Asymmetric Dendrimers Research Articles

High-Efficiency Asymmetric TADF Dendrimers via Promoting Mixing of Multiple Excited States toward Solution-Processed OLEDs with Low Efficiency Rolloff

High-Efficiency Asymmetric TADF Dendrimers via Promoting Mixing of Multiple Excited States toward Solution-Processed OLEDs with Low Efficiency Rolloff

Synthesis and Hydrogelation of Star-Shaped Graft Copolypetides with Asymmetric Topology.

To study the self-assembly and hydrogel formation of the star-shaped graft copolypeptides with asymmetric topology, star-shaped poly(L-lysine) with various arm numbers were synthesized by using asymmetric polyglycerol dendrimers (PGDs) as the initiators and 1,1,3,3-tetramethylguanidine (TMG) as an activator for OH groups, followed by deprotection and grafting with indole or phenyl group on the side chain. The packing of the grafting moiety via non-covalent interactions not only facilitated the polypeptide segments to adopt more ordered conformations but also triggered the spontaneous hydrogelation. The hydrogelation ability was found to be correlated with polypeptide composition and topology. The star-shaped polypeptides with asymmetric topology exhibited poorer hydrogelation ability than those with symmetric topology due to the less efficient packing of the grafted moiety. The star-shaped polypeptides grafted with indole group on the side chain exhibited better hydrogelation ability than those grafted with phenyl group with the same arm number. This report demonstrated that the grafted moiety and polypeptide topology possessed the potential ability to modulate the polypeptide hydrogelation and hydrogel characteristics.

The Branched Schiff Base Cationic Complexes of Iron(III) with Different Counter-Ions

The Fe(III) complexes of branched asymmetric dendrimers were obtained by a one-step reaction as the second-generation architectures. Mesomorphic behavior was found for complexes with PF6− and BF4− counter-ions. To obtain knowledge about the existence of HS and LS fractions of iron(III) ion and their evolution with temperature, EPR methods were used. It was demonstrated that compounds contain one low-spin (LS, S = 1/2) and two HS-spin (HS, S = 5/2) of Fe(III) centers and are packed into two magnetic sub-lattices. A floating layers of Fe(III) complexes and Langmuir–Blodgett films on their base were formed and investigated in the presence of a magnetic field.

Development of a hybrid peptide dendrimer micellar carrier system and its application in the reformulation of a hydrophobic therapeutic agent derived from traditional Chinese medicine.

The discovery that a cane toad poison-derived steroid, bufalin can significantly impact cancer cell proliferation supports its potential use in cancer therapy. However, its poor aqueous solubility and tissue deposition characteristics hamper its broader application as an anticancer therapeutic agent in its own right. To address this we developed an amphiphilic dendrimer-based delivery system, which self-assembles into discrete micelles in an aqueous environment. The bufalin–micelle inclusion complex was prepared by the co-precipitation method and their presence was confirmed by dynamic light scattering (DLS), zeta potential and differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) measurements. The self-assembled bufalin-containing micelles were found to form at/above the dendrimer concentration of 105.38 μmol L−1, and showed a more than threefold increase in the aqueous solubility (142.9 μg mL−1) of bufalin, when compared with a saturated bufalin aqueous solution (42.4 μg mL−1), and two non-assembling peptides of similar composition (79.3 and 62.5 μg mL−1 respectively).

High Sensitive Detection of Prostate Specific Antigen by Using Ferrocene Cored Asymmetric PAMAM Dendrimer Interface Screen Printed Electrodes

