Dendrimer Derivatives Research Articles

Polymeric Amphiphile Branching Leads to Rare Nanodisc Shaped Planar Self-Assemblies

Self-assembly is fundamental to the biological function of cells and the fabrication of nanomaterials. However, the origin of the shape of various self-assemblies, such as the shape of cells, is not altogether clear. Polymeric, oligomeric, or low molecular weight amphiphiles are a rich source of nanomaterials, and controlling their self-assembly is the route to tailored nanosystems with specific functionalities. Here, we provide direct evidence that a particular molecular architecture, polymeric branching, leads to a rare form of self-assembly, the planar nanodisc. Cholesterol containing self-assemblies formed from amphiphilic linear or branched cetyl poly(ethylenimine) (Mn approximately 1000 Da) or amphiphilic cetyl poly(propylenimine) dendrimer derivatives (Mn approximately 2000 Da) show that branching, by reducing the hydrophilic headgroup area, alters the shape of the self-assemblies transforming closed 60 nm spherical bilayer vesicles to rare 50 nm x 10 nm planar bilayer discs. Increasing the hydrophilic headgroup area, by the inclusion of methoxy poly(ethylene glycol) moieties into the amphiphilic headgroup, transforms the planar discs to 100 nm spherical bilayer vesicles. This study provides insight into the key role played by molecular shape on molecular self-organization into rare nanodiscs.

Application of the functionalized congener approach to dendrimer-based signaling agents acting through A2A adenosine receptors

As a continued effort to develop multivalent ligands to enhance the pharmacological effects of monomeric drugs, DITC-APEC, a chemically reactive nucleoside A2A adenosine receptor (AR) agonist, was employed to derivatize the surface of third-generation (G3) polyamidoamine (PAMAM) dendrimers. The resulting conjugates carried multiple copies of the agonist attached through a thiourea linkage and differed in the number of attachments and in the presence of a fluorophore or additional surface modification. Computer modeling studies suggested that these DITC-APEC-loaded dendrimers extended the overall diameter of the previously reported PAMAM-CGS21680 dendrimer derivatives (Kim et al., Bioconjugate Chem 2008 19:406–411) by ca. 20 Å, potentially increasing the conformational flexibility of the appended ligands to achieve optimal geometry for efficient binding at A2A ARs. Increased affinity and selectivity in binding in comparison to the CGS21680 conjugate were envisioned, due to the presence of an extended linker, i.e., a dithioureylenephenyl functionality. In vitro radioligand competition experiments showed effective binding of these PAMAM-DITC-APEC dendrimer conjugates at the human A2A and A3 ARs with submicromolar Ki values and selectivity in comparison to the human A1 AR. Furthermore, these nucleoside-loaded dendrimers exhibited an A2A AR-mediated inhibitory effect on ADP-induced aggregation of human platelets. The present study demonstrates the potential of applying the functionalized congener concept to engineer dendrimer-based multivalent ligands for G protein-coupled receptors.Electronic supplementary materialThe online version of this article (doi:10.1007/s11302-008-9113-3) contains supplementary material, which is available to authorized users.

Twisted π-Electron System Electrooptic Chromophores. Structural and Electronic Consequences of Relaxing Twist-Inducing Nonbonded Repulsions

