Here, we present a modular synthesis as well as physicochemical and biological evaluation of a new series of amphiphilic dendrons carrying triphenylphosphonium groups at their periphery. Within the series, the size and mutual balance of lipophilic and hydrophilic domains are systematically varied, changing the dendron shape from cylindrical to conical. In physiological solution, the dendrons exhibit very low critical micelle concentrations (2.6-4.9 μM) and form stable and uniform micelles 6-12 nm in diameter, depending on dendron shape; the results correlate well with molecular dynamics simulations. The compounds show relatively high cytotoxicity (IC50 1.2-21.0 μM) associated with micelle formation and inversely related to the size of assembled particles. Depending on their shape, the dendrons show promising results in terms of dendriplex formation and antibacterial activity. In addition to simple amphiphilic dendrons, a fluorescently labeled analogue was also prepared and utilized as an additive visualizing the dendron's cellular uptake.

• MeSH
• antibakteriální látky farmakologie   chemie   chemická syntéza   MeSH
• dendrimery * chemie   chemická syntéza   farmakologie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• micely * MeSH
• organofosforové sloučeniny * chemie   MeSH
• povrchově aktivní látky chemie   chemická syntéza   farmakologie   MeSH
• silany chemie   MeSH
• simulace molekulární dynamiky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• carbosilane MeSH Prohlížeč
• dendrimery * MeSH
• micely * MeSH
• organofosforové sloučeniny * MeSH
• povrchově aktivní látky MeSH
• silany MeSH

Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.

• MeSH
• dendrimery * chemie   MeSH
• lidé MeSH
• myši MeSH
• nosiče léků chemie   MeSH
• polyaminy MeSH
• polymery chemie   MeSH
• vakcíny proti AIDS imunologie   chemie   aplikace a dávkování   MeSH
• vakcíny imunologie   chemie   aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dendrimery * MeSH
• nosiče léků MeSH
• Poly(amidoamine) MeSH Prohlížeč
• polyaminy MeSH
• polymery MeSH
• vakcíny proti AIDS MeSH
• vakcíny MeSH

The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose-directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once-weekly administration, are on the horizon, there is still no approved therapy that offers glucose-responsive insulin function. Herein, a nanoscale complex combining both electrostatic- and dynamic-covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high-affinity glucose-binding motif yields an injectable insulin depot affording both glucose-directed and long-lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose-responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic- and dynamic-covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose-responsive insulin depot for week-long control following a single routine injection.

• Klíčová slova
• bioconjugation, drug delivery, materials chemistry, nanotechnology,
• MeSH
• dendrimery * MeSH
• diabetes mellitus * MeSH
• glukosa MeSH
• inzulin MeSH
• krevní glukóza MeSH
• myši MeSH
• prasata MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dendrimery * MeSH
• glukosa MeSH
• inzulin MeSH
• krevní glukóza MeSH

The consideration of human and environmental exposure to dendrimers, including cytotoxicity, acute toxicity, and cell and tissue accumulation, is essential due to their significant potential for various biomedical applications. This study aimed to evaluate the biodistribution and toxicity of a novel methoxyphenyl phosphonium carbosilane dendrimer, a potential mitochondria-targeting vector for cancer therapeutics, in 2D and 3D cancer cell cultures and zebrafish embryos. We assessed its cytotoxicity (via MTT, ATP, and Spheroid growth inhibition assays) and cellular biodistribution. The dendrimer cytotoxicity was higher in cancer cells, likely due to its specific targeting to the mitochondrial compartment. In vivo studies using zebrafish demonstrated dendrimer distribution within the vascular and gastrointestinal systems, indicating a biodistribution profile that may be beneficial for systemic therapeutic delivery strategies. The methoxyphenyl phosphonium carbosilane dendrimer shows promise for applications in cancer cell delivery, but additional studies are required to confirm these findings using alternative labelling methods and more physiologically relevant models. Our results contribute to the growing body of evidence supporting the potential of carbosilane dendrimers as vectors for cancer therapeutics.

