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Immunosuppression with glucocorticoids is a common treatment for autoimmune liver diseases and after liver transplant, which is however associated with severe side-effects. Targeted delivery of glucocorticoids to inflammatory cells, e.g. liver macrophages and Kupffer cells, is a promising approach for minimizing side effects. Herein, we prepare core–shell silica nanocapsules (SiO2 NCs) via a sol–gel process confined in nanodroplets for targeted delivery of dexamethasone (DXM) for liver immunosuppressive therapy. DXM with concentrations up to 100 mg mL−1 in olive oil are encapsulated while encapsulation efficiency remains over 95% after 15 days. Internalization of NCs by non-parenchymal murine liver cells significantly reduces the release of inflammatory cytokines, indicating an effective suppression of inflammatory response of liver macrophages. Fluorescent and magnetic labeling of the NCs allows for monitoring their intracellular trafficking and biodegradation. Controlled interaction with blood proteins and good colloidal stability in blood plasma are achieved via PEGylation of the NCs. Specific proteins responsible for stealth effect, such as apolipoprotein A-I, apolipoprotein A-IV, and clusterin, are present in large amounts on the PEGylated NCs. In vivo biodistribution investigations prove an efficient accumulation of NCs in the liver, underlining the suitability of the SiO2 NCs as a dexamethasone carrier for treating inflammatory liver diseases. Fil: Jiang, Shuai. Max-Planck-Institut für Polymerforschung; Alemania Fil: Prozeller, Domenik. Max-Planck-Institut für Polymerforschung; Alemania Fil: Pereira, Jorge. Max-Planck-Institut für Polymerforschung; Alemania Fil: Simon, Johanna. Max-Planck-Institut für Polymerforschung; Alemania. Johannes Gutenberg Universitat Mainz; Alemania Fil: Han, Shen. Max-Planck-Institut für Polymerforschung; Alemania Fil: Wirsching, Sebastian. Johannes Gutenberg Universitat Mainz; Alemania Fil: Fichter, Michael. Johannes Gutenberg Universitat Mainz; Alemania Fil: Mottola, Milagro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina. Max-Planck-Institut für Polymerforschung; Alemania Fil: Lieberwirth, Ingo. Max-Planck-Institut für Polymerforschung; Alemania Fil: Morsbach, Svenja. Max-Planck-Institut für Polymerforschung; Alemania Fil: Mailänder, Volker. Max-Planck-Institut für Polymerforschung; Alemania. Johannes Gutenberg Universitat Mainz; Alemania Fil: Gehring, Stephan. Johannes Gutenberg Universitat Mainz; Alemania Fil: Crespy, Daniel. Max-Planck-Institut für Polymerforschung; Alemania. Vidyasirimedhi Institute of Science and Technology; Tailandia Fil: Landfester, Katharina. Max-Planck-Institut für Polymerforschung; Alemania

In eukaryotic cells, enzymes are compartmentalized into specific organelles so that different reactions and processes can be performed efficiently and with a high degree of control. In this work, we show that these features can be artificially emulated in robust synthetic organelles constructed using an enzyme co-compartmentalization strategy. We describe an in-situ encapsulation approach that allows enzymes to be loaded into silica nanoreactors in well-defined compositions. The nanoreactors can be combined into integrated systems to produce a desired reaction outcome. We used the selective enzyme co-compartmentalization and nanoreactor integration to regulate competitive cascade reactions and to modulate the kinetics of sequential reactions involving multiple nanoreactors. Furthermore, we show that the nanoreactors can be efficiently loaded into giant polymer vesicles, resulting in multi-compartmentalized microreactors.