The synthesis, structural and spectroscopic characterization, and nonlinear optical response properties of a “slightly” twisted zwitterionic 4-quinopyran electrooptic chromophore FMC, 2-{4-[1-(2-propylheptyl)-1H-pyridine-4-ylidene]cyclohexa-2,5-dienylidene}malononitrile, are reported. X-ray diffraction data and density functional theory (DFT) minimized geometries confirm that deletion of the four o-, o′-, o′′-, and o′′′-methyl groups in the parent chromophore TMC-2, 2-{4-[3,5-dimethyl-1-(2-propylheptyl)-1H-pyridin-4-ylidene]-3,5-dimethylcyclohexa-2,5-dienylidene}malononitrile, relaxes the arene−arene twist angle from 89.6 to 9.0°. These geometrical changes result in a significantly increased contribution of the quinoidal structure to the molecular ground state of FMC (versus TMC-2), reduced solvatochromic shifts in the optical spectra, and a diminished electric-field-induced second-harmonic (EFISH) generation derived molecular hyperpolarizability (μβ = −2340 × 10−48 esu of DFMC, the dendrimer derivative of FMC, vs −24000 × 10−48 esu of TMC-2) in CH2Cl2 at 1907 nm. Pulsed field gradient spin–echo (PGSE) NMR spectroscopy and EFISH indicate that the levels of FMC aggregation in solution are comparable to those of TMC-2 (monomers and dimers) in CH2Cl2 solution. B3LYP and INDO/S computation of chromophore molecular structure, aggregation, and hyperpolarizability trends are in good agreement with experiment.

Efficient Synthesis of Dendrimers via A Chemoselective Approach

The dendrimer derivatives of the Fréchet-type and 2,2-bis(methylol)propionic acid (bis-MPA) dendrimers were synthesized via an accelerated growth approach, which is based on the combination of click chemistry with traditional esterification/etherification reactions. The required monomer units for one-step generation growth are AB2-monomer (2) and CD2-monomer (4). The synthetic strategy allows the divergent preparation of a fourth-generation dendrimer (2nd generation dendrimer 5 is shown) in only four steps and in multi-gram quantities with an overall yield of 70% from the starting triphenol 1. The obtained dendritic block copolymer contains alternating layers of benzyl ether, triazole and benzyl ether groups. The orthogonality and efficiency of this strategy were demonstrated by monitoring each reaction with NMR and MALDI-TOF techniques.

Optical study and structure modelling of PPI liquid crystalline dendrimer derivatives

Optical study of two families of poly(propylene imine) (PPI) dendrimers ( G = 1–5) are reported. The enlarging of the chain number (generations) of the PPI dendrimer leads to the spectra shift to IR region in solvent until 8 and 19 nm for both families, respectively. The theoretical modelling of the dendrimer structure was performed. The geometric characterization of dendrimer structure demonstrates that the preferable free space for encapsulation is periphery of the PPI dendrimer.

Synthesis and Characterization of PAMAM Dendrimer-Based Multifunctional Nanodevices for Targeting αvβ3 Integrins

We have synthesized a stable and clinically relevant nanodevice (cRGD-BT-ND; ND for short) that exhibits superior binding to the biologic target alphavbeta3 integrins, when either compared to the same free cRGD peptide or to the biotinylated nanodevice without covalently attached peptides (BT-ND). Selective targeting of alphavbeta3 integrins was achieved by coupling cyclic cRGD peptides to the nanodevice (ND) surface, while biotin groups (BT) were used for amplified detection of bound cRGD-BT-ND by anti-biotin antibody or avidin linked to horseradish peroxidase after binding. The synthesis involved the following steps: the amino-terminated ethylenediamine core generation 5 poly(amidoamine) (PAMAM_E5.NH2) dendrimer was first partially acetylated and then biotinylated, and residual primary amine termini were converted to succinamic acid groups (SAH), some of which finally were conjugated with cRGD peptide residues through the amino group of the lysine side chain. The starting material and all derivatives were extensively characterized by polyacrylamide gel electrophoresis (PAGE), size exclusion chromatography (SEC), potentiometric acid-base titration, MALDI-TOF, and NMR. Cytotoxicity of all dendrimer derivatives was examined in B16F10 melanoma cell cultures using the XTT colorimetric assay for cellular viability. Binding of nanodevices to the biological target was determined using plates coated with human alphavbeta3 integrin and alphavbeta3 receptor expressing human dermal microvascular endothelial cells (HDMECs). The PAMAM_E5.(NHAc)72(NHBT)8(NHSAH)35(NHSA-cR GD)4 nanodevice is nontoxic within physiologic concentration ranges and specifically binds to the alphavbeta3 integrins, apparently much stronger than the cyclic cRGD peptide itself.

