Nanoparticles (NPs) exhibit unique physicochemical properties that enable them to overcome biological barriers and to be considered one of the best materials with anticancer properties. Most of the ...administered NPs that end up in the bloodstream interact with the endothelial layer. The interaction of the NPs with the endothelium widens the existing gaps or induces new ones in the monolayer of vascular endothelial cells, thus increasing the access to the target sites in the organism. This type of interaction can lead to NP-modulated endothelial leakiness (NanoEL). The most important factors determining NanoEL are the physicochemical properties of the NPs. NP-modulated endothelial leakiness can lead to the discovery of new therapeutic targets and strategies to improve drug delivery through controlling and regulating NanoEL. Nevertheless, the NanoEL mechanism also carries some limitations that result from an incomplete understanding of NP metabolism and toxicity, and the possibility of their participation in the unintended bidirectional vascular permeability, which may contribute to the formation of cancer metastases. In this review we are focusing on the effect of metal and polymeric NPs on mechanism and degree of induction of NanoEL, as well as on the benefits and risks of using NPs that induce endothelial leakiness.
Protein–polymer conjugation is a widely used technique to develop protein therapeutics with improved pharmacokinetic properties as prolonged half-life, higher stability, water solubility, lower ...immunogenicity, and antigenicity. Combining biochemical methods, small angle scattering (SAXS/SANS), and neutron spin–echo spectroscopy, here we examine the impact of PEGylation (i.e., the covalent conjugation with poly(ethylene glycol) or PEG) on structure and internal domain dynamics of phosphoglycerate kinase (PGK) to elucidate the reason for reduced activity that is connected to PEGylation. PGK is a protein with a hinge motion between the two main domains that is directly related to function. We find that secondary structure and ligand access to the binding sites are not affected. The ligand induced cleft closing is unchanged. We observe an additional internal motion between covalent bonded PEG and the protein compatible with Brownian motion of PGK in a harmonic potential. Entropic interaction with the full PEG chain leads to a force constant of about 8 pN/nm independent of PEG chain length. This additional force preserves protein structure and has negligible effects on the functional domain dynamics of the protein. PEGylation seems to reduce activity just by acting as a local crowder for the ligands. The newly identified interaction mechanism might open possibilities to improve rational design of protein–polymer conjugates.
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The search for new microbicide compounds is of an urgent need, especially against difficult-to-eradicate biofilm-forming bacteria. One attractive option is the application of cationic multivalent ...dendrimers as antibacterials and also as carriers of active molecules. These compounds require an adequate hydrophilic/hydrophobic structural balance to maximize the effect. Herein, we evaluated the antimicrobial activity of cationic carbosilane (CBS) dendrimers unmodified or modified with polyethylene glycol (PEG) units, against planktonic and biofilm-forming
culture. Our study revealed that the presence of PEG destabilized the hydrophilic/hydrophobic balance but reduced the antibacterial activity measured by microbiological cultivation methods, laser interferometry and fluorescence microscopy. On the other hand, the activity can be improved by the combination of the CBS dendrimers with endolysin, a bacteriophage-encoded peptidoglycan hydrolase. This enzyme applied in the absence of the cationic CBS dendrimers is ineffective against Gram-negative bacteria because of the protective outer membrane shield. However, the endolysin-CBS dendrimer mixture enables the penetration through the membrane and then deterioration of the peptidoglycan layer, providing a synergic antimicrobial effect.
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Antimicrobial proteins, like lysozymes produced by animals or bacteriophage lysins, enable the degradation of bacterial peptidoglycan (PG) and, consequently, lead to bacterial cell lysis. However, ...the activity of those enzymes is not satisfactory against gram-negative bacteria because of the presence of an outer membrane (OM) barrier. Lytic enzymes can therefore be combined with membrane-disrupting agents, such as dendritic silver nanoparticles. Nevertheless, a lipopolysaccharide (LPS), especially the smooth type, could be the main hindrance for highly charged nanoparticles to get direct access to the bacterial OM and to help lytic enzymes to reach their target PG. Herein, we have investigated the interactions of PEGylated carbosilane dendritic nanoparticles with
010 LPS in the presence of lysozymes and KP27 endolysin to find out the main aspects of the OM destabilization process. Our results showed that PEGylated dendronized AgNPs overcame the LPS barrier and enhanced the antibacterial effect of endolysin more efficiently than unPEGylated nanoparticles.
Coralyne is a synthetic analog of berberine related to protoberberine-isoquinoline alkaloids. Isoquinoline derivatives and analogs are renowned as potent radiosensitizers with potential medical ...application. In the present study, we investigated the effect of coralyne on the cell death, cytoskeletal changes and cell cycle progression of irradiated A549 cells. A clonogenic assay revealed that coralyne pretreatment decreased the viability of A549 cells in a time- and dose-dependent manner. Moreover, exposure to coralyne and ionizing radiation (IR) markedly altered the filamentous actin cytoskeletal architecture and integrin-β binding sites of A549 cells. Treatment with 1–25 µM coralyne in combination with 2 Gy of IR significantly reduced the percentage of cells in G2/M phase compared with 2 Gy IR alone. These results indicate that coralyne is a potent radiosensitizing agent that may find an application in medicine.