Core–shell nanocapsules are receiving increasing interest for drug delivery applications. Silica nanocapsules have been the focus of intensive studies due to their biocompatibility, versatile silica chemistry, and tunable porosity. However, a versatile one-step preparation of silica nanocapsules with well-defined core–shell structure, tunable size, flexible interior loading, and tailored shell composition, permeability, and surface functionalization for site-specific drug release and therapeutic tracking remains a challenge. Herein, an interfacially confined sol–gel process in miniemulsion for the one-step versatile preparation of functional silica nanocapsules is developed. Uniform nanocapsules with diameters from 60 to 400 nm are obtained and a large variety of hydrophobic liquids are encapsulated in the core. When solvents with low boiling point are loaded, subsequent solvent evaporation converts the initially hydrophobic cavity into an aqueous environment. Stimuli-responsive permeability of nanocapsules is programmed by introducing disulfide or tetrasulfide bonds in the shell. Selective and sustained release of dexamethasone in response to glutathione tripeptide for over 10 d is achieved. Fluorescence labeling of the silica shell and magnetic loading in the internal cavity enable therapeutic tracking of nanocapsules by fluorescence and electron microscopies. Thus, silica nanocapsules represent a promising theranostic nanoplatform for targeted drug delivery applications. Fil: Jiang, Shuai. Max Planck Institute for Polymer Research; Alemania Fil: Mottola, Milagro. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina. Max Planck Institute For Polymer Research; Alemania Fil: Han, Shen. Max Planck Institute For Polymer Research; Alemania Fil: Thiramanas, Raweewan. Max Planck Institute For Polymer Research; Alemania Fil: Graf, Robert. Max Planck Institute For Polymer Research; Alemania Fil: Lieberwirth, Ingo. Max Planck Institute For Polymer Research; Alemania Fil: Mailänder, Volker. Max Planck Institute For Polymer Research; Alemania Fil: Crespy, Daniel. Max Planck Institute For Polymer Research; Alemania Fil: Landfester, Katharina. Max Planck Institute For Polymer Research; Alemania

We studied monomolecular layers at the oil/water interface (O/W int ) in a Langmuir interfacial trough using egg-yolk phosphatidylcholine (EPC) (the model phospholipid) and Vaseline (VAS) as oil phase. The temporal dynamics in the surface pressure (π) evolution depended on the method (spreading/adsorption) used for monolayers preparation and reflected the different distribution of EPC between all the system compartments (bulk phases and interfaces). We distinguished between EPC located either stable at the interface or hopping between the interface and bulk phases. The size order of the apparent mean molecular area, at constant π, of EPC at different interfaces (EPC O/W > EPC/VAS 0.02;A/W > EPC A/W ), suggested that VAS molecules intercalated between the hydrocarbon chains of EPC O/W , at a molar fraction x VAS > 0.02. However, EPC/VAS 0.02;A/W showed the highest compressional free energy. This leaded us to study the EPC/VAS 0.02 mixture at A/W by Brewster Angle Microscopy (BAM), finding that upon compression VAS segregated over the monolayer, forming non-coalescent lenses (as predicted by the spreading coefficient S = −13 mN/m) that remained after decompression and whose height changed (increase/decrease) accompanied the compression/decompression cycle. At the O/W int , while some VAS molecules remained at the interface up to the collapse, others squeezed out towards the VAS bulk phase with an energy requirement lower than towards the air. Fil: Mottola, Milagro. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: Caruso, Benjamin. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: Perillo, Maria Angelica. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina

In this work, we tested the hypothesis that the incorporation of amphiphilic drugs into lipid membranes may be regulated by their rheological properties. For this purpose, two members of the l-ascorbic acid alkyl esters family (ASCn) were selected, ASC16 and ASC14, which have different rheological properties when organized at the air/water interface. They are lipophilic forms of vitamin C used in topical pharmacological preparations. The effect of the phase state of the host lipid membranes on ASCn incorporation was explored using Langmuir monolayers. Films of pure lipids with known phase states have been selected, showing liquid-expanded, liquid-condensed, and solid phases as well as pure cholesterol films in liquid-ordered state. We also tested ternary and quaternary mixed films that mimic the properties of cholesterol containing membranes and of the stratum corneum. The compressibility and shear properties of those monolayers were assessed in order to define its phase character. We found that the length of the acyl chain of the ASCn compounds induces differential changes in the rheological properties of the host membrane and subtly regulates the kinetics and extent of the penetration process. The capacity for ASCn uptake was found to depend on the phase state of the host film. The increase in surface pressure resultant after amphiphile incorporation appears to be a function of the capacity of the host membrane to incorporate such amphiphile as well as the rheological response of the film. Hence, monolayers that show a solid phase state responded with a larger surface pressure increase to the incorporation of a comparable amount of amphiphile than liquid-expanded ones. The cholesterol-containing films, including the mixture that mimics stratum corneum, allowed a very scarce ASCn uptake independently of the membrane diffusional properties. This suggests an important contribution of Cho on the maintenance of the barrier function of stratum corneum.