Antibacterial Activities of Poly(amidoamine) Dendrimers Terminated with Amino and Poly(ethylene glycol) Groups

Poly(amidoamine) (PAMAM) dendrimer derivatives have been investigated for their biological applications, especially for delivery of drugs, including antimicrobial drugs to eukaryotic cells, but their effects on bacterial cells are largely unexplored. Herein we report that amino-terminated PAMAM dendrimers are highly toxic to the common Gram-negative pathogen Pseudomonas aeruginosa. The concentration that kills 50% of the bacteria (EC50) was in the range of approximately 0.9-1.5 microg/mL for the generation 5, amino-terminated dendrimers with or without partial (43%) coating of poly(ethylene glycol) (PEG). These EC50 values were lower than that ( approximately 1.9-2.8 microg/mL) for LL-37, a potent antimicrobial peptide expressed in a variety of epithelia. On the contrary, the dendrimers were far less toxic (EC50 > 21 microg/mL) to the Gram-positive pathogen Staphylococcus aureus than LL-37 (EC50 = approximately 1.9 microg/mL). In agreement with the previous studies on other cell types, the dendrimers were not cytotoxic to human corneal epithelial cells at the concentrations that were toxic to P. aeruginosa. Our findings indicate that amino-terminated PAMAM dendrimers and their partially PEG-coated derivatives possess attractive antimicrobial properties, particularly against Gram-negative bacteria, thus expanding the potential biological application of the dendrimers.

The intramolecular hydrogen bonds in some Schiff bases derived from dendrimers: DAB-Am-8 and PAMAM-G2

The hydrogen bonding in some DAB-Am-8 and PAMAM-G2 dendrimer derivatives have been investigated by heteronuclear NMR techniques in solution. The proton positions in the bridges ware estimated on the base of nitrogen chemical shift of imine atom. Some dynamic effects connected with different segmental motion of particular parts of the molecules were found by analysis of spectral line widths.

Comprehensive characterization of surface-functionalized poly(amidoamine) dendrimers with acetamide, hydroxyl, and carboxyl groups

Terminal amine groups of poly(amidoamine) (PAMAM) dendrimers can be substituted with different functional groups for various applications. In this study, PAMAM derivatives with acetamide, hydroxyl, and carboxyl termini were synthesized from ethylenediamine (EDA) core generation 4 and 5 primary amine-terminated PAMAM dendrimers. The reaction products were purified with dialysis and subsequently characterized by polyacrylamide gel electrophoresis (PAGE), capillary electrophoresis (CE), size exclusion chromatography (SEC), matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, potentiometric titration, 1H NMR, and 13C NMR. PAGE and CE electropherograms provide data regarding the purity, charge distribution, and electrophoretic mobility of the dendrimers and their derivatives. SEC and MALDI-TOF mass spectrometry detect the average absolute molar mass and the individual mass fractions, respectively. The combination of SEC with potentiometric titration provides quantitative evidence of the degree of the functional group substitution, while NMR techniques (both 1H NMR and 13C NMR) confirmed the changes in dendrimer surface functionalization. This study provides a general example for the comprehensive characterization of surface-functionalized PAMAM dendrimer nanoparticles. The synthesized dendrimer derivatives hold promise for environmental and medical applications.

Thermo- and pH-sensitive dendrimer derivatives with a shell of poly( N, N-dimethylaminoethyl methacrylate) and study of their controlled drug release behavior

