90 research outputs found
A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy
Colchicinoids are very potent tubulin-binding compounds, which interfere with microtubule formation, giving them strong cytotoxic properties, such as cell mitosis inhibition and induction of microcytoskeleton depolymerization. While this makes them promising vascular disrupting agents (VDAs) in cancer therapy, their dose-limiting toxicity has prevented any clinical application for this purpose. Therefore, colchicinoids are considered attractive lead molecules for the development of novel vascular disrupting nanomedicine. In a previous study, a polymeric colchicinoid prodrug that showed favorable hydrolysis characteristics at physiological conditions was developed. In the current study, this polymeric colchicinoid prodrug was evaluated in vitro and in vivo for its toxicity and vascular disrupting potential. Cell viability studies with human umbilical vein endothelial cells, as an in vitro measure for colchicine activity, reflected the degradation kinetics of the prodrug accordingly. Upon intravenous treatment, in vivo, of B16F10 melanoma-bearing mice with colchicine or with the polymeric colchicinoid prodrug, apparent vascular disruption and consequent tumor necrosis was observed for the prodrug but not for free colchicine at an equivalent dose. Moreover, a five-times-higher dose of the prodrug was well tolerated, indicating reduced toxicity. These findings demonstrate that the polymeric colchicinoid prodrug has a substantially improved efficacy/toxicity ratio compared with that of colchicine, making it a promising VDA for cancer therapy
Cell uptake and intracellular trafficking of bioreducible poly(amidoamine) nanoparticles for efficient mRNA translation in chondrocytes
Disulfide-containing poly(amidoamine) (PAA) is a cationic and bioreducible polymer, with potential use as a nanocarrier for mRNA delivery in the treatment of several diseases including osteoarthritis (OA). Successful transfection of joint cells with PAA-based nanoparticles (NPs) was shown previously, but cell uptake, endosomal escape and nanoparticle biodegradation were not studied in detail. In this study, C28/I2 human chondrocytes were transfected with NPs co-formulated with a PEG-polymer coating and loaded with EGFP mRNA for confocal imaging of intracellular trafficking and evaluation of transfection efficiency. Compared with uncoated NPs, PEG-coated NPs showed smaller particle size, neutral surface charge, higher colloidal stability and superior transfection efficiency. Furthermore, endosomal entrapment of these PEG-coated NPs decreased over time and mRNA release could be visualized both in vitro and in live cells. Importantly, cell treatment with modulators of the intracellular reducing environment showed that glutathione (GSH) concentrations affect translation of the mRNA payload. Finally, we applied a D-optimal experimental design to test different polymer-to-RNA loading ratios and dosages, thus obtaining an optimal formulation with up to ≈80% of GFP-positive cells and without toxic effects. Together, the biocompatibility and high transfection efficiency of this system may be a promising tool for intra-articular delivery of therapeutical mRNA in OA treatment
Large-amplitude driving of a superconducting artificial atom: Interferometry, cooling, and amplitude spectroscopy
Superconducting persistent-current qubits are quantum-coherent artificial
atoms with multiple, tunable energy levels. In the presence of large-amplitude
harmonic excitation, the qubit state can be driven through one or more of the
constituent energy-level avoided crossings. The resulting
Landau-Zener-Stueckelberg (LZS) transitions mediate a rich array of
quantum-coherent phenomena. We review here three experimental works based on
LZS transitions: Mach-Zehnder-type interferometry between repeated LZS
transitions, microwave-induced cooling, and amplitude spectroscopy. These
experiments exhibit a remarkable agreement with theory, and are extensible to
other solid-state and atomic qubit modalities. We anticipate they will find
application to qubit state-preparation and control methods for quantum
information science and technology.Comment: 13 pages, 5 figure
Construction of late Pleistocene Laurentide Ice History on earth with composite rheology
G44A: Cryosphere, Solid Earth, and Sea-Level Interactions and the Next Generation of Glacial Isostatic Models 1 / Session ID: 2169A good ice thickness history model is essential in the study of Glacial Isostatic Adjustment (GIA), its effects on coastal engineering, water resource management, fault stability and intraplate earthquakes, monitor global climate change, etc... Ice history models can be constructed based on glaciology and climate data only, but Peltier mainly used GIA observations and simple ice physics to construct global models ICE-4G, 5G & 6G where the main uncertainty is the ice thickness in Antarctica and western Laurentide during the last glacial maximum. One should note that most of the ice models constructed this way are based on the assumption that mantle rheology is