Hydroxyl-terminated Dendrimers Research Articles

Hydroxyl-terminated dendrimers with sulfonimide linkers as binders for metals of industrial significance.

First- and second-generation hydroxyl-terminated dendrimers were prepared starting from a 1,3-diaminopropane core and sulfonimide linkers. A first-generation mesitylene-derived dendrimer was also prepared with the same terminals. The dendrimers were then reacted with Fe3+, Al3+, and UO22+ separately in order to apply the dendrimers for binding these metals, which have important industrial applications and pose environmental problems simultaneously. The prepared dendrimers were also shown to bind Fe3+ selectively from mixtures with Al3+.

PH- and Functionalization-Dependent Host-Guest Interactions Between Fluorescein and Various Poly(amidoamine) Dendrimers.

Dendrimers are branched macromolecules that can be functionalized with a large variety of chemical moieties. Dendrimers can therefore be specifically designed to interact with target molecules. Although tailored dendrimers hold promise for targeted drug delivery and wastewater cleanup, these applications require more detailed and systematic studies on how dendrimer-guest interactions depend on environmental conditions. In light of this need, we studied pH-dependent interactions between fluorescein and poly(amidoamine) dendrimers with three different terminal groups. Crucially, both fluorescein and dendrimers have multiple protonation equilibria, which can enable interactions in different pH windows through various possible mechanisms. Such interactions are studied through UV-vis and fluorescence spectroscopies, which reveal a redshift that occurs upon fluorescein-dendrimer binding. The resulting pH-dependent spectra are complex but can be analyzed quantitatively with an open-source mathematical protocol. Consequently, we show that fluorescein binds across four pH units with amine-terminated dendrimers, across two units with hydroxyl-terminated dendrimers and does not interact attractively with carboxyl-terminated dendrimers. These functionalization-dependent host-guest interactions stabilize fluorescein's dianionic form and are predominantly electrostatically driven, with likely auxiliary hydrogen and CH-π bonding. Notably, these auxiliary mechanisms appear too weak to drive dendrimer-fluorescein interactions on their own. Overall, this work yields valuable insights into dendrimer-fluorescein association and provides a readily reproducible framework for studying host-guest interactions.

Polyester Dendrimers Based on Bis-MPA for Doxorubicin Delivery.

Although doxorubicin (DOX) is one of the most used chemotherapeutic drugs due to its efficacy against a wide group of cancer types, it presents severe side effects. As such, intensive research is being carried out to find new nanoscale systems that can help to overcome this problem. Polyester dendrimers based on the monomer 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) are very promising systems for biomedical applications due to their biodegradability properties. In this study, bis-MPA-based dendrimers were, for the first time, evaluated as DOX delivery vehicles. Generations 4 and 5 of bis-MPA-based dendrimers with hydroxyl groups at the surface were used (B-G4-OH and B-G5-OH), together with dendrimers partially functionalized with amine groups (B-G4-NH2/OH and B-G5-NH2/OH). Partial functionalization was chosen because the main purpose was to compare the effect of different functional groups on dendrimers' drug delivery behavior without compromising cell viability, which is often affected by dendrimers' cationic charge. Results revealed that bis-MPA-based dendrimers were cytocompatible, independently of the chemical groups that were present at their surface. The B-G4-NH2/OH and B-G5-NH2/OH dendrimers were able to retain a higher number of DOX molecules, but the in vitro release of the drug was faster. On the contrary, the hydroxyl-terminated dendrimers exhibited a lower loading capacity but were able to deliver the drug in a more sustained manner. These results were in accordance with the cytotoxicity studies performed in several models of cancer cell lines and human mesenchymal stem cells. Overall, the results confirmed that it is possible to tune the drug delivery properties of bis-MPA-based dendrimers by modifying surface functionalization. Moreover, molecular modeling studies provided insights into the nature of the interactions established between the drug and the bis-MPA-based dendrimers─DOX molecules attach to their surface rather than being physically encapsulated.

Hydroxyl-Terminated Triazine Derivatives Grafted Graphene Oxide for Epoxy Composites: Enhancement of Interfacial and Mechanical Properties.