Novel dendrimer derivatives combining the temperature- and pH-sensitivities are synthesized. At first, polyamidoamine (PAMAM) dendrimers with generations 1–5 are synthesized by the reaction of ethylenediamine with methyl acrylate, and then the dendrimers are acylated by chloroacetyl chloride to obtain PAMAM-Cl, which can act as a macroinitiator for further synthesizing functional dendrimers. For fulfilling this goal, the polymers consisting of a dendritic PAMAM core and poly( N, N-dimethylaminoethyl methacrylate) (PDMA) shell are synthesized by atom transfer radical polymerization (ATRP). Their macromolecular structures are characterized by FTIR, 1H NMR, DSC and particle size analyses, and their aqueous solutions are inspected by UV spectroscopy for understanding their thermo- and pH-sensitivities. The results show that novel dendrimer derivatives exhibit clearly thermo- and pH-respondings in accordance with the change of the environment. Using chlorambucil (CLB) as a model drug, the behaviors of the controlled drug release from polymers with different average graft length of PDMA are studied. The results indicate that the rate of the drug release can be effectively controlled by the pH value.

Synthesis and study of the properties of the homologous series of polyallylcarbosilane dendrimers and their nonfunctional analogs

A synthetic route combining the preparation of functional and nonfunctional carbosilane dendrimers has been developed. Using this route, two representative homologous series of carbosilane dendrimers have been prepared. The use of nonfunctional dendrimer derivatives ensures the possibility of performing long-term experiments both in solution and in the bulk. The intrinsic viscosity and the density of the specimens studied do not depend on the generation number. The obtained dendrimers of later generations were studied by atomic force microscopy and light scattering.

3H dendrimer nanoparticle organ/tumor distribution.

To determine the in vivo biodistribution for differently charged poly(amidoamine) (PAMAM) dendrimers in B16 melanoma and DU145 human prostate cancer mouse tumor model systems. Neutral (NSD) and positive surface charged (PSD) generation 5 (d = 5 nm) PAMAM dendrimers were synthesized by using 3H-labeled acetic anhydride and tested in vivo. Dendrimer derivatives were injected intravenously, and their biodistribution was determined via liquid scintillation counting of tritium in tissue and excretory samples. Mice were also monitored for acute toxicity. Both PSD and NSD localized to major organs and tumor. Dendrimers cleared rapidly from blood, with deposition peaking at 1 h for most organs and stabilizing from 24 h to 7 days postinjection. Maximal excretion occurred via urine within 24 h postinjection. Neither dendrimer showed acute toxicity. Changes in the net surface charge of polycationic PAMAMs modify their biodistribution. PSD deposition into tissues is higher than NSD, although the biodistribution trend is similar. Highest levels were found in lungs, liver, and kidney, followed by those in tumor, heart, pancreas, and spleen, while lowest levels were found in brain. These nanoparticles could have future utility as systemic biomedical delivery devices.

Potentiometric response characteristics of polycation-sensitive membrane electrodes toward poly(amidoamine) and poly(propylenimine) dendrimers.

The potentiometric response characteristics of polycation-sensitive membrane electrodes toward two classes of polycationic dendrimers are examined. Using appropriately formulated polymer membrane electrodes composed of a dinonylnaphthalenesulfonate (DNNS) salt in a plasticized polyurethane matrix, it is shown that poly(amidoamine) (PAMAM) and poly(propylenimine) (PPI) dendrimers are readily detected at submicrogram per milliliter levels via a nonequilibrium response mechanism. The relationship between the total EMF response (at equilibrium) and the specific dendrimer structure is also examined. For both the PAMAM and PPI species, it is shown that the total EMF response does not change significantly with dendrimer generation number; however, the nonequilibrium analytically useful response curves are shifted to higher mass concentrations as the generation number is increased. The relative contributions of the terminal primary amines and the interior tertiary amines of the dendrimers to the observed EMF response are investigated by synthesis of various dendrimer derivatives (acetylated, quaternized, etc.). By comparing the total EMF responses for these derivatives as a function of sample pH, it is demonstrated that the lipophilic cation exchanger (DNNS) within the membrane phase can likely interact electrostatically with both protonated forms of the terminal primary amines and interior tertiary amines of the dendrimer structures. The practical application of the nonequilibrium potentiometric detection of dendrimers for monitoring their interaction with DNA is also demonstrated.

Dendrimers as Potential Drug Carriers; Encapsulation of Acidic Hydrophobes within Water Soluble PAMAM Derivatives.

