Dendrimer Generation Number Research Articles

Biological Effects in Cancer Cells of Mono- and Bidentate Conjugation of Cisplatin on PAMAM Dendrimers: A Comparative Study.

Cisplatin (cis-diamminedichloroplatinum(II)) is a potent chemotherapeutic agent commonly used to treat cancer. However, its use also leads to serious side effects, such as nephrotoxicity, ototoxicity, and cardiotoxicity, which limit the dose that can be safely administered to patients. To minimize these problems, dendrimers may be used as carriers for cisplatin through the coordination of their terminal functional groups to platinum. Here, cisplatin was conjugated to half-generation anionic PAMAM dendrimers in mono- and bidentate forms, and their biological effects were assessed in vitro. After preparation and characterization of the metallodendrimers, their cytotoxicity was evaluated against several cancer cell lines (A2780, A2780cisR, MCF-7, and CACO-2 cells) and a non-cancer cell line (BJ cells). The results showed that all the metallodendrimers were cytotoxic and that the cytotoxicity level depended on the cell line and the type of coordination mode (mono- or bidentate). Although, in this study, a correlation between dendrimer generation (number of carried metallic fragments) and cytotoxicity could not be completely established, the monodentate coordination form of cisplatin resulted in lower IC50 values, thus revealing a more accessible cisplatin release from the dendritic scaffold. Moreover, most of the metallodendrimers were more potent than the cisplatin, especially for the A2780 and A2780cisR cell lines, which showed higher selectivity than for non-cancer cells (BJ cells). The monodentate G0.5COO(Pt(NH3)2Cl)8 and G2.5COO(Pt(NH3)2Cl)32 metallodendrimers, as well as the bidentate G2.5COO(Pt(NH3)2)16 metallodendrimer, were even more active towards the cisplatin-resistant cell line (A2780cisR cells) than the correspondent cisplatin-sensitive one (A2780 cells). Finally, the effect of the metallodendrimers on the hemolysis of human erythrocytes was neglectable, and metallodendrimers' interaction with calf thymus DNA seemed to be stronger than that of free cisplatin.

Size-tunable fluorescent dendrimersomes via aggregation-induced emission.

Tetraphenylethylene-functionalized amphiphilic Janus dendrimers of up to third generation are synthesized. Their self-assembly has been studied under kinetic and thermodynamic control. By varying the dendrimer generation number and the self-assembly condition, fluorescent dendrimersomes of tunable size (∼60-200 nm) and quantum yield (5.7-17.4%) are obtained in aqueous medium.

Muscle lineage switching by migratory behaviour-driven epigenetic modifications of human mesenchymal stem cells on a dendrimer-immobilized surface

Understanding of the fundamental mechanisms of epigenetic modification in the migration of human mesenchymal stem cells (hMSCs) provides surface design strategies for controlling self-renewal and lineage commitment. We investigated the mechanism underlying muscle lineage switching of hMSCs by cellular and nuclear deformation during cell migration on polyamidoamine dendrimer surfaces. With an increase in the dendrimer generation number, cells exhibited increased nuclear deformation and decreased lamin A/C and lamin B1 expression. Analysis of two repressive modifications (H3K9me3 and H3K27me3) and one activating modification (H3K9ac) revealed that H3K9me3 was suppressed, and H3K9ac and H3K27me3 were upregulated in the cultures on a higher-generation dendrimer surface. This induced significant hMSC lineage switching to smooth, skeletal, and cardiac muscle lineages. Thus, reorganizations of the nuclear lamina and cytoskeleton related to migration changes on dendrimer surfaces are responsible for the integrated regulation of histone modifications in hMSCs, thereby shifting the cells from the multipotent state to muscle lineages. These findings improve our understanding of the role of epigenetic modification in cell migration and provide new insights into how designed surfaces can be applied as cell-instructive materials in the field of biomaterial-guided differentiation of hMSCs to different cell types. Statement of SignificanceStem cell engineering strategies currently applied the mechanical cues that emerge from cellular microenvironment to regulate stem cell behaviour. This study significantly improved our understanding of the mechanotransduction mechanism involving cell-ECM and cytoskeleton-nucleoskeleton interactions, and of nuclear genome regulation based on cellular responses to biomaterial modifications. The new insights into how the physical environment on a culture surface influences cell behaviour improve our understanding of mechanical control mechanisms of the interactions of cells with the extracellular environment. Our findings are also expected to contribute to and play an essential role in the development of future material strategies for creating artificial cell-instructive niches.