An effective approach to the fabrication of progressive epoxy nanocomposites by the incorporation of hydroxyl-terminated dendrimers functionalized graphene oxide (GO-TCT-Tris) is reported. The relationship between surface grafting, chemical construction, morphology, dispersion, and interfacial interaction as well as the corresponding mechanical properties of the composites were studied in detail. It was shown that hydroxyl-terminated triazine derivatives have been resoundingly bonded onto the GO surface through covalent bonding, which effectively improved the dispersion and compatibility of GO sheets in epoxy resin. The tensile and flexural tests manifested that the GO-TCT-Tris/epoxy composites exhibited greater tensile/flexural strength and modulus than either the pure epoxy or the GO/epoxy composites. For GO-TCT-Tris (0.10 wt%)/epoxy composite, the tensile strength and elastic modulus increased from 63 ± 4 to 89 ± 6 MPa (41.27%) and from 2.8 ± 0.1 to 3.6 ± 0.2 GPa (28.57%), and the flexural strength and modulus increased from 106 ± 5 to 158 ± 6 MPa (49.06%) and from 3.0 ± 0.1 to 3.5 ± 0.2 GPa (16.67%), respectively, compared to the pure epoxy matrix. Moreover, the fractographic analysis also illustrated the ameliorative interfacial interaction between GO-TCT-Tris and epoxy matrix.

Hydroxyl‐Terminated Dendrimer Acting as a High Exhaustion Agent for Chrome Tanning

AbstractSevere restrictions for chromium discharge and scarcity of chromium resources have forced the tanners to seek for low‐waste and high exhaust chrome tanning technology. Based on the structural traits of dendrimers, in this paper, a series of hydroxyl terminated dendrimers (HTD) with different molecules weight (Mw) was synthesized and applied in the chrome tanning of pigskin. The effect of HTD was investigated on chromium discharge in effluent, and on the shrinkage temperature (Ts), denaturation temperature (Td), mechanical properties, and microstructure of the leather. The experimental results indicated that the chromium discharge in effluent by applying HTD (A1) was reduced to 236.0 mg/L, almost one‐sixth of the conventional chrome tanning. HTD that, possesses high hydroxyl density, has endowed the obtained leather with higher chrome uptake, Ts, and mechanical properties. Specially, HTD could slow down the basification process by the forming of hydrogen bonds with collagen residues. In addition, HTD could combine more chromium and form net crosslink, notably improve the chrome uptake and hydrothermal stability. Therefore, it is conceivable that the HTD could act as a high exhaustion agent in chrome tanning process.

Atomistic computer simulations on multi-loaded PAMAM dendrimers: a comparison of amine- and hydroxyl-terminated dendrimers.

Poly(amidoamine) (PAMAM) dendrimers have been extensively studied as delivery vectors in biomedical applications. A limited number of molecular dynamics (MD) simulation studies have investigated the effect of surface chemistry on therapeutic molecules loading, with the aim of providing insights for biocompatibility improvement and increase in drug loading capacity of PAMAM dendrimers. In this work, fully atomistic MD simulations were employed to study the association of 5-Fluorouracil (5-FU) with amine (NH2)- and hydroxyl (OH)-terminated PAMAM dendrimers of generations 3 and 4 (G3 and G4). MD results show a 1:12, 1:1, 1:27, and 1:4 stoichiometry, respectively, for G3NH2-FU, G3OH-FU, G4NH2-FU, and G4OH-FU complexes, which is in good agreement with the isothermal titration calorimetry results. The results obtained showed that NH2-terminated dendrimers assume segmented open structures with large cavities and more drug molecules can encapsulate inside the dendritic cavities of amine terminated dendrimers. However, OH-terminated have a densely packed structure and therefore, 5-FU drug molecules are more stable to locate close to the surface of the dendrimers. Intermolecular hydrogen bonding analysis showed that 5-FU drug molecules have more tendency to form hydrogen bonds with terminal monomers of OH-terminated dendrimers, while in NH2-terminated these occur both in the inner region and the surface. Furthermore, MM-PBSA analysis revealed that van der Waals and electrostatic energies are both important to stabilize the complexes. We found that drug molecules are distributed uniformly inside the amine and hydroxyl terminated dendrimers and therefore, both dendrimers are promising candidates as drug delivery systems for 5-FU drug molecules.

