Lower Generation Dendrimers Research Articles

Photophysical and Electrochemical Properties and Anticancer Activities of Porphyrin-Cored Fluorenodendrimers Synthesized by Click Chemistry

A new class of porphyrin-cored fluorenodendrimers were synthesized by a convergent approach through click chemistry. The zeroth-, first-, and second-generation porphyrin-cored fluorenodendrimers were characterized by means of 1H and 13C NMR spectroscopy, UV-vis spectroscopy, fluorescent spectroscopy, elemental analysis, and MALDI-TOF mass spectrometry. The UV-vis spectrum of the dendrimers showed an increase in the absorption intensity on increasing the dendrimer generation, and a bathochromic shift was observed for higher-generation dendrimers compared with lower-generation dendrimers. The dendrimers showed emission bands at 317, 604–668, and 617–668 nm, the intensity of which increased with increasing dendrimer generation. All the synthesized dendrimers exhibited a reversible oxidation potential in cyclic voltammetry. The therapeutic efficacy of the porphyrin-cored fluorenodendrimers for the inhibition of a growth tumor cell (PA-1) increased with increasing generation number of the dendrimer.

Synthesis, Photochemical, Electrochemical and Cytotoxic Studies on Azobenzene Cored Dendrimer Decorated with Chalcone Motif

Abstractp‐Nitroazobenzene cored dendrimers decorated with chalcone surface group has been synthesized upto second generation by click reaction through convergent strategy. Photoisomerisation of the synthesized azodendrimers at 365 nm reveal the isobestic point at 296 nm with photostationary state at 11 minutes. Cyclic voltammogram exhibited quasi reversible oxidation reduction potential for all the synthesized dendrimers. Further, the second generation azodendrimer show better cytotoxic effect against MCF‐7 human breast cancer cell lines than the lower generation dendrimers.

An unprecedented jump in the viscosity of high-generation carbosilane dendrimer melts

Rheological melt behavior of carbosilane dendrimers from the 3rd up to the 8th generation has been studied experimentally under steady shear, creep and dynamic oscillatory shear. Six orders of magnitude jump in viscosity was found between the 5th and the 6th generations. While the low-generation dendrimer melts demonstrate Newtonian behavior in a wide temperature range of 20÷80 °C, starting from the 6 t h generation, the dendrimer melts lose their ability to freely flow and acquire properties of a material with a well-pronounced yield stress. The storage modulus of high-generation dendrimer melts by far exceeds the loss modulus, furthermore, its value increases with temperature. It is demonstrated that the high-generation carbosilane dendrimers in bulk can be considered a polymer material with unique properties and as that, could find new applications in high-tech areas, in particular, as matrices for sensors.

A Self-Assembled Coumarin-Anchored Dendrimer for Efficient Gene Delivery and Light-Responsive Drug Delivery.

The assembly of low molecular weight polymers into highly efficient and nontoxic nanostructures has broad applicability in gene delivery. In this study, we reported the assembly of coumarin-anchored low generation dendrimers in aqueous solution via hydrophobic interactions. The synthesized material showed significantly improved DNA binding and gene delivery, and minimal toxicity on the transfected cells. Moreover, the coumarin moieties in the assembled nanostructures endow the materials with light-responsive drug delivery behaviors. The coumarin substitutes in the assembled nanostructures were cross-linked with each other upon irradiation at 365 nm, and the cross-linked assemblies were degraded upon further irradiation at 254 nm. As a result, the drug-loaded nanoparticle showed a light-responsive drug release behavior and light-enhanced anticancer activity. The assembled nanoparticle also exhibited a complementary anticancer activity through the codelivery of 5-fluorouracil and a therapeutic gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This study provided a facile strategy to develop light-responsive polymers for the codelivery of therapeutic genes and anticancer drugs.

