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1.
Adv Mater ; : e2401137, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38742799

RESUMEN

In contrast to biological cell membranes, it is still a major challenge for synthetic membranes to efficiently separate ions and small molecules due to their similar sizes in the sub-nanometer range. Inspired by biological ion channels with their unique channel wall chemistry that facilitates ion sieving by ion-channel interactions, the first free-standing, ultrathin (10-17 nm) nanomembranes composed entirely of polydopamine (PDA) are reported here as ion and molecular sieves. These nanomembranes are obtained via an easily scalable electropolymerization strategy and provide nanochannels with various amine and phenolic hydroxyl groups that offer a favorable chemical environment for ion-channel electrostatic and hydrogen bond interactions. They exhibit remarkable selectivity for monovalent ions over multivalent ions and larger species with K+/Mg2+ of ≈4.2, K+/[Fe(CN)6]3- of ≈10.3, and K+/Rhodamine B of ≈273.0 in a pressure-driven process, as well as cyclic reversible pH-responsive gating properties. Infrared spectra reveal hydrogen bond formation between hydrated multivalent ions and PDA, which prevents the transport of multivalent ions and facilitates high selectivity. Chemically rich, free-standing, and pH-responsive PDA nanomembranes with specific interaction sites are proposed as customizable high-performance sieves for a wide range of challenging separation requirements.

2.
J Am Chem Soc ; 146(17): 11991-11999, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38639465

RESUMEN

The complex dynamics and transience of assembly pathways in living systems complicate the understanding of these molecular to nanoscale processes. Current technologies are unable to track the molecular events leading to the onset of assembly, where real-time information is imperative to correlate their rich biology. Using a chemically designed pro-assembling molecule, we map its transformation into nanofibers and their fusion with endosomes to form hollow fiber clusters. Tracked by phasor-fluorescence lifetime imaging (phasor-FLIM) in epithelial cells (L929, A549, MDA-MB 231) and correlative light-electron microscopy and tomography (CLEM), spatiotemporal splicing of the assembly events shows time-correlated metabolic dysfunction. The biological impact begins with assembly-induced endosomal disruption that reduces glucose transport into the cells, which, in turn, stymies mitochondrial respiration.


Asunto(s)
Imagen Óptica , Humanos , Endosomas/metabolismo , Nanofibras/química , Línea Celular , Animales
3.
Angew Chem Int Ed Engl ; 63(18): e202400101, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38407424

RESUMEN

Investigations into the selective oxidation of inert sp3 C-H bonds using polymer photocatalysts under mild conditions have been limited. Additionally, the structure-activity relationship of photocatalysts often remains insufficiently explored. Here, a series of thiophene-based covalent triazine frameworks (CTFs) are used for the efficient and selective oxidation of hydrocarbons to aldehydes or ketones under ambient aerobic conditions. Spectroscopic methods conducted in situ and density functional theory (DFT) calculations revealed that the sulfur atoms within the thiophene units play a pivotal role as oxidation sites due to the generation of photogenerated holes. The effect of photogenerated holes on photocatalytic toluene oxidation was investigated by varying the length of the spacer in a CTF donor-acceptor based photocatalyst. Furthermore, the manipulation of reactive oxygen species was employed to enhance selectivity by weakening the peroxidative capacity. As an illustrative example, this study successfully demonstrated the synthesis of a precursor of the neurological drug AMG-579 using a photocatalytic protocol.

4.
Nat Commun ; 15(1): 39, 2024 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-38169470

RESUMEN

Artificial organelles can manipulate cellular functions and introduce non-biological processes into cells. Coacervate droplets have emerged as a close analog of membraneless cellular organelles. Their biomimetic properties, such as molecular crowding and selective partitioning, make them promising components for designing cell-like materials. However, their use as artificial organelles has been limited by their complex molecular structure, limited control over internal microenvironment properties, and inherent colloidal instability. Here we report the design of dipeptide coacervates that exhibit enhanced stability, biocompatibility, and a hydrophobic microenvironment. The hydrophobic character facilitates the encapsulation of hydrophobic species, including transition metal-based catalysts, enhancing their efficiency in aqueous environments. Dipeptide coacervates carrying a metal-based catalyst are incorporated as active artificial organelles in cells and trigger an internal non-biological chemical reaction. The development of coacervates with a hydrophobic microenvironment opens an alternative avenue in the field of biomimetic materials with applications in catalysis and synthetic biology.