Effect of Terminal Groups of Dendrimers in the Complexation with Antisense Oligonucleotides and Cell Uptake.

Poly(amidoamine) dendrimers are the most recognized class of dendrimer. Amino-terminated (PAMAM-NH2) and hydroxyl-terminated (PAMAM-OH) dendrimers of generation 4 are widely used, since they are commercially available. Both have different properties, mainly based on their different overall charges at physiological pH. Currently, an important function of dendrimers as carriers of short single-stranded DNA has been applied. These molecules, known as antisense oligonucleotides (asODNs), are able to inhibit the expression of a target mRNA. Whereas PAMAM-NH2 dendrimers have shown to be able to transfect plasmid DNA, PAMAM-OH dendrimers have not shown the same successful results. However, little is known about their interaction with shorter and more flexible molecules such as asODNs. Due to several initiatives, the use of these neutral dendrimers as a scaffold to introduce other functional groups has been proposed. Because of its low cytotoxicity, it is relevant to understand the molecular phenomena involving these types of dendrimers. In this work, we studied the behavior of an antisense oligonucleotide in presence of both types of dendrimers using molecular dynamics simulations, in order to elucidate if they are able to form stable complexes. In this manner, we demonstrated at atomic level that PAMAM-NH2, unlike PAMAM-OH, could form a well-compacted complex with asODN, albeit PAMAM-OH can also establish stable interactions with the oligonucleotide. The biological activity of asODN in complex with PAMAM-NH2 dendrimer was also shown. Finally, we revealed that in contact with PAMAM-OH, asODN remains outside the cells as TIRF microscopy results showed, due to its poor interaction with this dendrimer and cell membranes.

Next-generation sequencing reveals low-dose effects of cationic dendrimers in primary human bronchial epithelial cells.

Gene expression profiling has developed rapidly in recent years with the advent of deep sequencing technologies such as RNA sequencing (RNA Seq) and could be harnessed to predict and define mechanisms of toxicity of chemicals and nanomaterials. However, the full potential of these technologies in (nano)toxicology is yet to be realized. Here, we show that systems biology approaches can uncover mechanisms underlying cellular responses to nanomaterials. Using RNA Seq and computational approaches, we found that cationic poly(amidoamine) dendrimers (PAMAM-NH2) are capable of triggering down-regulation of cell-cycle-related genes in primary human bronchial epithelial cells at doses that do not elicit acute cytotoxicity, as demonstrated using conventional cell viability assays, while gene transcription was not affected by neutral PAMAM-OH dendrimers. The PAMAMs were internalized in an active manner by lung cells and localized mainly in lysosomes; amine-terminated dendrimers were internalized more efficiently when compared to the hydroxyl-terminated dendrimers. Upstream regulator analysis implicated NF-κB as a putative transcriptional regulator, and subsequent cell-based assays confirmed that PAMAM-NH2 caused NF-κB-dependent cell cycle arrest. However, PAMAM-NH2 did not affect cell cycle progression in the human A549 adenocarcinoma cell line. These results demonstrate the feasibility of applying systems biology approaches to predict cellular responses to nanomaterials and highlight the importance of using relevant (primary) cell models.

First evidences of PAMAM dendrimer internalization in microorganisms of environmental relevance: A linkage with toxicity and oxidative stress

This article reports novel results on the toxic mechanisms of action of amine- and hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers toward microorganisms of environmental relevance, namely a cyanobacterium of the genus Anabaena and the green alga Chlamydomonas reinhardtii. We used PAMAM ethylenediamine core dendrimers from generations G2 to G4, which displayed a positive charge, measured as ζ-potential, in culture media. All amine-terminated and most remarkably the G4 hydroxyl-terminated dendrimer inhibited the growth of both microorganisms. The effect on the growth of the green alga was significantly higher than that on the cyanobacterium. With concentrations expressed in terms of molarity, there was a clear relationship between dendrimer generation and toxicity, with higher toxicity for higher generation. Hormesis was observed for hydroxyl-terminated dendrimers at low concentrations. The cationic dendrimers and G4-OH significantly increased the formation of reactive oxygen species (ROS) in both organisms. ROS formation was not related with the chloroplast or photosynthetic membranes and photosystem II photochemistry was unaffected. Cell damage resulted in cytoplasm disorganization and cell deformities and was associated to an increase in ROS formation and lipid peroxidation in mitochondria in the green alga; cell wall and membrane disruption with apparent loss of cytoplasmic contents was found in the cyanobacterium. It was determined for the first time that cationic PAMAM dendrimers were quickly and largely internalized by both organisms. These results warn against the generalization of the use of dendrimers, which may pose significant risk for the environment and particularly for primary producers which are determinant for the health of natural ecosystems.