Optimal generation number in magnetic-cored dendrimers as Pb(II) and Cd(II) adsorbents

ABSTRACT As the generation number of dendrimers increases, more organic branches and terminal groups are synthesized on the surface. However, this may not be actual situations in all generations of dendrimers. Different generations of magnetic cored dendrimer (MCD) terminalized with amine functional groups were compared as adsorbents for heavy metal ions in water. To determine the optimal generation number as adsorbent, the maximal adsorption of lead and cadmium on generation 1, 2, and 3 (G1, G2, and G3) MCDs. Higher generation MCD had more organic contents and possibly terminal groups on its structure. However, G2 MCD was the highest in adsorbing both lead and cadmium. An acid–base titration was performed to quantify the amine functional groups. The active amine sites on G2 are 4.35 times as much as that of G1 and 0.12 times as much as that of G3, which coincided with the adsorption experimental result. Incomplete dendritic structure formation due to steric hindrance caused G2 MCD to be the most efficient among the three generations of MCDs in this research.

Core–Shell Nanoparticles Containing Peptide Dendrimers

Dealloying of bimetallic gold core–silver shell nanoparticles (NPs) is achieved using peptide dendrimers from generation 1 to generation 3. The resulting NPs exhibit optical properties characteristic of Au/Ag core–shell NPs with weak surface plasmon resonance interactions between the core and shell. Transmission electron microscopy and x-ray photoelectron spectroscopy of the core–shell NPs exhibit a size and composition dependence on the dendrimer generation number. Rutherford backscattering spectrometric analyses of core–shell NPs containing dendrimer innerlayer indicates that the NPs are consisting of discrete domains of Ag–shell and Au–core.

Removal of Co(II) from fuel ethanol by silica-gel supported PAMAM dendrimers: Combined experimental and theoretical study

Silica-gel supported PAMAM dendrimers (SiO2-G0.5∼SiO2-G3.0) were used for the removal of Co(II) from fuel ethanol by batch method. The adsorption mechanism was revealed by combining the results of experiment and density functional theory (DFT) calculation. Results indicated the adsorption capacity was closely related with the generation number of PAMAM dendrimer, contact time, Co(II) concentration, and temperature. Amino-terminated PAMAM dendrimers exhibited better adsorption performance than the corresponding ester-terminated ones. Kinetic adsorption followed pseudo-second-order model and dominated by film diffusion. Isotherm adsorption can be well depicted by Langmuir isotherm model and proceeded by chemical mechanism. Thermodynamic parameters implied the adsorption was spontaneous, endothermic, and randomness incremental process. DFT calculation demonstrated that ester-terminated PAMAM tended to chelate with Co(II) by secondary amine nitrogen atoms and carbonyl oxygen atoms in a quadri-coordinated manner, while amino-terminated PAMAM preferred to act as tetradentate and pentadentate ligand to bind Co(II) with secondary amine nitrogen atom, carbonyl oxygen atom, and primary amine nitrogen atom. Charge transfer of the adsorption process mainly occurred from PAMAM dendrimer to Co(II).

A molecular dynamics investigation of the planar elongational rheology of chemically identical dendrimer-linear polymer blends.

The structure and rheology of model polymer blends under planar elongational flow have been investigated through nonequilibrium molecular dynamics simulations. The polymeric blends consist of linear polymer chains (187 monomers per chain) and dendrimer polymers of generations g = 1 - 4. The number fraction, x, of the dendrimer species is varied (4%, 8%, and 12%) in the blend melt. We study the effect of extension rate, dendrimer generation, and dendrimer number fraction on pair distribution functions for different blend systems. We also calculate the extension-rate dependent radius of gyration and ratios of the eigenvalues of the gyration tensor to study the elongation-induced deformation of the molecules in the blend. Melt rheological properties including the first and second extensional viscosities are found to fall into the range between those of pure dendrimer and pure linear polymer melts, which are correlated with the mass fraction and generation of the dendrimers in the blend.