High-performance one-pack ambient cross-linking latex binders containing low-generation PAMAM dendrimers and ZnO nanoparticles

This study focuses on ambient-temperature self-crosslinking acrylic latex coating compositions containing poly(amidoamine) (PAMAM) dendrimers and ZnO nanoparticles in the role of inter-particle cross-linking agents and flash rust inhibitors. Low-generation amine-terminated PAMAM dendrimers as aqueous solutions were added into latices containing diacetone acrylamide repeat units in their polymer structure. The incorporation of ZnO nanoparticles (without any surface treatment) was performed during the synthesis of a polymer dispersion carried out by the semi-continuous emulsion polymerization technique. The latex storage stability and coating performance with respect to zinc oxide and PAMAM presence were evaluated and compared with a conventional zinc oxide-free coating composition containing adipic acid dihydrazide as the cross-linking agent. It was found that the novel latices containing both PAMAM dendrimers and ZnO nanoparticles exhibited a long-term storage stability and provided crosslinked transparent coating films of high gloss, enhanced mechanical properties, solvent resistance and excellent water whitening resistance. Moreover, the latex compositions containing PAMAM dendrimers as the inter-particle cross-linkers were shown to provide flash rust resistance.

Synthesis, optical properties, and antioxidant and anticancer activity of benzoheterazole dendrimers with triazole bridging unit

Benzoheterazole dendrimers with triazole bridges and bisphenol A/benzophenone core units have been successfully synthesized by click chemistry. Higher generation dendrimers exhibit better antioxidant and anticancer activities than the lower generation dendrimers.

Structure-activity relationship of novel low-generation dendrimers for gene delivery.

Structure-activity relationship (SAR) studies are very critical to design ideal gene vectors for gene delivery. However, It is difficult to obtain SAR information of low-generation dendrimers due to the lack of easy structural modification ways. Here, we synthesized a novel family of rigid aromatic backbone-based low-generation polyamidoamine (PAMAM) dendrimers. According to the number of primary amines, they were divided into two types: four-amine-containing PAMAM (DL1-DL5) and eight-amine-containing PAMAM (DL6-DL10). Due to the introduction of a rigid aromatic backbone, the low-generation PAMAM could be modified easier by different hydrophobic aliphatic chains. Several assays were used to study the interactions of the PAMAM dendrimers with plasmid DNA, and the results revealed that they not only had good DNA binding ability but also could efficiently condense DNA into spherical-shaped nanoparticles with suitable sizes and zeta potentials. The SAR studies indicated that the gene-transfection efficiency of the synthesized materials depended on not only the structure of their hydrophobic chains but also the number of primary amines. It was found that four-amine-containing PAMAM prepared from oleylamine (DL5) gave the best transfection efficiency, which was 3 times higher than that of lipofectamine 2000 in HEK293 cells. The cellular uptake mechanism mediated by DL5 was further investigated, and the results indicated that DL5/DNA complexes entered the cells mainly via caveolae and clathrin-mediated endocytosis. In addition, these low-generation PAMAMs modified with a single hydrophobic tail showed lower toxicity than lipofectamine 2000 in MC3T3-E1, MG63, HeLa, and HEK293 cells. These results reveal that such a type of low-generation polyamidoamines might be promising non-viral gene vectors, and also give us clues for the design of safe and high-efficiency gene vectors.

Size Stability and H2/CO Selectivity for Au Nanoparticles during Electrocatalytic CO2 Reduction.

In this paper, we show that Au nanoparticles (AuNPs) stabilized with either citrate or by low-generation dendrimers rapidly grow during electrocatalytic reduction of CO2. For example, citrate-stabilized AuNPs and AuNPs encapsulated within sixth-generation, hydroxyl-terminated, poly(amidoamine) dendrimers (G6-OH DENs) having diameters of ∼2 nm grow substantially in size (to 6-7 nm) and polydispersity during just 15 min of electrolysis at -0.80 V (vs RHE). This degree of instability makes it impossible to correlate the structure of AuNPs determined prior to electrocatalysis to their catalytic function. In contrast to the G6-OH dendrimer, the higher generation G8-OH analogue stabilizes AuNPs under the same conditions that lead to instability of the other two materials. More specifically, G8-OH DENs having an initial size of 1.7 ± 0.3 nm increase to only 2.2 ± 0.5 nm during electrolysis in 0.10 M NaHCO3 at -0.80 V (vs RHE). Even when the electrolysis is carried out at -1.20 V, the higher-generation dendrimer stabilizes encapsulated AuNPs. This is presumably due to the compactness of the periphery of the G8-OH dendrimer. Although the G8-OH dendrimer nearly eliminates AuNP growth, the surface of the AuNP is still accessible for electrocatalytic reactions. The smaller, more stable G8-OH DENs strongly favor formation of H2 over CO. Some previous reports have suggested that AuNPs in the ∼2 nm size range yield primarily CO, but we believe these findings are a consequence of the growth of the AuNPs during catalysis and do not reflect the true function of ∼2 nm AuNPs.