Dendrimer stabilized silver particles for the antimicrobial finishing of textiles

Herein a simple approach to fabricate hybrid nanomaterials based on dendrimers as polymeric stabilizers for the preparation of silver nanoparticles in aqueous medium were presented. Solutions of these functional nanomaterials were used as finishing agents to produce antimicrobial textiles. The concept was verified on different generations of hydroxyl-terminated dendrimers with increasing size from first to fifth generation. The application was tested on two different fabrics types made of cotton and polyester. The thermal fixation was performed at 120 or 160°C. The antimicrobial properties of the treated fabrics were investigated using the bacteria Escherichia coli and Staphylococcus aureus. The antimicrobial effect of the treated fabrics was found which significant correlates not only with the amount of the silver content in the finishing agent but also with size of the generated Ag-nanoparticles. Furthermore, the results confirmed that the antimicrobial effect rises with increasing the dendrimers’ generations suggested due to decreasing the size of the formed silver particles. By changing both parameters thermal fixation and dendrimers’ generations, the strength of the antimicrobial effect can be controlled in a wide manner. This could be advantageous for applications demanding a textile with a certain antimicrobial effect.

Charge affects the oral toxicity of poly(amidoamine) dendrimers

Poly(amidoamine) (PAMAM) dendrimers have been evaluated for the influence of surface functionality and size on the epithelial barrier of the gut with the goal of identifying safe carriers that can be used for oral drug delivery. Limited studies are conducted to date, however, to assess the toxicity of PAMAM dendrimers in vivo when administered by the oral route. The goal of this research was to conduct an oral acute toxicity study of PAMAM dendrimers as a function of size and charge in immune competent CD-1 mice. Maximum tolerated doses (MTD) of PAMAM dendrimers as a function of size and surface functionality were established and clinical signs of toxicity monitored. Results demonstrate that positively charged dendrimers caused more toxicity, whereas their anionic counterparts were tolerated at ten times higher doses. Severe signs of toxicity observed for large (G7) cationic amine- or hydroxyl-terminated dendrimers include hemobilia and spleenomegaly. The MTD for these dendrimers ranged from 30mg/kg to 200mg/kg. Anionic G6.5 or smaller molecular weight carboxyl-, amine-, or hydroxyl-terminated dendrimers (G3.5-COOH, G4-NH2, G4-OH) on the other hand were tolerated at doses of up to 500mg/kg (300mg/kg in some cases) with minimal or no signs of toxicity. Establishing the MTD of orally delivered PAMAM dendrimers and the influence of surface functionality and size on toxicity aids in the rational design of PAMAM-drug conjugates for oral drug delivery applications.

Size and surface charge significantly influence the toxicity of silica and dendritic nanoparticles

The influence of size, surface charge and surface functionality of poly(amido amine) dendrimers and silica nanoparticles (SNPs) on their toxicity was studied in immunocompetent mice. After systematic characterization of nanoparticles, they were administered to CD-1 (caesarean derived-1) mice to evaluate acute toxicity. A distinct trend in nanotoxicity based on surface charge and functional group was observed with dendrimers regardless of their size. Amine-terminated dendrimers were fatal at doses >10 mg/kg causing haematological complications such as disseminated intravascular coagulation-like manifestations whereas carboxyl- and hydroxyl-terminated dendrimers of similar sizes were tolerated at 50-fold higher doses. In contrast, larger SNPs were less tolerated than smaller SNPs irrespective of their surface functionality. These findings have important implications in the use of these nanoparticles for various biomedical applications.