Asunto(s)
Células Artificiales , Elementos de Transición , Dipéptidos , Células Artificiales/química , Condensados Biomoleculares , Elementos de Transición/química , Catálisis , Orgánulos/química
5.
J Am Chem Soc ; 146(8): 5195-5203, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38275287

RESUMEN

Single-molecule localization microscopy (SMLM) is a powerful technique to achieve super-resolution imaging beyond the diffraction limit. Although various types of blinking fluorophores are currently considered for SMLM, intrinsic blinking fluorophores remain rare at the single-molecule level. Here, we report the synthesis of nanographene-based intrinsic burst-blinking fluorophores for highly versatile SMLM. We image amyloid fibrils in air and in various pH solutions without any additive and lysosome dynamics in live mammalian cells under physiological conditions. In addition, the single-molecule labeling of nascent proteins in primary sensory neurons was achieved with azide-functionalized nanographenes via click chemistry. SMLM imaging reveals higher local translation at axonal branching with unprecedented detail, while the size of translation foci remained similar throughout the entire network. These various results demonstrate the potential of nanographene-based fluorophores to drastically expand the applicability of super-resolution imaging.


Asunto(s)
Parpadeo , Colorantes Fluorescentes , Animales , Microscopía Fluorescente/métodos , Colorantes Fluorescentes/química , Imagen Individual de Molécula/métodos , Lisosomas/metabolismo , Mamíferos/metabolismo
6.
Macromol Biosci ; 24(2): e2300197, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37639236

RESUMEN

Encapsulating drugs into functionalized nanoparticles (NPs) is an alternative to reach the specific therapeutic target with lower doses. However, when the NPs are in contact with physiological media, proteins adsorb on their surfaces, forming a protein corona (PC) biomolecular layer, acquiring a distinct biological identity that alters their interactions with cells. Itraconazole (ITZ), an antifungal agent, is encapsulated into PEGylated and/or functionalized NPs with high specificity for macrophages. It is evaluated how the PC impacts their cell uptake and antifungal effect. The minimum inhibitory concentration and colony-forming unit assays demonstrate that encapsulated ITZ into poly(ethylene glycol) (PEG) NPs improves the antifungal effect compared with NPs lacking PEGylation. The improvement can be related to the synergistic effect of the encapsulated ITZ and NPs composition and the reduction of PC formation in PEG NPs. Functionalized NPs with anti-F4/80 and anti-MARCO antibodies, or mannose without PEG and treated with PC, show an improved uptake but, in the presence of PEG, significantly reduce the endocytosis, dominating the stealth effect from PEG. Therefore, the PC plays a crucial role in the nanosystem uptake and antifungal effects, which suggests the need for in vivo model studies to evaluate the effect of PC in the specificity and biodistribution.


Asunto(s)
Nanopartículas , Corona de Proteínas , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Distribución Tisular , Itraconazol/farmacología , Itraconazol/uso terapéutico , Polietilenglicoles , Nanopartículas/uso terapéutico
7.
J Extracell Vesicles ; 12(12): e12399, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38124271

RESUMEN

The influence of a protein corona on the uptake of nanoparticles in cells has been demonstrated in various publications over the last years. Extracellular vesicles (EVs), can be seen as natural nanoparticles. However, EVs are produced under different cell culture conditions and little is known about the protein corona forming on EVs and its influence on their uptake by target cells. Here, we use a proteomic approach in order to analyze the protein composition of the EVs themselves and the protein composition of a human blood plasma protein corona around EVs. Moreover, we analyze the influence of the protein corona on EV uptake into human monocytes and compare it with the influence on the uptake of engineered liposomes. We show that the presence of a protein corona increases the uptake of EVs in human monocytes. While for liposomes this seems to be triggered by the presence of immunoglobulins in the protein corona, for EVs blocking the Fc receptors on monocytes did not show an influence of uptake. Therefore, other mechanisms of docking to the cell membrane and uptake are most like involved, demonstrating a clear difference between EVs and liposomes as technically produced nanocarriers.