Designing, characterization, and thermal behavior of triazine-based dendrimers

Abstract Different generations of dendritic architecture with piperazine in core moiety and hydroxyl groups on the periphery were designed by divergent method. 1,4-biz(4,6-trichloro-1,3,5-triazin-2-yl)piperazine was synthesized as a core for dendrimer synthesis. Dendrimer was then grown to G3 from core compound using diethanolamine and cyanuric chloride as branching units. Dendrimer generations were characterized by infrared (IR) spectroscopy [Fourier transform IR (FTIR)], 1H-nuclear magnetic resonance (NMR), 13C-NMR, electrospray ionization-mass spectrometry (ESI-MS), and elemental analysis. The thermal behavior of both full- and half-generation dendrimers was investigated by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The TGA study revealed that dendrimer generations had a moderate thermal stability. Chlorine-terminated half-generation dendrimers were thermally more stable than hydroxyl-terminated full-generation dendrimers. The DSC technique was employed to determine the glass transition temperatures (Tg) of dendrimer generations. It was observed that the glass transition temperatures of synthesized dendrimer generations were of low value, which is similar to the values reported for the polyamidoamine (PAMAM) dendrimer of the same generation. It was also observed that, with the increase in the molecular weight or generation number of dendrimer, the glass transition temperature was also increased.

Computer simulations of dendrimer-polyelectrolyte complexes.

We carry out a systematic analysis of static properties of the clusters formed by complexation between charged dendrimers and linear polyelectrolyte (LPE) chains in a dilute solution under good solvent conditions. We use single chain in mean-field simulations and analyze the structure of the clusters through radial distribution functions of the dendrimer, cluster size, and charge distributions. The effects of LPE length, charge ratio between LPE and dendrimer, the influence of salt concentration, and the dendrimer generation number are examined. Systems with short LPEs showed a reduced propensity for aggregation with dendrimers, leading to formation of smaller clusters. In contrast, larger dendrimers and longer LPEs lead to larger clusters with significant bridging. Increasing salt concentration was seen to reduce aggregation between dendrimers as a result of screening of electrostatic interactions. Generally, maximum complexation was observed in systems with an equal amount of net dendrimer and LPE charges, whereas either excess LPE or dendrimer concentrations resulted in reduced clustering between dendrimers.

Mean-Field Modeling of the Encapsulation of Weakly Acidic Molecules in Polyelectrolyte Dendrimers

The unique architecture of dendrimers has attracted interest in a wide variety of biomedical applications such as drug delivery. In order to gain insight into the solubilization of drugs inside dendrimer architectures, we have developed and numerically implemented a self-consistent field theory model for the equilibrium characteristics of charged dendrimer molecules in the presence of weakly acidic drug molecules. Using such a model, we examine the relative influence of excluded volume, electrostatic, and local enthalpic interactions upon the solubilization of drugs in dendrimers. When only excluded volume interactions are accounted, there is no driving force for drug solubilization inside the dendrimer, and hence depletion of the drug from the dendrimer molecule (relative to the bulk drug concentration) is observed. The inclusion of electrostatic interactions within the model results in solubilization of drugs within the dendrimer. The solubilization of the drugs is shown to increase with increasing drug charge density and increasing dendrimer generation number. We probe the effect of enthalpic interactions and demonstrate that the number of drug molecules encapsulated through enthalpic interaction is dependent upon the number of dendrimer monomers, the enthalpic interaction parameters between the dendrimer and drug (χPD), and the drug and solvent (χDS). We also analyze the combined effects of the preceding interactions to identify the synergism in their influence and delineate the relative importance of different parameters such as pOH, size of the drugs, and the Bjerrum length of the solution in influencing the encapsulation of drugs by dendrimer molecules.