• MeSH
• dánio pruhované MeSH
• dendrimery * toxicita   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• techniky 3D buněčné kultury MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• carbosilane MeSH Prohlížeč
• dendrimery * MeSH

Amphiphilic dendrons represent a relatively novel class of molecules which may show many unique properties suitable for applications in a field of molecular biology and nanomedicine. They were frequently studied as platforms suitable for drug delivery systems as were, e.g. polymersomes or hybrid lipid-polymer nanoparticles. Recently, natural extracellular lipid vesicles (EVs), called exosomes (EXs), were shown to be a promising candidate in drug delivery applications. Formation of hybrid exosome-dendron nanovesicles could bring benefits in their simple conjugation with selective targeting moieties. Unfortunately, the complex architecture of biological membranes, EXs included, makes obstacles in elucidating the important parameters and mechanisms of interaction with the artificial amphiphilic structures. The aim of the presented work was to study the interaction of two types of amphiphilic carbosilane dendritic structures (denoted as DDN-1 and DDN-2) suitable for further modification with streptavidin (DDN-1) or using click-chemistry approach (DDN-2), with selected neutral and negatively charged lipid model membranes, partially mimicking the basic properties of natural EXs biomembranes. To meet the goal, a number of biophysical methods were used for determination of the degree and mechanisms of the interaction. The results showed that the strength of interactions of amphiphilic dendrons with liposomes was related with surface charge of liposomes. Several steps of interactions were disclosed. The initialization step was mainly coupled with amphiphilic dendrons - liposomes surface interaction resulting in destabilization of large self-assembled amphiphilic dendrons structures. Such destabilization was more significant with liposomes of higher negative charge. With increasing concentration of amphiphilic dendrons in a solution the interactions were taking place also in the hydrophobic part of bilayer. Further increase of nanoparticle concentration resulted in a gradual dendritic cluster formation in a lipid bilayer structure. Due to high affinity of amphiphilic dendrons to model lipid bilayers the conclusion can be drawn that they represent promising platforms also for decoration of exosomes or other kinds of natural lipid vehicles. Such organized hybrid dendron-lipid biomembranes may be advantageous for their subsequent post-functionalization with small molecules, large biomacromolecules or polymers suitable for targeted drug-delivery or theranostic applications.

• Klíčová slova
• Amphiphilic dendrons, Hybrid liposomes, Liposomes, Model membranes, Self-assembling,
• MeSH
• anizotropie MeSH
• dendrimery * chemická syntéza   chemie   MeSH
• kalorimetrie MeSH
• liposomy * chemie   MeSH
• membránové potenciály MeSH
• nanočástice chemie   MeSH
• silany * chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• carbosilane MeSH Prohlížeč
• dendrimery * MeSH
• liposomy * MeSH
• silany * MeSH

HYPOTHESIS: The intricate entropy-enthalpy interplay of dendrimers confined in pores affects their conformation and retention in the porous stationary phase. This work aims at providing important insights into its impacts on partitioning and chromatographic separation in both size-exclusion chromatography (SEC) and interaction chromatography (IC) regimes. SIMULATIONS: Using Monte Carlo (MC) simulations, we investigated the bulk-pore phase equilibria and the conformational behavior of flexible dendrimers differing in generation, in spacer length and in fraction of modified terminal groups interacting differently with pore walls than the majority building units. FINDINGS: With increasing interaction strength, a distinct transition from a roughly spherical shape caused by simultaneous interactions with two walls to an ellipsoidal (or even disklike) conformation tenaciously adhering to only one wall was observed for moderately confined dendrimers. The strongly deformed dendrimers subjected to severe confinement gain high energy and the samples differing in the degree of modification become chromatographically discernable thanks to large energy differences. Consequently, our results suggest that the column fillings with fairly narrow pores which are ineffective in SEC, are highly efficient separation media for dendrimer studies by IC above the critical adsorption point (CAP). Overall, our simulations reveal useful information for advancing and optimizing experimental liquid chromatography studies of dendrimers.