Asunto(s)
Vesículas Extracelulares , Corona de Proteínas , Humanos , Vesículas Extracelulares/metabolismo , Corona de Proteínas/metabolismo , Liposomas , Proteómica , Transporte Biológico
8.
Acta Biomater ; 172: 355-368, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37839632

RESUMEN

The intracellular protein corona has not been fully investigated in the field of nanotechnology-biology (nano-bio) interactions. To effectively understand intracellular protein corona formation and dynamics, we established a workflow to isolate the intracellular protein corona at different uptake times of two nanoparticles - magnetic hydroxyethyl starch nanoparticles (HES-NPs) and magnetic human serum albumin nanocapsules (HSA-NCs). We performed label-free quantitative LC-MS proteomics to analyze the composition of the intracellular protein corona and correlated our findings with results from conventional methods for intracellular trafficking of nanocarriers, such as flow cytometry, transmission electron microscopy (TEM), and confocal microscopy (cLSM). We determined the evolution of the intracellular protein corona. At different time stages the protein corona of the HES-NPs with a slower uptake changed, but there were fewer changes in that of the HSA-NCs with a more rapid uptake. We identified proteins that are involved in macropinocytosis (RAC1, ASAP2) as well as caveolin. This was confirmed by blocking experiments and by TEM studies. The investigated nanocarrier predominantly trafficked from early endosomes as determined by RAB5 identification in proteomics and in cLSM to late endosomes/lysosomes (RAB7, LAMP1, cathepsin K and HSP 90-beta) We further demonstrated differences between nanoparticles with slower and faster uptake kinetics and determined the associated proteome at different time points. Analysis of the intracellular protein corona provides us with effective data to examine the intracellular trafficking of nanocarriers used in efficient drug delivery and intracellular applications. STATEMENT OF SIGNIFICANCE: Many research papers focus on the protein corona on nanoparticles formed in biological fluids, but there are hardly any articles dealing with proteins that come in contact with nanoparticles inside cells. The "intracellular protein corona" studied here is a far more complex and highly demanding field. Most nanocarriers are designed to be taken up into cells. Given this, we chose two different nanocarriers to reveal changes in the proteins in dendritic cells during contact at specific times. Further studies will allow us to examine molecular target proteins using these methods. Our research is a significant addition towards the goal of understanding and thus improving the efficacy of drug nanocarriers.


Asunto(s)
Nanocápsulas , Nanopartículas , Corona de Proteínas , Humanos , Proteómica , Nanopartículas/metabolismo , Proteoma , Albúmina Sérica Humana , Proteínas Activadoras de GTPasa
9.
Artículo en Inglés | MEDLINE | ID: mdl-37903081

RESUMEN

Lipid and polymer vesicles provide versatile means of creating systems that mimic the architecture of cells. However, these constructs cannot mimic the adaptive compartmentalization observed in cells, where the assembly and disassembly of subcompartments are dynamically modulated by environmental cues. Here, we describe a fully polymeric microreactor with a coacervate-in-vesicle architecture that exhibits an adaptive response to pH. The system was fabricated by microfluidic generation of semipermeable biomimetic polymer vesicles within 1 min using oleyl alcohol as the oil phase. The polymersomes allowed for the diffusion of protons and substrates acting as external signals. Using this method, we were able to construct adaptive microreactors containing internal polyelectrolyte-based catalytic organelles capable of sequestering and localizing enzymes and reaction products in a dynamic process driven by an external stimulus. This approach provides a platform for the rapid and efficient construction of robust adaptive microreactors that can be used in catalysis, biosensing, and cell mimicry.