Ionic conductivity of bis(2-cyanoethyl) ether-lithium salt and poly(propylether imine)-lithium salt liquid electrolytes

We report here a multiple-nitrile based lithium-salt liquid electrolyte. The ionic conductivity of poly (propyl ether imine) (abbreviated as PETIM) lithium salt dendrimer liquid electrolyte was observed to be a function of dendrimer generation number, n=0 (monomer)-3. While the highest room temperature ionic conductivity value (similar to 10(-1) Sm-1) was recorded for the bis-2cyanoethyl ether monomer (i.e. zeroth generation; G(0)-CN), conductivity decreased progressively to lower values (similar to 10(-3) Sm-1) with increase in generation number (G(1)-CN -> G(3)-CN). The G(0)-CN and higher dendrimer generations showed high thermal stability (approximate to 150 to 200 degrees C), low moisture sensitivity and tunable viscosity (similar to 10(-2) (G(0)-CN) to 3 (G(3)-CN) Pa s). The linker ether group was found to be crucial for ion transport and also eliminated a large number of detrimental features, chiefly moisture sensitivity, chemical instability associated typically with prevalent molecular liquid solvents. Based on the combination of several beneficial physicochemical properties, we presently envisage that the PETIM dendrimers especially the G(0)-CN electrolytes hold promise as electrolytes in electrochemical devices such as lithium-ion batteries.

Internal Dynamics of Dendritic Molecules Probed by Pyrene Excimer Formation

This review exposes the current poor understanding of the internal segmental chain dynamics of dendrimers in solution probed by monitoring the process of excimer formation between pyrene labels covalently attached to the chain ends of dendrimers. The review begins by covering the bases of fluorescence and the kinetics of pyrene excimer formation before describing a procedure based on the Model Free (MF) analysis that is used to analyze quantitatively the fluorescence decays acquired for dendrimers, the ends of which have been fully and covalently labeled with pyrene. Comparison of the various trends obtained by different research groups describing the efficiency of pyrene excimer formation with the generation number of dendrimers illustrates the lack of consensus between the few studies devoted to the topic. One possible reason for this disagreement might reside in the presence of minute amounts of unattached pyrene labels which act as potent fluorescent impurities and affect the analysis of the fluorescence spectra and decays in an uncontrolled manner. The review points out that the MF analysis of the fluorescence decays acquired with pyrene-labeled dendrimers enables one to account for the presence of unattached pyrene and to retrieve information about the internal segmental dynamics of the dendrimer. It provides guidelines that should enable future studies on pyrene-labeled dendrimers to yield results that are more straightforward to interpret.

Beads-on-String Structure of the Electrostatic Complex of DNA with a High-Generation PAMAM Dendrimer

The electrostatic complexes of polyanionic DNA with cationic dendrimer have been considered as a potential non-viral vector for gene delivery and a model system for understanding DNA-histone interaction. Although it is believed that the gene transfection efficiency may be influenced by the structure of the complex, the supramolecular structure of DNA-dendirmer complexes and its dependence on various system parameters such as dendrimer generation number, charge density, charge ratio and ionic strength are not well resolved. In this study, we investigate the structure of the complex of DNA with polyamidoamine (PAMAM) dendrimer of generation nine (G9) by means of synchrotron small angle X-ray scattering (SAXS). It is found that DNA is always able to wrap around the dendrimer to yield the beads-on-string structure irrespective of the charge density of the dendrimer. The effect of charge density on the persistence length of the chromatin-like fiber thus formed and the pitch length of the DNA superheix wrapping around the dendrimer are elucidated from the calculation of the SAXS profiles based on beads-on-string structure models. The first section in your paper

Kinetic analysis of the interaction between poly(amidoamine) dendrimers and model lipid membranes

We used fluorescence spectroscopy and surface tensiometry to study the interaction between low-generation (G1 and G4) poly(amidoamine) (PAMAM) dendrimers, potential vehicles for intracellular drug delivery, and model lipid bilayers. Membrane association of fluorescently labeled dendrimers, measured by fluorescence anisotropy, increased with increasing size of the dendrimer and with increasing negative charge density in the membrane, indicating the electrostatic nature of the interaction. When the membrane was doped with pyrene-labeled phosphatidyl glycerol (pyrene-PG), pyrene excimer fluorescence demonstrated a dendrimer-induced selective aggregation of negatively charged lipids when the membrane was in the liquid crystalline state. A nonlinear Stern–Volmer quenching of dendrimer fluorescence with cobalt bromide suggested a dendrimer-induced aggregation of lipid vesicles, which increased with the dendrimer's generation number. Surface tensiometry measurements showed that dendrimers penetrated into the lipid monolayer only at subphysiologic surface pressures (<30mN/m). We conclude that the low-generation PAMAM dendrimers associate with lipid membranes predominantly electrostatically, without significantly compromising the bilayer integrity. They bind stronger to membranes with higher fluidity and lower surface pressure, which are characteristic of rapidly dividing cells.