AbstractIn this study, electrochemical immunosensors were developed for the detection of prostate specific antigen (PSA) using ferrocene (Fc) and polyamidoamine dendrimer (PAMAM) constructs. The biosensor fabrication was designed by modifying the screen‐printed gold electrode (Au) with ferrocene cored dendrimers (FcPAMAM) synthesized in three different generations. The self‐assembled monolayer principle was followed, to obtain sensitive, selective and disposable electrodes. Therefore, the Au electrodes were modified with cysteamine (Cys) to obtain a functional surface for FcPAMAM dendrimers to bind. Dendrimer generations were attached to this surface using a cross‐linker (glutaraldehyde) so that a suitable surface was obtained for binding of biological components. The Monoclonal PSA antibody (anti‐PSA) was immobilized on the Au electrode surface which coated with dendrimer, and (Au/Cys/FcPAMAM/anti‐PSA) biosensing electrode was obtained. The PSA detection performances of electrochemical impedance spectroscopy (EIS) and Amperometry based immunosensors exhibited very low detection limits; 0.001 ng mL−1 and 0.1 pg mL−1, respectively. In addition, EIS and Amperometry based biosensors using Au/Cys/FcPAMAM/anti‐PSA sensing electrode were represented excellent linear ranges of 0.01 ng mL−1 to 100 ng mL−1 and 0.001 ng mL−1 to 100 ng mL−1. In order to determine the applicability recovery and selectivity tests were performed using three different proteins in human serum.

A Three Component Synthetic Vaccine Containing a β-Mannan T-Cell Peptide Epitope and a β-Glucan Dendritic Cell Ligand.

Glycoconjugates prepared from the capsular polysaccharide of several pathogenic bacteria and carrier proteins, such as CRM 197 or tetanus toxoid, have been one of the most successful public health measures to be implemented in the last quarter century. A crucial element in the success of conjugate vaccines has been the recruitment of T-cell help and systematic induction of a secondary immune response. The seminal discovery, that degraded polysaccharide fragments with attached peptide are presented to the T-cell receptor of carbohydrate specific T-cells by MHC-II molecules that bind to the peptide component of degraded vaccine, suggests potentially novel designs for conjugate vaccines. A fully synthetic conjugate vaccine was constructed from a 1,2-linked β-mannose trisaccharide conjugated to a T-cell peptide, previously shown to afford protection against Candida albicans. This combined B- and T-cell epitope was synthesized with a C-terminal azidolysine residue for subsequent conjugation by click chemistry. Four copies of a β-1,3 linked hexaglucan dendritic cell epitope were conjugated to an asymmetric dendrimer bearing an alkyne terminated tether. Click chemistry of these two components created a conjugate vaccine that induced antibodies to all three epitopes of the fully synthetic construct.

Effect of an asymmetry of branching on structural characteristics of dendrimers revealed by Brownian dynamics simulations

Dendrimers in dilute solution with asymmetry of branching were simulated by the Brownian dynamics method. In this simulation a coarse-grained dendrimer model and athermal solvent conditions were implemented, extending previous work to a wider range of branch asymmetries at fixed average spacer lengths and high generation numbers close to the theoretical limit. We considered both global and local structural characteristics of dendrimers. The global ones, such as the average distance of ends from the center, the radius of gyration, the hydrodynamic radius and the dendrimer shape anisotropy, are practically insensitive to the asymmetry of branching. The effect of the spacer asymmetry is revealed mainly in the local structure of dendrimers. In particular the radial density profile changes its shape from a convex to a concave one with an increase of the asymmetry. As compared to symmetrical case, the distribution of terminal monomer units in asymmetrical dendrimers shifts towards the dendrimers periphery. The terminal monomers in an asymmetrical dendrimer are on average in a denser environment compared to their symmetrical analogs. The shorter spacers are less stretched and more turned back to the core than the longer ones located at the same topological distance from the dendrimer periphery. The simulations also demonstrated that the asymmetry of branching leads to a smaller radial overlap of dendron fragments inside the dendrimer as compared to the symmetrical case. However, the total overlap was found to be independent of the asymmetry of branching.