Multiscale Molecular Simulations Applied to Nucleic Acid-Dendrimer Interactions Studies

As shown in the present review, molecular dynamics simulations can contribute by studying at theoretical level dendrimer-nucleic acid complexes at different conditions, such as pH or ionic strength. Therefore, different cell conditions such as the stay at the cytoplasm and the transit towards endosomes can be addressed. The influence of different terminal groups of dendrimers to DNA/RNA binding can also be evaluated using molecular simulations and especially, by using free energy methods, which aim to determine affinity of dendrimers for nucleic acids. The development of a library of terminal groups for dendrimers may represent a significant contribution to the design of new dendrimers. In this regard, protein-DNA interactions of structure databases have been analyzed as a way to identify suitable residues that can be incorporated as terminal groups of dendrimers. In summary, computational chemistry and biology tools will aim the design of new dendrimers for different kinds of cargo molecules.

Bioreducible Peptide-Dendrimeric Nanogels with Abundant Expanded Voids for Efficient Drug Entrapment and Delivery.

Dendrimer-based nanoplatforms have exhibited wide prospects in the field of nanomedicine for drug delivery, without great success due to many predicaments of cytotoxicity, high cost, and low yield. In this work, we report a feasible strategy on dynamic cross-linkings of low-generation peptide dendrimers into bioreducible nanogels for efficient drug controlled release. With a facile fabrication, the disulfide cross-linking of biocompatible peptide dendrimers successfully possess well-defined and stable nanostructures with abundant expanded voids for efficient molecular encapsulation. More importantly, high reducing condition is capable of triggering the cleavage of disulfide bonds, the disintegration of peptide-dendrimeric nanogels, and stimuli-responsive release of guest molecules. The bioreducible nanogels improve antitumor drug internalization, contribute to endosomal escape, and realize intracellular drug controlled release. The doxorubicin-loaded nanogels afford high antitumor efficiency and reduce the side effects to BALB/c mice bearing 4T1 tumor. Therefore, dynamic cross-linkings of low-generation dendrimers into smart nanogels will be an alternative and promising strategy to resolve the dilemmas of current dendrimer-based nanocarriers as well as develop innovative nanoplatforms.

Synthesis and anticancer activity of bile acid dendrimers with triazole as bridging unit through click chemistry

Triazole-based novel dendrimers with bile acid surface groups have been synthesized through click chemistry by divergent approach and characterized by spectral data. All the dendrimers exhibit excellent anticancer activity. Higher-generation dendrimers exhibit better anticancer activity than the lower-generation dendrimers.

Fabrication of Low-Generation Dendrimers into Nanostructures for Efficient and Nontoxic Gene Delivery.

Dendrimers with well-defined molecular structure and high monodispersity have gained tremendous interest in gene delivery. However, current gene carriers based on dendrimers are either not effective or are too toxic on the transfected cells. The efficacy and cytotoxicity of dendrimers are strongly correlated with their molecular weight or generation. High-generation dendrimers are reported with relatively high transfection efficacy but serious cytotoxicity due to the excess positive charges on the polymers, while low-generation dendrimers with minimal toxicity have poor polyplex stability and thus weak transfection efficacy. To break up the correlation between efficacy and toxicity, low-generation dendrimers were fabricated into various nanostructures by several strategies to improve their gene-binding capacity, polyplex stability, and transfection efficacy without inducing additional toxicity. In this review article, we will highlight recent advances in the development of assembled dendrimer nanostructures for efficient and non-toxic gene delivery. Specifically, the principles and strategies in the fabrication of dendrimer nanostructures are intensively reviewed.