This paper describes the synthesis of three neutral water soluble poly(amidoamine) (PAMAM) dendrimer derivatives. The ability of the two larger dendrimers to bind small acidic hydrophobic molecules is reported. Spectroscopic data and pH behaviour suggested that the acidic hydrophobes were forming stable ion pairs with the dendrimer's internal, basic tertiary nitrogens. With respect to forming 1:1 and 2:1 substrate/dendrimer complexes, both of the larger dendrimers were equally efficient at binding. All dendrimer/substrate complexes were completely miscible with water in all proportions (i.e. infinitely water soluble). When the bound substrates are drug moieties, then the resulting complexes could be considered as potential drug delivery systems. Flow calorimetry demonstrated that the dendrimers were able to release their hydrophobic guests when in contact with a biological cell.

Dendrimers as potential drug carriers; encapsulation of acidic hydrophobes within water soluble PAMAM derivatives

This paper describes the synthesis of three neutral water soluble poly(amidoamine) (PAMAM) dendrimer derivatives. The ability of the two larger dendrimers to bind small acidic hydrophobic molecules is reported. Spectroscopic data and pH behaviour suggested that the acidic hydrophobes were forming stable ion pairs with the dendrimer's internal, basic tertiary nitrogens. With respect to forming 1:1 and 2:1 substrate/dendrimer complexes, both of the larger dendrimers were equally efficient at binding. All dendrimer/substrate complexes were completely miscible with water in all proportions (i.e. infinitely water soluble). When the bound substrates are drug moieties, then the resulting complexes could be considered as potential drug delivery systems. Flow calorimetry demonstrated that the dendrimers were able to release their hydrophobic guests when in contact with a biological cell.

Synthesis and Metal Binding Properties of Salicylate-, Catecholate-, and Hydroxypyridinonate-Functionalized Dendrimers

The synthesis, characterization, and metal-binding studies of chelate-functionalized dendrimers is reported. Salicylate, catecholate, and hydroxypyridinonate bidentate chelators have been coupled to the surface of both poly(propyleneimine) (Astramol) and poly(amidoamine) (Starburst, PAMAM) dendrimers up to the fifth generation (64 endgroups). A general method has been developed for the facile and high quality chromatographic purification of poly(propyleneimine) and poly(amidoamine) dendrimer derivatives. One- and two-dimensional (TOCSY) 1H NMR experiments and electrospray ionization mass spectrometry (ESI-MS) have confirmed the exhaustive coupling of these chelators to the primary amine functionalities of the dendrimers. Spectrophotometric titrations were used to investigate the metal binding ability of these macrochelates. Spectral analysis shows that ferric iron binding to these ligands is localized to the chelating endgroups. The ability of these dendritic polymers to bind large numbers of metal ions may lead to applications as metal sequestering agents for waste remediation technologies.

Synthesis and metal binding properties of salicylate-, catecholate-, and hydroxypyridinonate-functionalized dendrimers.

The synthesis, characterization, and metal-binding studies of chelate-functionalized dendrimers is reported. Salicylate, catecholate, and hydroxypyridinonate bidentate chelators have been coupled to the surface of both poly(propyleneimine) (Astramol) and poly(amidoamine) (Starburst, PAMAM) dendrimers up to the fifth generation (64 endgroups). A general method has been developed for the facile and high quality chromatographic purification of poly(propyleneimine) and poly(amidoamine) dendrimer derivatives. One- and two-dimensional (TOCSY) 1H NMR experiments and electrospray ionization mass spectrometry (ESI-MS) have confirmed the exhaustive coupling of these chelators to the primary amine functionalities of the dendrimers. Spectrophotometric titrations were used to investigate the metal binding ability of these macrochelates. Spectral analysis shows that ferric iron binding to these ligands is localized to the chelating endgroups. The ability of these dendritic polymers to bind large numbers of metal ions may lead to applications as metal sequestering agents for waste remediation technologies.