Self-assembling asymmetric peptide-dendrimer micelles \u2013 a platform for effective and versatile in vitro nucleic acid delivery

Despite advancements in the development of high generation cationic-dendrimer systems for delivery of nucleic acid-based therapeutics, commercially available chemical agents suffer from major drawbacks such as cytotoxicity while being laborious and costly to synthesize. To overcome the aforementioned limitations, low-generation cationic peptide asymmetric dendrimers with side arm lipid (cholic and decanoic acid) conjugation were designed, synthesized and systematically screened for their ability to self-assemble into micelles using dynamic light scattering. Cytotoxicity profiling revealed that our entire asymmetric peptide dendrimer library when trialled alone, or as asymmetric dendrimer micelle-nucleic acid complexes, were non-cytotoxic across a broad concentration range. Further, the delivery efficiency of asymmetric peptide dendrimers in H-4-II-E (rat hepatoma), H2K (mdx mouse myoblast), and DAOY (human medulloblastoma) cells demonstrated that cholic acid-conjugated asymmetric dendrimers possess far superior delivery efficiency when compared to the commercial standards, Lipofectamine 2000 or Lipofectin®.

Structure of asymmetrical peptide dendrimers: Insights given by self-consistent field theory

Structural properties of asymmetric peptide dendrimers up to the 11th generation are studied on the basis of the self-consistent field Scheutjens-Fleer numerical approach. It is demonstrated that large scale properties such as, e.g., the gyration radius, are relatively weakly affected by the asymmetry that is, by difference in the length of short and long spacers. However, the asymmetry has strong influence on the internal structure of the dendrimers and on the radial distribution of polymer density and terminal segments. In particular, symmetrical and weakly asymmetrical dendimers are characterized by quasi-uniform intramolecular concentration profiles of monomer units whereas strongly asymmetric dendrimers are characterized by sharply decreasing in a radial direction polymer density profile reminiscent to that in star-shaped polymers. This finding may have important implication for the use of peptide dendrimers as carriers for biologically active molecules.

Express in Vitro Plasmid Transfection Achieved with 16+ Asymmetric Peptide Dendrimers.

Asymmetric cationic amino acid-based dendrimers are highly branched chemically derived gene vectors developed to transport cargo such as plasmid DNA across the plasma membrane. We have previously demonstrated their propensity to enter cells that form caveolae, driven by positive charge density and promoted by arginine head groups. Caveolae are plasma membrane subdomains serving a number of cellular functions including endocytosis. Their formation requires membrane proteins (caveolins) and cytoplasmic proteins (cavins), so that gene disruption of either caveolin-1 or cavin-1 (also known as PTRF, i.e., polymerase I and transcript release factor) results in caveola deficiency. Here we evaluated the ability of a 16+ charged asymmetric arginine dendrimer to transfect plasmid DNA into cultured cells. We unveiled efficient transfection efficiencies (≥30%) 24-48 h after exposing the cells to dendrimer/pDNA complexes for only 5 min. Using wild type (WT) and caveolin-1 or PTRF gene-disrupted, i.e., caveola-deficient mouse embryo fibroblasts, we further show that caveolae promote pDNA transfection by 16+ charged asymmetric arginine dendrimers.

Molecular Determinants of the Cellular Entry of Asymmetric Peptide Dendrimers and Role of Caveolae.

Caveolae are flask-shaped plasma membrane subdomains abundant in most cell types that participate in endocytosis. Caveola formation and functions require membrane proteins of the caveolin family, and cytoplasmic proteins of the cavin family. Cationic peptide dendrimers are non-vesicular chemical carriers that can transport pharmacological agents or genetic material across the plasma membrane. We prepared a panel of cationic dendrimers and investigated whether they require caveolae to enter into cells. Cell-based studies were performed using wild type or caveola-deficient i.e. caveolin-1 or PTRF gene-disrupted cells. There was a statistically significant difference in entry of cationic dendrimers between wild type and caveola-deficient cells. We further unveiled differences between dendrimers with varying charge density and head groups. Our results show, using a molecular approach, that (i) expression of caveola-forming proteins promotes cellular entry of cationic dendrimers and (ii) dendrimer structure can be modified to promote endocytosis in caveola-forming cells.

Asymmetric dendrimers with improved electro-optic performance: synthesis and characterization

A new series of electro-optical dendrimers with asymmetric configurations was synthesized through a Cu-(I) catalyzed Huisgen reaction.