High-Resolution Imaging of the Intramolecular Structure of Indomethacin−Carrying Dendrimers by Scanning Tunneling Microscopy

Dendrimers have shown great potential in drug delivery because of their enhancement of drug solubility in aqueous media, leading to an increase in in vivo circulation and efficacy to targets. The structure of drug-dendrimer complexes however, is not well-known owing to the difficulties associated with visualizing individual drug molecules attached to dendrimers. Scanning tunneling microscopy (STM) enables visualization of dendrimer intramolecular structures using our approach of metal ion tagging. This work extends the approach to reveal the hierarchical structure of indomethacin-loaded poly(amidoamine) hydroxyl-terminated dendrimers. STM imaging provides structural information such as their height, lateral dimensions, and volume. High-resolution STM images enable the identification and count of individual indomethacin molecules bound to the anterior of dendrimers. Removal of drug molecules by the STM tip allows the calculation of individual drug-dendrimer binding energy, which is consistent with 1-3 hydrogen bonds. These investigations provide new insight into the hierarchical structure and nature of indomethacin-dendrimer interactions and deepen our understanding of the stability and pharmacokinetic behavior of dendrimer-based drug delivery vehicles.

Deformation and Hyperfine Structures of Dendrimers Investigated by Scanning Tunneling Microscopy

Scanning tunneling microscopy (STM) is known to provide the highest spatial resolution in real space imaging of materials, and its applications are most common among conductive and semiconductive systems. The high tunneling barrier of insulators diminishes the tunneling probability and thus compromises STM's resolution. This work introduces a simple method to approach this problem, by using STM for high-resolution imaging of insulating materials such as the fourth and fifth generations of poly(amidoamine) hydroxyl-terminated dendrimers. The tunneling barrier is lowered by precoordination with Cu(II) or Pt(II) ions, enabling intramolecular hyperfine features be resolved with 0.2 nm resolution. The spatial distribution, size, and overall number of hyperfine features are consistent with the location of dendrimer termini. The immobilization process deforms dendrimers from the spherical geometry in solution phase to asymmetrical domes in ambient. The ultrahigh vacuum (UHV) environment leads to a higher degree of deformation with reduction of volume. The high-resolution images enable the determination of fundamental parameters of individual dendrimers, including axis, height, asymmetry, and volume. From STM spectroscopy and prior knowledge of dendritic systems, the STM imaging mechanism under UHV is consistent with metal(0) nanoparticles encapsulated by dendrimers, while ambient imaging is most likely via metal-ion-facilitated charge transport. The results from this investigation bring us one step closer toward structural characterization at atomistic level and should enable direct comparison of dendrimer structures with simulations, and deepen our understanding of charge transport in dendrimer systems.

A PEM Fuel Cell based on Carbon-Fiber Electrodes Modified with Platinum Nanoparticles Encapsulated in PAMAM Dendrimers

This report describes the construction and testing of fuel cells based on carbon-fiber-paper electrodes that were first functionalized in acid media by anodic pretreatment and then modified with platinum nanoparticles encapsulated in hydroxyl-terminated dendrimers (G4OHPt). Scanning the potential of the functionalized carbon-fiber electrodes in a solution containing the dendrimer-encapsulated nanoparticles immobilizes the material on the carbon surface. Previous studies have shown the capacity of the supported nanoparticles to catalyze the oxygen-reduction reaction and suggested some promising approaches that such electrodes offer for the development of more efficient fuel cells. Here we present preliminary results on the performance of experimental fuel cells based on nanoparticle-modified carbon-fiber electrodes.

Synthesis and Electrochemical Characterization of Platinum and Ruthenium Nanoparticles Encapsulated in PAMAM-G4OH Dendrimer for Oxygen Reduction in the Presence of Methanol.

In this work, we describe the preparation of composites of Pt, Ru and bimetallic Pt-Ru nanoparticles encapsulated in generation-four hydroxyl-terminated dendrimers (PAMAM-G4OH). The absorption of the metal ions and their chemical reduction were followed by UV-vis spectroscopy. Subsequently, the dendrimers encapsulating the Pt, Ru or Pt-Ru particles were immobilized on the oxidized surface of a glassy carbon electrode (GCE). Cyclic voltammetry (CV) and rotating disk electrode (RDE) measurements were used to determine the oxygen reduction reaction (ORR) kinetics on this surface in aqueous sulfuric acid media and in sulfuric acid solution containing methanol. Preliminary results show that the nanoelectrocatalyst exhibits good stability in these media and good electrocatalytic activity for the ORR in the presence of methanol.

