Factors affecting intracellular delivery and release of hydrophilic versus hydrophobic cargo from mesoporous silica nanoparticles on 2D and 3D cell cultures

Intracellular drug delivery by mesoporous silica nanoparticles (MSNs) carrying hydrophilic and hydrophobic fluorophores as model drug cargo is demonstrated on 2D cellular and 3D tumor organoid level. Two different MSN designs, chosen on the basis of the characteristics of the loaded cargo, were used: MSNs with a surface-grown poly(ethylene imine), PEI, coating only for hydrophobic cargo and MSNs with lipid bilayers covalently coupled to the PEI layer as a diffusion barrier for hydrophilic cargo. First, the effect of hydrophobicity corresponding to loading degree (hydrophobic cargo) as well as surface charge (hydrophilic cargo) on intracellular drug release was studied on the cellular level. All incorporated agents were able to release to varying degrees from the endosomes into the cytoplasm in a loading degree (hydrophobic) or surface charge (hydrophilic) dependent manner as detected by live cell imaging. When administered to organotypic 3D tumor models, the hydrophilic versus hydrophobic cargo-carrying MSNs showed remarkable differences in labeling efficiency, which in this case also corresponds to drug delivery efficacy in 3D. The obtained results could thus indicate design aspects to be taken into account for the development of efficacious intracellular drug delivery systems, especially in the translation from standard 2D culture to more biologically relevant organotypic 3D cultures.</p

Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.Peer reviewe

Systemic hypertonic saline enhances glymphatic spinal cord delivery of lumbar intrathecal morphine

The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13-L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.Peer reviewe

Combination of photothermal, prodrug and tumor cell camouflage technologies for triple-negative breast cancer treatment

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype. In the presented work, we have combined several emerging technologies to build up a nanoplatform for TNBC treatment: photothermal therapy, prodrug design and tumor cell camouflage formulation. First, we synthesized a paclitaxel (PTX) based prodrug PTX-SS, and then conjugated it to the surface of gold nanorod (Au NR) @ mesoporous silica (MSN) core-shell nanoparticles (Au@MSN-NH2 NPs). Subsequently, doxorubicin (DOX) was loaded into the Au@PTXSS-MSN NPs and further coated with cell membranes isolated from MDA-MB-231 cells to form cell camouflaged Au@PTXSS-MSN/DOX@CM NPs. The Au@PTXSS-MSN/DOX@CM NPs exhibited very good DOX loading capacity and the prodrug strategy enabled the precise adjustability of PTX-SS loading to achieve the optimized ratio between PTX and DOX to maximize the synergistic effect of these two drugs, as well as enabled GSH-responsive intracellular drug release. More interestingly, the cell membrane coating not only protected the drug from premature release, but also significantly improved the targeting ability of NPs to breast cancer MDA-MB-231 cells. The NPs also showed good photothermal responsiveness with clear improvement in inhibiting MDA-MB231 cell proliferation under laser irradiation. The in vivo studies further confirmed the effectiveness of Au@PTXSS-MSN/DOX@CM NPs on TNBC tumor inhibition in 4T1 cell grafted tumor mice model. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Solvent-Induced Reversal of Activities between Two Closely Related Heterogeneous Catalysts in the Aldol Reaction

The relative rates of the aldol reaction catalyzed by supported primary and secondary amines can be inverted by 2 orders of magnitude, depending on the use of hexane or water as a solvent. Our analyses suggest that this dramatic shift in the catalytic behavior of the supported amines does not involve differences in reaction mechanism, but is caused by activation of imine to enamine equilibria and stabilization of iminium species. The effects of solvent polarity and acidity were found to be important to the performance of the catalytic reaction. This study highlights the critical role of solvent in multicomponent heterogeneous catalytic processes

At the intersection of globalization and "civilizational originality' : cultural production in Putin's Russia