l-ascorbic acid alkyl esters (ASCn) are molecules of pharmaceutical interest for their amphiphilic nature and proposed antioxidant power. In contrast to l-ascorbic acid, ASCn with different acyl chain lengths behaved stably upon oxidation and a tautomeric isomerization was observed. In Langmuir films, when the ascorbic ring has a negative charge, ASC14 and ASC16 form stable monolayers, contrary to ASC10 and ASC12. ASC16 films showed transition from liquid-expanded (LE) to liquid-condensed phase, whereas ASC14 showed only an LE phase. When ASCn are mainly neutral, ASC14 showed phase transition from LE to a crystalline phase, as previously reported for ASC16. The two-dimensional domains displayed crystal-like shapes with anisotropic optical activity when interacting with the polarized light under Brewster angle microscopy. The compounds with the longer acyl chain (ASC16, ASC14 and ASC12) exhibited good surface activity, forming Gibbs monolayers. They also were able to penetrate into phospholipid monolayers up to a critical point of 45-50mN/m. The 1-palmitoyl-2-oleoylphosphatidylcholine/ASCn films showed LC and/or crystalline domains only for ASC16. This study provides valuable evidence regarding the stability and surface properties of this drug family, and casts light into the differential interaction of these drugs with lipid membranes, which is important for understanding its differential pharmacological activity. Fil: Mottola, Milagro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina Fil: Vico, Raquel Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina Fil: Villanueva, Martín Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina Fil: Fanani, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina

l-ascorbic acid alkyl esters (ASCn) are lipophilic forms of vitamin C, which maintain some of its antioxidant power. Those properties make this drug family attractive to be used in pharmacological preparations protecting other redox-sensible drugs or designed to reduce possible toxic oxidative processes. In this work, we tested the ability of l-ascorbic acid alkyl esters (ASCn) to modulate the structure, permeability, and rheological properties of phospholipid bilayers. The ASCn studied here (ASC16, ASC14, and ASC12) alter the structural integrity as well as the rheological properties of phospholipid membranes without showing any evident detergent activity. ASC14 appeared as the most efficient drug in destabilize the membrane structure of nano- and micro-size phospholipid liposomes inducing vesicle content leakage and shape elongation on giant unilamellar vesicles. It also was the most potent enhancer of membrane microviscosity and surface water structuring. Only ASC16 induced the formation of drug-enriched condensed domains after its incorporation into the lipid bilayer, while ASC12 appeared as the less membrane-disturbing compound, likely because of its poor, and more superficial, partition into the membrane. We also found that incorporation of ASCn into the lipid bilayers enhanced the reduction of membrane components, compared with soluble vitamin C. Our study shows that ASCn compounds, which vary in the length of the acyl chain, show different effects on phospholipid vesicles used as biomembrane models. Those variances may account for subtly differences in the effectiveness on their pharmacological applications.

Ascorbyl palmitate (ASC16) is an anionic amphiphilicmolecule of pharmacological interest due to its antioxidant properties. We found that ASC16 strongly interacted with model membranes. ASC16 penetrated phospholipid monolayers, with a cutoff near the theoretical surface pressure limit. The presence of a lipid filmat the interface favored ASC16 insertion compared with a bare air/water surface. The adsorption and penetration time curves showed a biphasic behavior: the first rapid peak evidenced a fast adsorption of charged ASC16 molecules to the interface that promoted a lowering of surface pH, thus partially neutralizing and compacting the film. The second rise represented an approach to the equilibrium between the ASC16 molecules in the subphase and the surface monolayer, whose kinetics depended on the ionization state of the film. Based on the Langmuir DMPC + ASC16 monolayer data, we estimated an ASC16 partition coefficient to DMPC monolayers of 1.5 × 105 30 Q2 and a ΔGp = −6.7 kcal·mol 31 −1. The rheological properties of the host membrane were determinant for ASC16 penetration kinetics: a fluid membrane, as provided by Chol, disrupted the liquid-condensed ASC16-enriched domains and favored ASC16 penetration. Subphase pH conditions affected ASC16 aggregation in bulk: the smaller structures at acidic pHs showed a faster equilibrium with the surface film than large lamellar ones. Our results revealed that the ASC16 interaction withmodelmembranes has a highly complex regulation. The polymorphism in the ASC16 bulk aggregation added complexity to the equilibrium between the surface and subphase form of ASC16, whose understanding may shed light on the pharmacological function of this drug. Fil: Mottola, Milagro. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (p); Argentina Fil: Wilke, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Química Biológica de Córdoba (p); Argentina. Universidad Nacional de Córdoba; Argentina Fil: Benedini, Luciano Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina Fil: Oliveira, Rafael Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Química Biológica de Córdoba (p); Argentina. Universidad Nacional de Córdoba; Argentina Fil: Fanani, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones En Química Biológica de Córdoba (p); Argentina. Universidad Nacional de Córdoba; Argentina