Synthesis of asymmetric dendrimers with controllable chromophore concentration and improved electro-optical performance

In this work, we provided a simple work-up procedure to prepare a new kind of electro-optical dendrimer with an asymmetric configurationviaa Cu-(i) catalyzed Huisgen-reaction.

Asymmetric peptide dendrimers are effective linkers for antibody-mediated delivery of diverse payloads to b cells in vitro and in vivo.

Safe, targeted delivery of therapeutics remains a focus of drug/gene delivery, the aim being to achieve optimal efficacy while minimising off-target delivery. Dendrimers have a vast array of potential applications and have great potential as gene and drug delivery tools. We previously reported the development of peptide dendrimers that effectively complexed DNA and that have distinct advantages over conventional spherical dendrimers. Here, to expand the application of peptide-based low generation dendrimers we tested their capacity to be transformed into linkers for antibody-based targeting of diverse payloads. Peptide-based low-generation asymmetric dendrimers were generated and conjugated to partially-reduced antibodies specific for B cell surface antigens or an irrelevant antigen. Preservation of antigen binding by the antibodies and targeting of the conjugated dendrimers carrying a small molecule (biotin) or plasmid DNA payloads was tested. Peptide-based low generation dendrimers were efficiently and site-specifically conjugated to antibodies with retention of antigen-binding capacity. Altering the branching termini of dendrimers facilitated delivery of diverse payloads in vitro and in vivo. We propose that safe, non-toxic peptide dendrimers, which are readily synthesised and modifiable for a variety of applications, form the basis of a new family of biocompatible "linkers" with substantial potential for targeted delivery applications.

Molecular analysis of interactions between dendrimers and asymmetric membranes at different transport stages

Studying dendrimer-biomembrane interactions is important for understanding drug and gene delivery. In this study, coarse-grained molecular dynamics simulations were performed to investigate the behaviors of polyamidoamine (PAMAM) dendrimers (G4 and G5) as they interacted with asymmetric membranes from different sides of the bilayer, thus mimicking different dendrimer transport stages. The G4 dendrimer could insert into the membrane during an equilibrated state, and the G5 dendrimer could induce pore formation in the membrane when the dendrimers interacted with the outer side (outer interactions) of an asymmetric membrane [with 10% dipalmitoyl phosphatidylserine (DPPS) in the inner leaflet of the membrane]. During the interaction with the inner side of the asymmetric membrane (inner interactions), the G4 and G5 dendrimers only adsorbed onto the membrane. As the membrane asymmetry increased (e.g., increased DPPS percentage in the inner leaflet of the membrane), the G4 and G5 dendrimers penetrated deeper into the membrane during the outer interactions and the G4 and G5 dendrimers were adsorbed more tightly onto the membrane for the inner interactions. When the DPPS content reached 50%, the G4 dendrimer could completely penetrate through the membrane from the outer side to the inner side. Our study provides molecular understanding and reference information about different dendrimer transport stages during drug and gene delivery.

Are structural properties of dendrimers sensitive to the symmetry of branching? Computer simulation of lysine dendrimers

Poly-L-lysine (PLL) dendrimers are promising systems for biomedical applications due to their biocompatibility. These dendrimers have a specific topology: two spacers of different lengths come out of each branching point and thus the branching is asymmetric. Because of this asymmetry terminal groups are located at branches of different lengths, unlike dendrimers with a symmetric branching. This paper presents the results of the first systematic molecular dynamics simulation of such asymmetric PLL dendrimers. It is shown that PLL dendrimers are porous molecules with all terminal groups equally accessible to water. We have found that in spite of an asymmetry of branching the general structural characteristics of PLL dendrimers are rather similar to those of dendrimers with symmetric branching. We have also found that the structural characteristics of PLL dendrimers obey the general laws for dendrimers and that their electrostatic properties agree with the predictions of a general analytic theory.

