and induced pluripotent stem cells will be invaluable for understanding embryonic bone development and postnatal bone disease. (Blood. 2010; 115(14): 2769-2776)This study was supported (in part) by research funding from the Nuffield Foundation-Oliver Bird Rheumatism Program to A.E.G., Arthritis Research Campaign (ARC ref 18197) to G.S., National Institutes of Health grants R01 HL080627 and P20 GM075019 to G.M.K., and Austrian Science Fund (FWF) and Anabonos EU-FP7 to E.F.W

Small Cationic DDA:TDB Liposomes as Protein Vaccine Adjuvants Obviate the Need for TLR Agonists in Inducing Cellular and Humoral Responses

Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes - including size, antigen association and addition of TLR agonists – to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes

CAF01 Potentiates Immune Responses and Efficacy of an Inactivated Influenza Vaccine in Ferrets

Trivalent inactivated vaccines (TIV) against influenza are given to 350 million people every year. Most of these are non-adjuvanted vaccines whose immunogenicity and protective efficacy are considered suboptimal. Commercially available non-adjuvanted TIV are known to elicit mainly a humoral immune response, whereas the induction of cell-mediated immune responses is negligible. Recently, a cationic liposomal adjuvant (dimethyldioctadecylammonium/trehalose 6,6′-dibehenate, CAF01) was developed. CAF01 has proven to enhance both humoral and cell-mediated immune responses to a number of different experimental vaccine candidates. In this study, we compared the immune responses in ferrets to a commercially available TIV with the responses to the same vaccine mixed with the CAF01 adjuvant. Two recently circulating H1N1 viruses were used as challenge to test the vaccine efficacy. CAF01 improved the immunogenicity of the vaccine, with increased influenza-specific IgA and IgG levels. Additionally, CAF01 promoted cellular-mediated immunity as indicated by interferon-gamma expressing lymphocytes, measured by flow cytometry. CAF01 also enhanced the protection conferred by the vaccine by reducing the viral load measured in nasal washes by RT-PCR. Finally, CAF01 allowed for dose-reduction and led to higher levels of protection compared to TIV adjuvanted with a squalene emulsion. The data obtained in this human-relevant challenge model supports the potential of CAF01 in future influenza vaccines