Cardiomyogenic induction of human mesenchymal stem cells by altered Rho family GTPase expression on dendrimer-immobilized surface with d-glucose display

The commitment of stem cells to different lineages is regulated by many cues in the intercellular signals from the microenvironment system. In the present study, we found that alterations in Rho family GTPase activities derived from cytoskeletal formation can lead to guidance of cardiomyogenic differentiation of human mesenchymal stem cells (hMSCs) during in vitro culture. To regulate the cytoskeletal formation of hMSCs, we employed a dendrimer-immobilized substrate that displayed d-glucose. With an increase in the dendrimer generation number, the cells exhibited active migration, accompanied by cell morphological changes of stretching and contracting. Fluorescence microscopy for F-actin, vinculin and glucose transporter1 (GLUT1) clarified the localization of integrin-mediated and GLUT-mediated anchoring, introducing the idea that the morphological changes of the cells were responsive to variations in the generation number of the dendrimer with d-glucose display. On the 5th-generation dendrimer surface, in particular, the cells exhibited RhoA down-regulation and Rac1 up-regulation during the culture, associated with alterations in the cellular morphology and migratory behaviors. It was found that cell aggregation was promoted on this surface, supporting the notion that an increase in N-cadherin-mediated cell–cell contacts and Wnt signaling regulate hMSC differentiation into cardiomyocyte-like cells.

Triazine Dendrimers as Nonviral Vectors for in Vitro and in Vivo RNAi: The Effects of Peripheral Groups and Core Structure on Biological Activity

A family of triazine dendrimers, differing in their core flexibility, generation number, and surface functionality, was prepared and evaluated for its ability to accomplish RNAi. The dendriplexes were analyzed with respect to their physicochemical and biological properties, including condensation of siRNA, complex size, surface charge, cellular uptake and subcellular distribution, their potential for reporter gene knockdown in HeLa/Luc cells, and ultimately their stability, biodistribution, pharmacokinetics and intracellular uptake in mice after intravenous (iv) administration. The structure of the backbone was found to significantly influence siRNA transfection efficiency, with rigid, second generation dendrimers displaying higher gene knockdown than the flexible analogues while maintaining less off-target effects than Lipofectamine. Additionally, among the rigid, second generation dendrimers, those with either arginine-like exteriors or peripheries containing hydrophobic functionalities mediated the most effective gene knockdown, thus showing that dendrimer surface groups also affect transfection efficiency. Moreover, these two most effective dendriplexes were stable in circulation upon intravenous administration and showed passive targeting to the lung. Both dendriplex formulations were taken up into the alveolar epithelium, making them promising candidates for RNAi in the lung. The ability to correlate the effects of triazine dendrimer core scaffolds, generation number, and surface functionality with siRNA transfection efficiency yields valuable information for further modifying this nonviral delivery system and stresses the importance of only loosely correlating effective gene delivery vectors with siRNA transfection agents.