This special issue originates from a transnational collaboration of scholars in philology, comparative literature, social theory, sociology, anthropology, ethnography, and media studies. The collection strives to advance a research agenda built on the nexus of three intellectual and academic domains: post-Soviet Russian cultural studies', the research paradigm put forward by Cultural Studies, as well as empirical methods developed in sociology. The collection illustrates the importance of expanding the experience of Cultural Studies beyond its established spheres of national investigation, while it also speaks to the necessity to re-evaluate the hegemony of the English-language academic and cultural production on the global scale. The collection offers insights into the gamut of cultural practices and institutional environments in which Russian cultural production happens today. It shows how cultural industries and institutions in Russia are integrated into the global marketplace and transnational communities, while they also draw on and contribute to local lives and experiences by trying to create an autonomous space for symbolic production at personal and collective levels. Through diverse topics, the issue sheds light on the agency, i.e. practitioners and participants, creators and consumers, of Russian cultural production and the neoliberal practices implemented on creative work and cultural administration in Russia today. The Introduction outlines the development of academic studies on Russian cultural practices since 1991; describes main political developments shaping the cultural field in Putin's Russia; and, finally, identifies the Cultural Studies debates the editors of the collection find most productive for investigations of Russia, i.e. the instrumentalization of culture and culture as resource. Relocated in an analysis of a post-socialist society, these conceptualisations seem increasingly problematic in a situation where local and federal policies governing cultural and creative work focus simultaneously on marketization and on nationalism as the main tools of legitimizing the federal government.Peer reviewe

In vitro studies and preliminary in vivo evaluation of silicified concentrated collagen hydrogels

Hybrid and nanocomposite silicacollagen materials derived from concentrated collagen hydrogels were evaluated in vitro and in vivo to establish their potentialities for biological dressings. Silicification significantly improved the mechanical and thermal stability of the collagen network within the hybrid systems. Nanocomposites were found to favor the metabolic activity of immobilized human dermal fibroblastswhile decreasing the hydrogel contraction. Cell adhesion experiments suggested that in vitro cell behavior was dictated by mechanical properties and surface structure of the scaffold. First-to-date in vivo implantation of bulk hydrogels in subcutaneous sites of rats was performed over the vascular inflammatory period. These materials were colonized and vascularized without inducing strong inflammatory response. These data raise reasonable hope for the future application of silicacollagen biomaterials as biological dressings.Fil: Desimone, Martín Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Hélary, Christophe. Université Pierre et Marie Curie; FranciaFil: Quignard, Sandrine. Université Pierre et Marie Curie; FranciaFil: Rietveld, Ivo B. Universite de Paris; FranciaFil: Bataille, Clement. Université de Versailles Saint-quentin-en-yvelines.; FranciaFil: Copello, Guillermo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Mosser, Gervaise. Université Pierre et Marie Curie; FranciaFil: Giraud Guille, Marie-Madeleine. Université Pierre et Marie Curie; FranciaFil: Livage, Jacques. Université Pierre et Marie Curie; FranciaFil: Meddahi Pellé, Anne. Université de Versailles Saint-quentin-en-yvelines.; FranciaFil: Coradin, Thibaud. Université Pierre et Marie Curie; Franci

Mechanisms and Kinetics for Sorption of CO2 on Bicontinuous Mesoporous Silica Modified with n-Propylamine

We studied equilibrium adsorption and uptake kinetics and identified molecular species that formed during sorption of carbon dioxide on amine-modified silica. Bicontinuous silicas (AMS-6 and MCM-48) were postsynthetically modified with (3-aminopropyl)triethoxysilane or (3-aminopropyl)methyldiethoxysilane, and amine-modified AMS-6 adsorbed more CO(2) than did amine-modified MCM-48. By in situ FTIR spectroscopy, we showed that the amine groups reacted with CO(2) and formed ammonium carbamate ion pairs as well as carbamic acids under both dry and moist conditions. The carbamic acid was stabilized by hydrogen bonds, and ammonium carbamate ion pairs formed preferably on sorbents with high densities of amine groups. Under dry conditions, silylpropylcarbamate formed, slowly, by condensing carbamic acid and silanol groups. The ratio of ammonium carbamate ion pairs to silylpropylcarbamate was higher for samples with high amine contents than samples with low amine contents. Bicarbonates or carbonates did not form under dry or moist conditions. The uptake of CO(2) was enhanced in the presence of water, which was rationalized by the observed release of additional amine groups under these conditions and related formation of ammonium carbamate ion pairs. Distinct evidence for a fourth and irreversibly formed moiety was observed under sorption of CO(2) under dry conditions. Significant amounts of physisorbed, linear CO(2) were detected at relatively high partial pressures of CO(2), such that they could adsorb only after the reactive amine groups were consumed.authorCount :7</p