linear and that rheology varies in the radial direction only. However, surface geology and seismic tomography show that Earth properties also vary strongly in the lateral direction. Moreover, high temperature creep experiments on mantle rocks show that mantle flow is better described by composite rheology since both diffusion (linear) and dislocation (nonlinear) creep operate in the mantle at the same time. The aim of our study is to construct global ice history models that are consistent with composite rheology and lateral heterogeneity. Thus we use the Coupled Poisson-Finite Element method to model GIA in a spherical, self-gravitating viscoelastic Earth with composite rheology and lateral heterogeneity. We shall follow the approach of Peltier and use GIA observations and simple ice physics as constraints to our ice model. The limitation of using sea level data is that they only lie near the coast and thus there is little constraint on ice thickness inland. To overcome this, we will use gravity rate-of-change data from GRACE with the effect of hydrology accurately removed using GPS observations (rather than GIA models which introduce large uncertainties). However, these data only give the current-day rate-of-change, which is more than 8,000 years after the end of deglaciation. To further constrain our ice model, we also use river incision data which records tilting of the land since the formation of the river after local ice melted. We will also use the paleo-stress orientations induced from postglacial faults formed near the end of deglaciation to further constrain ice thickness changes. Some preliminary results will be presented
Synthesis and systematic evaluation of symmetric sulfonated centrally C-C bonded cyanine near-infrared dyes for protein labelling
The most commonly used near-infrared cyanine dyes contain an aryl ether that is not fully stable towards nucleophiles. Replacement of the aryl ether by a more stable carbon-carbon bond can improve the stability. In this work we have synthesized a series of four negatively-charged symmetrical C-C bond-containing Cy7 derivatives and compared them to the known dyes indocyanine green (ICG) and IRDye 800CW. The extent of stacking of these C-C bond-containing dyes was higher than reported for aryl ether dyes, but stacking could be minimized by altering the surface charge of the molecules and by introducing sulfonate groups. Furthermore, the degree of stacked dye in an antibody-dye conjugate was similar to the degree of stacking of free dye under labeling conditions. In our view, C-C bond-containing Cy7 dyes provide a chemical platform, based on which one can improve the photophysical properties and stacking behavior, thereby generating interesting additions to the conjugation toolbox available for e.g. antibodies.</p
Optimal locations for absolute gravity measurements and sensitivity of GRACE observations for constraining glacial isostatic adjustment on the northern hemisphere
The use of Non-Linear Geometry (NLGEOM) and gravity loading in flat and spherical Finite Element models of Abaqus for Glacial Isostatic Adjustment (GIA)
Simulating horizontal crustal motions of glacial isostatic adjustment using compressible cartesian models
Significant land uplift and horizontal motions have been recorded with Global Navigation Satellite Systems (GNSS) in areas such as Alaska, Iceland and the Northern Antarctic Peninsula (NAP) as a result of Glacial Isostatic Adjustment (GIA) due to ice melt after the Little Ice Age. Here, analysis of horizontal displacement rates can be of extra importance, as they are more sensitive to Earth properties in shallower layers than vertical displacement rates. Proper modelling of horizontal displacement rates with dedicated GIA models requires a spherical Earth with compressible rheology. However, in these small areas, the used GIA models are often incompressible using a Cartesian geometry to ease computation and in some cases allow for lateral viscosity changes or more complex rheology. We investigate the validity of modelled horizontal displacement rates using different approximations, that is using spherical or Cartesian Earth structures, and incompressible, material compressible or compressible rheology. Although the lack of self-gravity and sphericity compensate each other in the vertical, this is less the case for the horizontal. For a disc ice sheet with a radius just over 200 km and a thickness of 1000 m, differences due to sphericity are minimal and the modelled horizontal displacement rates of compressible Cartesian models differ from those simulated by a compressible spherical model by 0.63 mm a-1. Thus, compressible Cartesian GIA models can be applied for modelling horizontal displacement rates of small ice sheets like those in Alaska, Iceland and NAP. Unfortunately, the implementation of compressibility in Abaqus that we use here cannot be extended to spherical models as gravity can not be specified for a spherical body. Other modelling approaches are recommended in such cases.Astrodynamics & Space Mission
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