Toxicity of PAMAM dendrimers to Chlamydomonas reinhardtii

In recent decades, a new class of polymeric materials, PAMAM dendrimers, has attracted marked interest owing to their unique nanoscopic architecture and their hopeful perspectives in nanomedicine and therapeutics. However, the potential release of dendrimers into the aquatic environment raises the issue about their toxicity on aquatic organisms. Our investigation sought to estimate the toxicity of cationic PAMAM dendrimers on the green alga, Chlamydomonas reinhardtii. Algal cultures were exposed to different concentrations (0.3–10 mg L −1) of low dendrimer generations (G2, G4 and G5) for 72 h. Potential adverse effects on Chlamydomonas were assessed using esterase activity (cell viability), photosynthetic O 2 evolution, pigments content and chlorophyll a fluorescence transient. According to the median inhibitory concentration (IC 50) appraised from esterase activity, toxicity on cell viability decreased with dendrimer generation number (2, 3 and 5 mg L −1 for G2, G4 and G5 dendrimers, respectively). Moreover, the three generations of dendrimers did not induce the same changes in the photosynthetic metabolism of the green alga. O 2 evolution was stimulated in cultures exposed to the lowest generations tested (i.e. G2 and G4) whereas no significant effects were observed with G5. In addition, total chlorophyll content was increased after G2 treatment at 2.5 mg L −1. Finally, G2 and G4 had positive effects on photosystem II (PSII): the amount of active PSII reaction centers, the primary charge separation and the electron transport between Q A and Q B were all increased inducing activation of the photosynthetic electron transport chain. These changes resulted in stimulation of full photosynthetic performance.

Investigations of Energy Migration in an Organic Dendrimer Macromolecule for Sensory Signal Amplification

The issue of macromolecular exciton delocalization length and fluorescence sensing of energetic materials is investigated and modeled from results of nonlinear optical and time-resolved spectroscopy. By using two- and three-photon absorption techniques the fluorescence quenching effects of an organic dendrimer for sensing TNT were carried out. The Stern-Volmer plots for the set of dendrimers were examined and a large quenching constant for the dendrimer G4 was obtained (1400 M(-1)). The quenching constant was found to increase with the dendrimer generation number. The mechanism for the enhanced sensitivity of the dendrimer system was examined by probing the exciton dynamics with femtosecond fluorescence up-conversion. Fluorescence lifetime measurements revealed a multicomponent relaxation that varied with dendrimer generation. Fluorescence anisotropy decay measurements were used to probe the exciton migration length in these dendrimer systems and for the large structure the excitation migration area covers approximately 20 units. All of these results were used in a model that describes the exciton localization length with the fluorescence quenching strength. The use of time-resolved techniques allows for a closer and more detailed description of the mechanism of sensory amplification in organic macromolecules.

Interaction of water-soluble polypyridylphenylene dendrimers with a polymethacrylate anion

Cationic water-soluble dendrimers have been prepared by the alkylation of pyridyl groups in polypyridylphenylene dendrimers of the first four generations, and their interaction with a polymethacrylate anion has been studied. The stability of polyelectrolyte complexes in aqueoussaline solutions has been studied by fluorimetric titration with the use of the pyrenyl-tagged polyanion, and it has been shown that the stability of these complexes significantly increases with the dendrimer generation number and the content of hydrophobic phenylene groups. Based on sedimentation analysis and turbidimetric titration, it is inferred that a significant part of charged groups of dendrimers are inaccessible to interaction with the polyanion and that water-soluble nonstoichiometric polyelectrolyte complexes develop in mixtures of higher generation dendrimers. Modeling results of this study may be useful for designing efficient cationic dendrimer carriers of genetic material and hydrophobic physiologically active compounds.

Long-Lived Hole Stabilized at a Triphenylamine Core and Shielded by Rigid Phenylazomethine Dendrons: A Pulse Radiolysis Study

The optical properties and reactivity of one-electron oxidized states (radical cations) of dendrimers are investigated in benzonitrile solutions by nanosecond pulse radiolysis. The hole stabilized at the triphenylamine (TPA) core is effectively shielded by a rigid dendritic phenylazomethine (DPA) shell of four generations, leading to an extension of its lifetime by nearly 2 orders of magnitude in comparison with a core radical cation without dendrons. A continuous red shift of the peak in the photoabsorption spectrum in the visible region and a decrease in the extinction coefficients (oscillator strengths) are found with increasing dendrimer generation number. These experimental observations are compared to the results of time-dependent density functional theory. It is suggested that bulky, rigid, insulating DPA dendrons shield against outer reactants and stabilize hole at the TPA core. Correlating the dendrimer generation number with the optical properties and reactivities of the radical cations could shed light on fundamental aspects of structurally defined nanoenvironments having hyperbranched entities.