• Klíčová slova
• Chromatography, Confinement, Dendrimer, Enthalpy, Entropy, Monte Carlo simulation, Phase equilibrium, Terminal group,
• MeSH
• dendrimery * MeSH
• metoda Monte Carlo MeSH
• molekulární konformace MeSH
• poréznost MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dendrimery * MeSH

Glycodendrimers are a novel group of dendrimers (DDMs) characterized by surface modifications with various types of glycosides. It has been shown previously that such modifications significantly decrease the cytotoxicity of DDMs. Here, we present an investigation of glucose-modified carbosilane DDMs (first-third-generation, DDM1-3Glu) interactions with two models of biological structures: lipid membranes (liposomes) and serum protein (human serum albumin, HSA). The changes in lipid membrane fluidity with increasing concentration of DDMs was monitored by spectrofluorimetry and calorimetry methods. The influence of glycodendrimers on serum protein was investigated by monitoring changes in protein fluorescence intensity (fluorescence quenching) and as protein secondary structure alterations by circular dichroism spectrometry. Generally, all generations of DDMGlu induced a decrease of membrane fluidity and interacted weakly with HSA. Interestingly, in contrast to other dendritic type polymers, the extent of the DDM interaction with both biological models was not related to DDM generation. The most significant interaction with protein was shown in the case of DDM2Glu, whereas DDM1Glu induced the highest number of changes in membrane fluidity. In conclusion, our results suggest that the flexibility of a DDM molecule, as well as its typical structure (hydrophobic interior and hydrophilic surface) along with the formation of larger aggregates of DDM2-3Glu, significantly affect the type and extent of interaction with biological structures.

• Klíčová slova
• Circular dichroism, Differential scanning calorimetry, Glucose-modified carbosilane dendrimers, Liposomes, Membrane fluidity, Model lipid membranes, Proteins,
• MeSH
• cirkulární dichroismus MeSH
• dendrimery chemie   farmakologie   MeSH
• fluidita membrány účinky léků   MeSH
• fluorescenční spektrometrie MeSH
• glukosa chemie   farmakologie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• lidský sérový albumin metabolismus   MeSH
• liposomy MeSH
• nádory farmakoterapie   MeSH
• nosiče léků chemie   farmakologie   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• silany chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• carbosilane MeSH Prohlížeč
• dendrimery MeSH
• glukosa MeSH
• lidský sérový albumin MeSH
• liposomy MeSH
• nosiče léků MeSH
• protinádorové látky MeSH
• silany MeSH

A recently described bangle lectin (PHL) from the bacterium Photorhabdus asymbiotica was identified as a mainly fucose-binding protein that could play an important role in the host-pathogen interaction and in the modulation of host immune response. Structural studies showed that PHL is a homo-dimer that contains up to seven L-fucose-specific binding sites per monomer. For these reasons, potential ligands of the PHL lectin: α-L-fucopyranosyl-containing mono-, di-, tetra-, hexa- and dodecavalent ligands were tested. Two types of polyvalent structures were investigated - calix[4]arenes and dendrimers. The shared feature of all these structures was a C-glycosidic bond instead of the more common but physiologically unstable O-glycosidic bond. The inhibition potential of the tested structures was assessed using different techniques - hemagglutination, surface plasmon resonance, isothermal titration calorimetry, and cell cross-linking. All the ligands proved to be better than free L-fucose. The most active hexavalent dendrimer exhibited affinity three orders of magnitude higher than that of standard L-fucose. To determine the binding mode of some ligands, crystal complex PHL/fucosides 2 - 4 were prepared and studied using X-ray crystallography. The electron density in complexes proved the presence of the compounds in 6 out of 7 fucose-binding sites.