12.
Int J Biol Macromol ; 250: 126094, 2023 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-37544569

RESUMEN

In the light of recent retrovirus pandemics, the issue of discovering new and diverse RNA-specific fluorochromes for research and diagnostics became of acute importance. The great majority of nucleic acid-specific probes either do not stain RNA or cannot distinguish between DNA and RNA. The versatility of polymethine dyes makes them suitable as stains for visualization, analysis, and detection of nucleic acids, proteins, and other biomolecules. We synthesized the asymmetric dicationic homodimeric monomethine cyanine dyes 1,1'-(1,3-phenylenebis(methylene))bis(4-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)pyridin-1-ium) bromide (Т1) and 1,1'-(1,3-phenylenebis(methylene))bis(4-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)quinolin-1-ium) bromide (M1) and tested their binding specificity, spectral characteristics, membrane penetration in living and fixed cells, cellular toxicity, and stability of fluorescent emission. Mesenchymal cells have diverse phenotypes and extensive proliferation and differentiation properties. We found dyes T1 and M1 to show high photochemical stability in living mesenchymal stem cells from apical papilla (SCAP) with a strong fluorescent signal when bound to nucleic acids. We found M1 to perform better than control fluorochrome (Hoechst 33342) for in vivo DNA visualization. T1, on the other hand, stains granular cellular structures resembling ribosomes in living cells and after permeabilization of the nuclear membrane stains the nucleoli and not the chromatin in the nucleus. This makes T1 suitable for the visualization of structures rich in RNA in living and fixed cells.

13.
Nanoscale Horiz ; 8(10): 1377-1385, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37591816

RESUMEN

Poly(ethylene glycol) (PEG) is the gold standard used to reduce unspecific protein adsorption and prolong nanocarrier circulation time. However, this stealth effect could be counteracted by the increasing prevalence of anti-PEG antibodies in the bloodstream. Up to now, the presence of anti-PEG antibodies in the protein corona and their effect on cell uptake has not been investigated yet. Our results showed a high concentration and prevalence of anti-PEG antibodies in the German population. PEGylated nanocarriers exhibited a higher level of anti-PEG antibodies in the protein corona compared to non-PEGylated, which lead to higher uptake in macrophages. Consequently, the anti-PEG antibodies in the protein corona could mitigate the stealth effect of PEG, leading to accelerated blood clearance and unwanted side effects.


Asunto(s)
Nanopartículas , Corona de Proteínas , Corona de Proteínas/metabolismo , Polietilenglicoles , Transporte Biológico , Macrófagos
14.
Int J Mol Sci ; 24(15)2023 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-37569548

RESUMEN

Finding a long-term cure for tumor patients still represents a major challenge. Immunotherapies offer promising therapy options, since they are designed to specifically prime the immune system against the tumor and modulate the immunosuppressive tumor microenvironment. Using nucleic-acid-based vaccines or cellular vaccines often does not achieve sufficient activation of the immune system in clinical trials. Additionally, the rapid degradation of drugs and their non-specific uptake into tissues and cells as well as their severe side effects pose a challenge. The encapsulation of immunomodulatory molecules into nanocarriers provides the opportunity of protected cargo transport and targeted uptake by antigen-presenting cells. In addition, different immunomodulatory cargos can be co-delivered, which enables versatile stimulation of the immune system, enhances anti-tumor immune responses and improves the toxicity profile of conventional chemotherapeutic agents.

15.
Angew Chem Int Ed Engl ; 62(44): e202308761, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37496129

RESUMEN

Enzymatic reactions can consume endogenous nutrients of tumors and produce cytotoxic species and are therefore promising tools for treating malignant tumors. Inspired by nature where enzymes are compartmentalized in membranes to achieve high reaction efficiency and separate biological processes with the environment, we develop liposomal nanoreactors that can perform enzymatic cascade reactions in the aqueous nanoconfinement of liposomes. The nanoreactors effectively inhibited tumor growth in vivo by consuming tumor nutrients (glucose and oxygen) and producing highly cytotoxic hydroxyl radicals (⋅OH). Co-compartmentalization of glucose oxidase (GOx) and horseradish peroxidase (HRP) in liposomes could increase local concentration of the intermediate product hydrogen peroxide (H2 O2 ) as well as the acidity due to the generation of gluconic acid by GOx. Both H2 O2 and acidity accelerate the second-step reaction by HRP, hence improving the overall efficiency of the cascade reaction. The biomimetic compartmentalization of enzymatic tandem reactions in biocompatible liposomes provides a promising direction for developing catalytic nanomedicines in antitumor therapy.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Liposomas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Glucosa Oxidasa/farmacología , Peroxidasa de Rábano Silvestre , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Nanotecnología , Peróxido de Hidrógeno/uso terapéutico
16.
Small ; 19(25): e2206454, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36929281

RESUMEN

Typically, 2D nanosheets have a homogeneous surface, making them a major challenge to structure. This study proposes a novel concept of 2D organic nanosheets with a heterogeneously functionalized surface. This work achieves this by consecutively crystallizing two precisely synthesized polymers with different functional groups in the polymer backbone in a two-step process. First, the core platelet is formed and then the second polymer is crystallized around it. As a result, the central area of the platelets has a different surface functionality than the periphery. This concept offers two advantages: the resulting polymeric 2D platelets are stable in dispersion, which simplifies further processing and makes both crystal surfaces accessible for subsequent functionalization. Additionally, a wide variety of polymers can be used, making the process and the choice of surface functionalization very flexible.