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Fabrication and characterization of hybrid nanomats containing quantum dots can play a prominent role in the development of advanced biosensors and bio-based semiconductors. Owing to their ...size-dependent properties and controlled nanostructures, quantum dots (QDs) exhibit distinct optical and electronic characteristics. However, QDs include heavy metals and often require stabilizing agents which are toxic for biological applications. Here, to mitigate the use of toxic ligands, cadmium selenide quantum dots (CdSe QDs) were synthesized in situ with polyvinylpyrrolidone (PVP) at room temperature. The addition of PVP polymer provided size regulation, stability, and control over size distribution of CdSe QDs. The characterization of the optical properties of the CdSe QDs was performed using fluorescence and ultraviolet-visible (UV-Vis) spectroscopy. CdSe QDs exhibited a typical absorbance peak at 280 nm and a photoluminescence emission peak at 580 nm. Transmission electron microscopy (TEM) micrographs demonstrated that CdSe QDs having an average size of 6 ± 4 nm were obtained via wet chemistry method. CdSe QDs were immobilized in a blend of PVP and poly(L-lactide-co-ε-caprolactone) (PL-b-CL) copolymer that was electrospun to produce nanofibers. Scanning electron microscopy (SEM), thermal analyses and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) were used to characterize properties of fabricated nanofibers. Both pristine and hybrid nanofibers possessed cylindrical geometry and rough surface features, facilitating increased surface area. Infrared absorption spectra showed a slight shift in absorbance peaks due to interaction of PVP-coated CdSe QDs and nanofiber matrix. The presence of CdSe QDs influenced the fiber diameter and their thermal stability. Further, in vitro biological analyses of hybrid nanofibers showed promising antibacterial effect and decline in cancer cell viability. This study offers a simple approach to obtain hybrid nanomats immobilized with size-controlled PVP-coated CdSe QDs, which have potential applications as biosensors and antibacterial and anticancer cell agents.
Some biological properties of eight dendrimers incorporating both phosphorus linkages and viologen units within their cascade structure or at the periphery were investigated for the first time. In ...particular cytotoxicity, hemotoxicity, and antimicrobial and antifungal activity of these new macromolecules were examined. Even if for example all these species exhibited good antimicrobial properties, it was demonstrated that their behavior strongly depends on several parameters as their size and molecular weight, the number of viologen units and the nature of the terminal groups.
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The study of drugs diffusion through different biological membranes constitutes an essential step in the development of new pharmaceuticals. In this study, the method based on the monolayer cell ...culture of CHO-K1 cells has been developed in order to emulate the epithelial cells barrier in permeability studies by laser interferometry. Laser interferometry was employed for the experimental analysis of nickel(II) and cobalt(II) complexes with 1-allylimidazole or their chlorides' diffusion through eukaryotic cell monolayers. The amount (mol) of nickel(II) and cobalt(II) chlorides transported through the monolayer was greater than that of metals complexed with 1-allylimidazole by 4.34-fold and 1.45-fold, respectively, after 60 min. Thus, laser interferometry can be used for the quantitative analysis of the transport of compounds through eukaryotic cell monolayers, and the resulting parameters can be used to formulate a mathematical description of this process.
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Rodzaj śmierci komórkowej, tj. apoptoza, autofagia, nekroza czy pyroptoza zależy od czynnika indukującego oraz fazy cyklu komórkowego. Główną rolę w odpowiedzi immunologicznej organizmu na ...mikroorganizmy odgrywa proces zwany pyroptozą. Pyroptoza jest rodzajem śmierci komórki indukowanym przez różnego rodzaju czynniki zapalne aktywowane w odpowiedzi na wzorce cząsteczkowe i molekularne związane z patogenami w tym lipopolisacharyd bakteryjny na drodze szlaku kanonicznego lub niekanonicznego w zależności od rodzaju biorących w nich udział kaspaz. W pyroptozie istotną rolę pełni białko gazdermina D należące do rodziny białek gazdermin (A, B, C, D, E i DFNB59), która charakteryzuje się swoistą tkankowo ekspresją genów, głównie w komórkach nabłonkowych, skóry oraz układu pokarmowego i odpowiada za regulację proliferacji i różnicowania komórek, a także za hamowanie lub rozwój nowotworów w różnych narządach. Rodzina GSDM jest odpowiedzialna za tworzenie porów w błonie komórkowej, umożliwiając sekrecję cytokin prozapalnych (IL-1β i IL-18), biorących udział w inicjacji szlaków reakcji zapalnej przez rekrutację i aktywację komórek odpornościowych w miejscu infekcji. Zasadniczą rolę w procesie pyroptozy na drodze niekanonicznej pełni białko gazdermina D, którego N-koniec, tworząc pory w błonie komórkowej powoduje powstanie obrzęku, lizy osmotycznej aż do śmierci zainfekowanej komórki.
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Cationic dendrimers are considered one of the best drug transporters in the body. However, in order to improve their biocompatibility, modification of them is required to reduce toxicity. In this ...way, many dendrimers may lose their original properties, for example, anticancer. To improve biocompatibility of dendrimers, it is possible to complex them with albumin, as is done very often in drug delivery. However, the interaction of dendrimers with albumin can lead to protein structure disruption or no complexation at all. Therefore, the investigation of the interaction between cationic poly‐(propylene imine) dendrimers and polyethylene glycol (PEG)‐albumin by fluorescence, circular dichroism, small angle X‐ray scattering (SAXS), and transmission electron microscopy was carried out. Results show that cationic dendrimers bind to PEGylated albumin at PEG and albumin surfaces. The obtained results for 5k‐PEG indicate a preferential binding of the dendrimers to PEG. For 20k‐PEG binding of dendrimers to PEG and protein could induce a collapse of the PEG chain onto the protein surface. This opens up new possibilities to the use of PEGylated albumin as a platform to carry dendrimers without changing the albumin structure and improve the pharmacokinetic properties of dendrimers without further modification.
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