• MeSH
• antibakteriální látky chemie   farmakologie   terapeutické užití   MeSH
• bakteriální infekce farmakoterapie   mikrobiologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   chemie   izolace a purifikace   metabolismus   MeSH
• dendrimery chemie   farmakologie   terapeutické užití   MeSH
• erytrocyty MeSH
• fukosa analogy a deriváty   farmakologie   terapeutické užití   MeSH
• hemaglutinace účinky léků   MeSH
• interakce hostitele a patogenu účinky léků   MeSH
• krystalografie rentgenová MeSH
• lektiny antagonisté a inhibitory   chemie   izolace a purifikace   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely MeSH
• Photorhabdus metabolismus   MeSH
• povrchová plasmonová rezonance MeSH
• rekombinantní proteiny chemie   izolace a purifikace   metabolismus   MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• dendrimery MeSH
• fucose-binding lectin MeSH Prohlížeč
• fukosa MeSH
• lektiny MeSH
• ligandy MeSH
• rekombinantní proteiny MeSH

Over the last decades, multidrug-resistant bacteria have emerged and spread, increasing the number of bacteria, against which commonly used antibiotics are no longer effective. It has become a serious public health problem whose solution requires medical research in order to explore novel effective antimicrobial molecules. On the one hand, antimicrobial peptides (AMPs) are regarded as good alternatives because of their generally broad-spectrum activities, but sometimes they can be easily degraded by the organism or be toxic to animal cells. On the other hand, cationic carbosilane dendrons, whose focal point can be functionalized in many different ways, have also shown good antimicrobial activity. In this work, we synthetized first- and second-generation cationic carbosilane dendrons with a maleimide molecule on their focal point, enabling their functionalization with three different AMPs. After different microbiology studies, we found an additive effect between first-generation dendron and AMP3 whose study reveals three interesting effects: (i) bacteria aggregation due to AMP3, which could facilitate bacteria detection or even contribute to antibacterial activity by preventing host cell attack, (ii) bacteria disaggregation capability of second-generation cationic dendrons, and (iii) a higher AMP3 aggregation ability when dendrons were added previously to peptide treatment. These compounds and their different effects observed over bacteria constitute an interesting system for further mechanism studies.

• Klíčová slova
• antibacterial peptides, carbosilane dendrons, molecular modeling and molecular dynamics,
• MeSH
• antiinfekční látky chemie   MeSH
• dendrimery chemie   MeSH
• maleimidy chemie   MeSH
• nanokonjugáty chemie   MeSH
• silany chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiinfekční látky MeSH
• carbosilane MeSH Prohlížeč
• dendrimery MeSH
• maleimide MeSH Prohlížeč
• maleimidy MeSH
• nanokonjugáty MeSH
• silany MeSH

Non-viral gene delivery vectors studied in the gene therapy applications are often designed with the cationic nitrogen containing groups necessary for binding and cell release of nucleic acids. Disadvantage is a relatively high toxicity which restricts the in vivo use of such nanoparticles. Here we show, that the 3rd generation carbosilane dendrimers possessing (trimethyl)phosphonium (PMe3) groups on their periphery were able to effectively deliver the functional siRNA into the cells (B14, Cricetulus griseus), release it into the cytosol and finally to achieve up to 40% gene silencing of targeted gene (glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) with the comparable or, in some cases, even better effectivity as their ammonium counterparts. Moreover, such cationic dendrimers show relatively low in vivo toxicity as compared to their ammonium analogues when analyzed by standard fish embryo test (FET) on Danio rerio in vivo model, with LD50 = 6.26 µM after 48 h of incubation. This is more than 10-fold improvement as compared to published values for various other types of cationic dendrimers. We discuss the potential of further increase of the transfection efficiency, endosomal escape and decrease of toxicity of such non-viral vectors, based on the systematic screening of different types of substituents on central phosphonium atom.

• Klíčová slova
• Gene therapy, Molecular dynamics, Non-viral vectors, Phosphonium carbosilane dendrimers, Small interfering RNA, Transfection,
• MeSH
• buněčné linie MeSH
• Cricetulus MeSH
• dánio pruhované MeSH
• dendrimery aplikace a dávkování   toxicita   MeSH
• embryo nesavčí MeSH
• LD50 MeSH
• malá interferující RNA aplikace a dávkování   MeSH
• organofosforové sloučeniny aplikace a dávkování   toxicita   MeSH
• silany aplikace a dávkování   toxicita   MeSH
• transfekce metody   MeSH
• umlčování genů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• carbosilane MeSH Prohlížeč
• dendrimery MeSH
• malá interferující RNA MeSH
• organofosforové sloučeniny MeSH
• silany MeSH