Investigation of Silver Binding to Polyamidoamine (PAMAM) Dendrimers by ESI Tandem Mass Spectrometry

Electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to probe the binding of silver ions and reduced silver species with polyamidoamine generation 1 amine-terminated (PAMAMG1NH2) and generation 2 hydroxyl-terminated (PAMAMG2OH) dendrimers. At Ag(+)/PAMAMG2OH molar ratios of </=1, 1:1 complexes are observed, while at ratios >1, 2:1 and low abundance 3:1 complexes emerge. Similar results were observed for PAMAMG1NH2. The collisional activated dissociation (CAD) patterns of the dendrimer ions are characterized by losses of amidoamine branches resulting largely from hydrogen migration and cleavage reactions. Ag+/dendrimer complexes are characterized by the loss of a dendrimer branch from the complex, with the silver ion remaining bound to a dendrimer fragment. When the Ag+-bound dendrimer complexes are reduced by hydrazine, low abundance complexes, whose m/z values are consistent with ones containing zerovalent silver species, are observed in the mass spectra. Complexes with three silver atoms are observed in the spectrum containing PAMAMG1NH2, and complexes with four and five silver atoms are observed with PAMAMG2OH. The CAD fragmentation patterns of the complexes formed after the silver reduction are different than those observed for complexes containing one silver ion and are characterized by the ejection of all silver species, possibly as a cluster, leaving the intact dendrimer ion. Experiments with Cu+, Cu2+, and Pt2+ binding to PAMAMG2OH were also done, but reduced metal clusters were not observed in the mass spectra after the addition of hydrazine.

Fluorometric assay for detection and quantitation of polyamidoamine dendrimers

Polyamidoamine dendrimers are protein-like nanomaterials that have many potential biological applications. Research studies using dendrimers often require their detection and quantitation. This article describes a simple, inexpensive, and rapid fluorometric assay based on the ability of dendrimers to bind the fluorescent probe, 8-anilino-1-naphthalene-sulfonic acid. This interaction leads to an enhanced fluorescence intensity of the dye that shows a linear relationship with dendrimer concentration. The procedure is applicable to dendrimers that have various surface functional groups and internal cores. Amine- and hydroxyl-terminated dendrimers gave the best calibration curves under alkaline conditions (pH 7.4). Carboxyl-terminated dendrimers required acidic conditions for their measurement. The assay for dendrimers with an amine surface and an ethylene diamine core was accurate between 0 and 100 μM and produced a within-run coefficient of less than 5%. Under the assay conditions used, the fluorescence signal strength was dependent on type of surface group and core length of the dendrimer.

Determination of the Intrinsic Proton Binding Constants for Poly(amidoamine) Dendrimers via Potentiometric pH Titration

Protonation of fourth-generation poly(amidoamine) dendrimers terminated with hydroxyl and amine functional groups has been studied by potentiometric pH titration. The titration data are analyzed using a multishell structural model and a Frumkin adsorption isotherm to approximate proton- dendrimer binding equilibria. Site-to-site correlation is ignored, and counterions are treated according to the standard Debye-Huckel theory. This analysis yields two binding parameters: the intrinsic proton binding constant and a constant that characterizes the strength of electrostatic interactions among occupied binding sites. For the hydroxyl-terminated dendrimers, the internal tertiary amines have an average binding constant (pK ) 6.30) 1-2 pH units lower than the value expected for a single, isolated binding site. This shift in pK is attributed to a hydrophobic microenvironment within the dendrimer interior. In contrast, no significant shift has been observed in the binding constant (pK ) 9.23) for the peripheral primary amines in the amine-terminated dendrimer because the microenvironment around the primary amines is more hydrophilic. The strength of electrostatic interactions obtained from titration data is 3 times (primary amines) and 8 times (tertiary amines) smaller than the calculated values based on the multishell model. We hypothesize that the diminished interaction strength results from ion pairing between bound protons and counterions. In addition to the Debye-Huckel contribution from mobile ions, ion pairing provides extra Coulomb charge screening.