Novel reagentless glucose biosensor based on ferrocene cored asymmetric PAMAM dendrimers

A novel amperometric glucose biosensor is fabricated with immobilization of glucose oxidase (GOx) onto PAMAM-Fc dendrimers decorated gold electrode. Series of asymmetric PAMAM dendrimers containing a single ferrocene unit located in the focal point of these macromolecules have been synthesized and characterized. Surface of the gold electrode was covalently modified with 3-mercaptopropionic acid, PAMAM-Fc dendrimers and GOx enzyme by using coupling agents, respectively. The PAMAM-Fc/GOx biosensor shows an excellent performance for glucose at +0.25 V with a high sensitivity (6.54 μA/mM) and lower response time (∼3 s) in a wide concentration range of 1–22 mM (correlation coefficient of 0.9988). In addition, PAMAM-Fc/GOx biosensor possesses better reproducibility, storage stability and there is negligible interference from other electroactive components.

Metal Ion Coordination with an Asymmetric Fan-Shaped Dendrimer at the Air–Water Interface

Metal coordination to monolayers of 4-{10-[4-(3,5-bis-benzyloxy)-phenyl]-anthracen-9-yl}-benzoic acid ([G1-An]-CO(2)H, G1) and 4-(10-{4-[3,5-bis-(3,5-bis-benzyloxy)-benzyloxy]-phenyl}-anthracen-9-yl)-benzoic acid ([G2-An]-CO(2)H, G2) at the air-water interface and to Langmuir-Blodgett (LB) films was investigated using surface pressure-area isotherms, ultraviolet-visible (UV-vis) spectroscopy, atomic force microscopy (AFM), and X-ray reflectivity (XRR). Surface pressure-area isotherms show that G1 and G2 have different limiting areas according to the type of subphase. The limiting area of G1 and G2 increased more with Al(3+) than with Eu(3+) in the subphase. This result indicates that the hydrophilic core group is anchored to ions in the water via bidentate chelates with the carboxylate oxygen atoms of G1 and G2. Circular domains and aggregates were observed for the LB film. The different behavior of Eu(3+) and Al(3+) complexes is originated from the intrinsic nature of the ion, i.e., coordination number.

Low‐generation asymmetric dendrimers exhibit minimal toxicity and effectively complex DNA

Conventional dendrimers are spherical symmetrically branched polymers ending with active surface functional groups. Polyamidoamine (PAMAM) dendrimers have been widely studied as gene delivery vectors and have proven effective at delivering DNA to cells in vitro. However, higher-generation (G4-G8) PAMAM dendrimers exhibit toxicity due to their high cationic charge density and this has limited their application in vitro and in vivo. Another limitation arises when attempts are made to functionalize spherical dendrimers as targeting moieties cannot be site-specifically attached. Therefore, we propose that lower-generation asymmetric dendrimers, which are likely devoid of toxicity and to which site-specific attachment of targeting ligands can be achieved, would be a viable alternative to currently available dendrimers. We synthesized and characterized a series of peptide-based asymmetric dendrimers and compared their toxicity profile and ability to condense DNA to spherical PAMAM G1 dendrimers. We show that asymmetric dendrimers are minimally toxic and condense DNA into stable toroids which have been reported necessary for efficient cell transfection. This paves the way for these systems to be conjugated with targeting ligands for gene delivery in vitro and in vivo.

Designer peptide dendrimers using click reaction

We designed and synthesized various peptide dendrimers using a 1,3-dipolar cycloaddition (Click) reaction. The dendritic structures reported here include symmetrical, asymmetrical, and cationic dendrimers with triazole, cystine, aromatic, aliphatic, and Lys–Asp dipeptide cores. The high chemoselectivity of the click reaction allowed us to synthesize good yields of high-purity protected and unprotected dendritic structures. Triazole is an excellent peptide bond mimic, which remains hydrolytically stable. Dendrimer 15a and the core unit 21 gelate in a mixture of organic solvents. We also demonstrated the versatility of the design by synthesizing various carbohydrate-based dendrimers.