Formation of Dendrimer Nanoassemblies by Oligomerization-Induced Liquid–Liquid Phase Separation

Dendrimers are hyperbranched macromolecules with applications in host-guest chemistry, self-assembly, nanocatalysis, and nanomedicine. We show that dendrimer-based globular nanoparticles are formed by using dendrimer oligomerization to isothermally induce liquid-liquid phase separation (LLPS). We first determined that LLPS of aqueous mixtures of the fourth-generation amino-functionalized poly(amido amine) dendrimer is observed by lowering temperature in the presence of sodium sulfate. In relation to LLPS, we experimentally characterized the effect of salt and dendrimer concentrations on the LLPS temperature and salt-dendrimer isothermal partitioning. Our results were theoretically examined using a two-parameter thermodynamic model. We then showed that the addition of a small amount of glutaraldehyde, which leads to the formation of soluble dendrimer oligomers by chemical cross-linking, increases the LLPS temperature. This implies that a dendrimer aqueous mixture, which is initially homogeneous at room temperature and exhibits LLPS only at relatively low temperatures, can exhibit LLPS at room temperature due to dendrimer oligomerization. The high dendrimer concentration inside the nanodroplets, produced from LLPS, accelerates dendrimer cross-linking, thereby yielding stable globular nanoparticles. These nanomaterials retain the host-guest properties of the initial dendrimers, indicating potential applications as nanocatalysts, extracting agents and drug carriers. Our work provides the basis for a new approach for obtaining dendrimer-based nanoassemblies by employing low-generation dendrimers as building blocks.

Synthesis and optical and electrochemical properties of glucose-cored ferrocenyl dendrimers

ABSTRACTTriazole-based ferrocenyl glycoconjugates 1, 2, and 3 were synthesized by regiospecific copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of azidoferrocenyl derivatives with glucose pentaacetylide. Higher generation ferrocenyl glycoconjugates form the stable ferrocenium cation and exhibit increased light harvesting property as revealed from cyclic voltammogram studies and ultraviolet–visible spectrum respectively due to the presence of more ferrocenyl and triazolyl units than the lower generation dendrimer.

Insight into the Structure of Polybutylcarbosilane Dendrimer Melts via Extensive Molecular Dynamics Simulations

Extensive molecular dynamics simulations of polybutylcarbosilane dendrimer melts were performed in a wide temperature range from 300 to 600 K. The melt macroscopic and structural characteristics were analyzed for the third up to the eighth generation dendrimers for the systems consisting of 8 and 27 dendrimer molecules in the simulation box. For every system, averaging was performed over 8 independent simulation runs and along equilibrium time trajectories of up to 5 ns. Calculated values of the thermal expansion coefficients, heat capacity, and self-diffusion coefficients are in a good agreement with experimental observations. Analysis of the molecular mass dependence of the gyration radius and shape factor, detailed radial density distributions of dendrimer structural units, mobility of the branching points, and intermolecular interaction energy allowed to shed light on the basics of distinction in behavior of low and high generation dendrimer melts and formulate the directions of further research.

(99m)Tc-Labeled Multifunctional Low-Generation Dendrimer-Entrapped Gold Nanoparticles for Targeted SPECT/CT Dual-Mode Imaging of Tumors.

Development of cost-effective and highly efficient nanoprobes for targeted tumor single-photon emission computed tomography (SPECT)/computed tomography (CT) dual-mode imaging remains a challenging task. Here, multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) modified with folic acid (FA) and labeled with (99m)Tc were synthesized for targeted dual-mode SPECT/CT imaging of tumors. Generation 2 (G2) poly(amidoamine) (PAMAM) dendrimers (G2-NH2) conjugated with cyclic diethylenetriamine pentaacetic anhydride (cDTPAA) via an amide linkage and FA via a spacer of polyethylene glycol (PEG) were used for templated synthesis of Au core NPs, followed by labeling of (99m)Tc via chelation. The thus created multifunctional Au DENPs were well-characterized. It is shown that particles with an average Au core diameter of 1.6 nm can be dispersed in water, display stability under different conditions, and are cytocompatible in the studied concentration range. Further results demonstrate that the multifunctional nanoprobe is able to be utilized for targeted SPECT/CT dual-mode imaging of cancer cells having FA receptor (FAR)-overexpression in vitro and the established subcutaneous tumor model in vivo within a time frame up to 4 h. The formed multifunctional Au DENPs synthesized using dendrimers of low-generation may be employed as an effective and economic nanoprobe for SPECT/CT imaging of different types of FAR-expressing tumors.