17.
Pharmaceutics ; 15(2)2023 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-36839931

RESUMEN

Hair follicles constitute important drug delivery targets for skin antisepsis since they contain ≈25% of the skin microbiome. Nanoparticles are known to penetrate deeply into hair follicles. By massaging the skin, the follicular penetration process is enhanced based on a ratchet effect. Subsequently, an intrafollicular drug release can be initiated by various trigger mechanisms. Here, we present novel ultraviolet A (UVA)-responsive nanocapsules (NCs) with a size between 400 and 600 nm containing hydroxyethyl starch (HES) functionalized by an o-nitrobenzyl linker. A phase transfer into phosphate-buffered saline (PBS) and ethanol was carried out, during which an aggregation of the particles was observed by means of dynamic light scattering (DLS). The highest stabilization for the target medium ethanol as well as UVA-dependent release of ethanol from the HES-NCs was achieved by adding 0.1% betaine monohydrate. Furthermore, sufficient cytocompatibility of the HES-NCs was demonstrated. On ex vivo porcine ear skin, a strong UVA-induced release of the model drug sulforhodamine 101 (SR101) could be demonstrated after application of the NCs in cyclohexane using laser scanning microscopy. In a final experiment, a microbial reduction comparable to that of an ethanol control was demonstrated on ex vivo porcine ear skin using a novel UVA-LED lamp for triggering the release of ethanol from HES-NCs. Our study provides first indications that an advanced skin antisepsis based on the eradication of intrafollicular microorganisms could be achieved by the topical application of UVA-responsive NCs.

19.
Angew Chem Int Ed Engl ; 62(17): e202217652, 2023 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-36749562

RESUMEN

Pseudo-homogeneous polymeric photocatalysts are an emerging class of highly efficient and tunable photocatalytic materials, where the photocatalytic centers are easily accessible. The creation of highly efficient photocatalytic materials that can be rapidly separated and recovered is one of the critical challenges in photocatalytic chemistry. Here, we describe pH-responsive photocatalytic nanoparticles that are active and well-dispersed under acidic conditions but aggregate instantly upon elevation of pH, enabling easy recovery. These responsive photocatalytic polymers can be used in various photocatalytic transformations, including CrVI reduction and photoredox alkylation of indole derivative. Notably, the cationic nature of the photocatalyst accelerates reaction rate of an anionic substrate compared to uncharged species. These photocatalytic particles could be readily recycled allowing multiple successive photocatalytic reactions with no clear loss in activity.

20.
ACS Appl Mater Interfaces ; 15(2): 2891-2900, 2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36594942

RESUMEN

The favored production of one product over another is a major challenge in synthetic chemistry, reducing the formation of byproducts and enhancing atom efficacy. The formation of catalytic species that have differing reactivities based on the substrate being converted, has been targeted to selectively control reactions. Here, we report the production of photocatalytic self-assembled amphiphilic polymers, with either hydrophilic or hydrophobic microenvironments at the reactive center. Benzothiadiazole-based photocatalysts were polymerized into either the hydrophilic or the hydrophobic compartment of a diblock copolymer by RAFT polymerization. The difference in the reactivity of each microenvironment was dictated by the physical properties of the substrate. Stark differences in reactivity were observed for polar substrates, where a hydrophilic microenvironment was favored. Conversely, both microenvironments performed similarly for very hydrophobic substrates, showing that reagent partitioning is not the only factor that drives photocatalytic conversion. Furthermore, the use of secondary swelling solvents allowed an additional reagent exchange between the continuous phase and the heterogeneous photocatalyst, resulting in a significant 5-fold increase in conversion for a radical carbon-carbon coupling.

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