Fluorescence of aminofluoresceins as an indicative process allowing one to distinguish between micelles of cationic surfactants and micelle-like aggregates

Among the vast set of fluorescein derivatives, the double charged R2− anions of aminofluoresceins are known to exhibit only low quantum yields of fluorescence, . The value becomes as high as that of the fluorescein dianion when the lone electron pair of the amino group is involved in a covalent bond. According to Munkholm et al (1990 J. Am. Chem. Soc. 112 2608–12), a much smaller increase in the emission intensity can be observed in the presence of surfactant micelles. However, all these observations refer to aqueous or alcoholic solvents. In this paper, we show that in the non-hydrogen bond donor (or ‘aprotic’) solvents DMSO and acetone, the quantum yields, φ, of the 4′- (or 5′)-aminofluorescein R2− species amount to 61–67% and approach that of fluorescein (φ = 87%), whereas in water φ is only 0.6–0.8%. In glycerol, a solvent with an extremely high viscosity, the φ value is only 6–10%.We report on the enhancement of the fluorescence of the aminofluorescein dianions as an indicative process, which allows us to distinguish between the micelle-like aggregates of cationic dendrimers of low generation, common spherical surfactant micelles, and surfactant bilayers. Some of these colloidal aggregates partly restore the fluorescence of aminofluoresceins in aqueous media. By contrast, other positively charged micellar-like aggregates do not enhance the quantum yield of aminofluorescein R2− species. Results for several related systems, such as CTAB-coated SiO2 particles and reverse microemulsions, are briefly described, and the possible reasons for the observed phenomena are discussed.

Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers in zebrafish embryos and cancer cell lines

Dendrimers are an emerging class of polymeric nanoparticles with beneficial biomedical applications like early diagnostics, in vitro gene transfection or controlled drug delivery. However, the potential toxic impact of exposure on human health or the environment is often inadequately defined. Thus, polyamidoamine (PAMAM) dendrimers of generations G3.0, 3.5, 4.0, 4.5 and 5.0 and polypropylenimine (PPI) dendrimers G3.0, 4.0 and 5.0 were tested in zebrafish embryos for 96h and human cancer cell lines for 24h, to assess and compare developmental in vivo toxicity with cytotoxicity. The zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time, with EC50 values ranging from 0.16 to just below 1.7μM at 24 and 48hpf. The predominant effects were mortality, plus reduced heartbeat and blood circulation for PPI dendrimers. Apoptosis in the embryos increased in line with the general toxicity concentration-dependently. Hatch and dechorionation of the embryos increased the toxicity, suggesting a protective role of the chorion. Lower generation dendrimers were more toxic in the embryos whereas the toxicity in the HepG2 and DU145 cell lines increased with increasing generation of cationic PAMAMs and PPI dendrimers. HepG2 were less sensitive than DU145 cells, with IC50 values≥402μM (PAMAMs) and ≤240μM (PPIs) for HepG2 and ≤13.24μM (PAMAMs) and ≤12.84μM (PPIs) for DU145. Neither in fish embryos nor cells toxicity thresholds were determinable for anionic PAMAM G3.5 and G4.5. The study demonstrated that the cytotoxicity underestimated the in-vivo toxicity of the dendrimers in the fish embryos.

Complexes of CuCl2 with low generation dendrimer G1-4S-Bu. Density functional calculations of structure and physicochemical properties

Density functional calculations (DFT) of a structure of dendrimer G1-4S-Bu (Si5C20H132S4) and its complexes with one, two, three, and four molecules of CuCl2 have been carried out for the first time. The geometric structures of the complexes and spin-density distribution have been determined. For the studied complexes the states with maximum multiplicity are the most favorable. The interaction energies of the dendrimer G1-4S-Bu with CuCl2 molecules have been calculated. It has been demonstrated that the formation of complexes with one or two molecules of CuCl2 is the most favorable under standard conditions, which is consistent with the experimental data. Paramagnetic centers exist in all four studied complexes, and the unpaired electron is «localized» in four atoms: Cu, S, Cl, and Cl.

Synthesis, photophysical, electrochemical, and DSSC application of novel donor–acceptor triazole bridged dendrimers with a triphenylamine core and benzoheterazole as a surface unit

Triazole bridged novel donor–acceptor dendrimers were synthesized via click chemistry. Lower generation dendrimers when used as additives exhibit better current-generating capacity and power conversion efficiency in DSSCs.