Interactions and Encapsulation of Vitamins C,B3, and B6 with Dendrimers in Water

Titrations of commercial diaminobutane (DAB) and polyamidoamine (PAMAM) dendrimers by vitamins C (ascorbic acid, AA), B₃ (nicotinic acid), and B₆ (pyridoxine) were monitored by ¹H NMR spectroscopy using the chemical shifts of both dendrimer and vitamin protons and analyzed by comparison with the titration of propylamine. Quaternarizations of the terminal primary amino groups and intradendritic tertiary amino groups, which are nearly quantitative with vitamin C, were characterized by more or less sharp variations (Δδ) of the ¹H chemical shift (δ) at the equivalence points. The peripheral primary amino groups of the DAB dendrimers were quaternarized first, but not selectively, whereas a sharp chemical‐shift variation was recorded for the inner methylene protons near the tertiary amines, thereby indicating encapsulation, when all the dendritic amines were quaternarized. With DAB‐G5‐64‐NH₂, some excess acid is required to protonate the inner amino groups, presumably because of basicity decrease due to excess charge repulsion. On the other hand, this selectivity was not observed with PAMAM dendrimers. The special case of the titration of the dendrimers by vitamin B₆ indicates only dominant supramolecular hydrogen‐bonding interactions and no quaternarization, with core amino groups being privileged, which indicates the strong tendency to encapsulate vitamins. With vitamin B₃, a carboxylic acid, titration of DAB‐G3‐16‐NH₂ shows that only six peripheral amino groups are protonated on average, even with excess vitamin B₃, because protonation is all the more difficult due to increased charge repulsion, as positive charges accumulate around the dendrimer. Inner amino groups interact with this vitamin, however, thus indicating encapsulation presumably with supramolecular hydrogen bonding without much charge transfer.     

A Penicillamine Biosensor Based on Tyrosinase Immobilized on Nano‐Au/ PAMAM Dendrimer Modified Gold Electrode

Gold electrodes were modified with submonolayers of 3‐mercaptopropionic acid and further reacted with poly(amidoamine) (PAMAM) dendrimers to obtain thin films. The high affinity of PAMAM dendrimer for nano‐Au with its amine groups was used to realize the role of nano‐Au as an intermediator to immobilize the enzyme of tyrosinase. The characterization of the modified electrode was investigated by cyclic voltammetry, electrochemical impedance spectroscopy and atomic force microscopy (AFM). Tyrosinase can catalyze the oxidation of catechol to o‐benzoquinone. When penicillamine was added to the solution, it reacted with o‐benzoquinone to form the corresponding thioquinone derivatives, which resulted in decrease of the reduction current of o‐benzoquinone. Based on this, a new electrochemical sensor for determination of penicillamine has been developed.     

Dendritic chelating agents. 1. Cu(II) binding to ethylene diamine core poly(amidoamine) dendrimers in aqueous solutions

This paper describes an investigation of the uptake of Cu(II) by poly(amidoamine) (PAMAM) dendrimers with an ethylenediamine (EDA) core in aqueous solutions. We use bench scale measurements of proton and metal ion binding to assess the effects of (i) metal ion-dendrimer loading, (ii) dendrimer generation/terminal group chemistry, and (iii) solution pH on the extent of binding of Cu(II) in aqueous solutions of EDA core PAMAM dendrimers with primary amine, succinamic acid, glycidol, and acetamide terminal groups. We employ extended X-ray absorption fine structure (EXAFS) spectroscopy to probe the structures of Cu(II) complexes with Gx-NH2 EDA core PAMAM dendrimers in aqueous solutions at pH 7.0. The overall results of the proton and metal ion binding measurements suggest that the uptake of Cu(II) by EDA core PAMAM dendrimers involves both the dendrimer tertiary amine and terminal groups. However, the extents of protonation of these groups control the ability of the dendrimers to bind Cu(II). Analysis of the EXAFS spectra suggests that Cu(II) forms octahedral complexes involving the tertiary amine groups of Gx-NH2 EDA core PAMAM dendrimers at pH 7.0. The central Cu(II) metal ion of each of these complexes appears to be coordinated to 2-4 dendrimer tertiary amine groups located in the equatorial plane and 2 axial water molecules. Finally, we combine the results of our experiments with literature data to formulate and evaluate a phenomenological model of Cu(II) uptake by Gx-NH2 PAMAM dendrimers in aqueous solutions. At low metal ion-dendrimer loadings, the model provides a good fit of the measured extent of binding of Cu(II) in aqueous solutions of G4-NH2 and G5-NH2 PAMAM dendrimers at pH 7.0.     

树状大分子聚酰胺-胺的合成及对药物分子增溶性能研究

采用发散法合成了以乙二胺为核的1．0～3．0树状大分子聚酰胺-胺(PAMAM)．采用红外光谱和核磁共振对PAMAM的结构进行了表征，并考察了不同pH值、不同浓度的PAMAM对难溶药物布洛芬的增溶能力．结果表明：PAMAM较十二烷基苯磺酸钠(SDS)对布洛芬有较强的增溶能力，增溶量随PAMAM浓度增加而增大，其增溶机理是由于PAMAM的氨基与布洛芬的羧基之间存在静电作用．     

Scaling trend in diffusion coefficients of low generation G0–G3 PAMAM dendrimers in aqueous solution at high and neutral pH

Aqueous solution diffusion coefficients for G0–G3 PAMAM dendrimers were determined from DOSY-NMR spectroscopy at high and neutral pH. The study was performed in a dilute regime and diffusion coefficients at infinite dilution (D ₀) were estimated from the variation of diffusion coefficients with dendrimer concentration. Hydrodynamic radii (R _h) for each dendrimer were estimated from D ₀ using the Stoke–Einstein relationship at both pH. According to D ₀ and R _h values, the structure of G0–G1 PAMAM dendrimers is almost insensitive to pH variations, whereas G2–G3 PAMAM dendrimers undergo swelling at neutral pH, due to surface amino groups protonation. Experimental diffusion coefficients show a scaling trend with the number of dendrimer atoms (N), with scaling laws of the type D₀ μ N^a D_{0} \propto N^{\alpha } , where α takes values of −0.39 and −0.50 at pH 12 and 7, respectively. For the first time, experimental data accounts for the scaling behavior of aqueous diffusion coefficients for low generation PAMAM dendrimers, as previously reported from molecular dynamics simulations.     

Polyelectrolyte behavior and interpolyelectrolyte matching of AstramolTM poly(propylene imine) dendrimers

Polyelectrolyte behavior of Astramol^TM poly(propylene imine) dendrimers of five generations, G1‐G5, namely DAB‐dendr‐(NH₂)_x (where x is equal to 4, 8, 16, 32 or 64) was studied by means of potentiometric titration in salt‐free water solutions and also in the presence of a shielding low molecular electrolyte (NaCI). In addition to x outer primary amine groups the dendrimer molecule contains x‐2 inner tertiary amine groups. The repeating unit, the core molecule and the fifth generation dendrimer structure are shown in the following Scheme.     

Evaluation of different PAMAM dendrimers as molecular vehicle of 1,2,4-triazine N-oxide derivative with potential antitumor activity

The interaction between a 1,2,4-triazine N-oxide derivative, that holds potential antitumor activity under hypoxic conditions, and diverse polyamidoamine (PAMAM) dendrimers were investigated with the purpose of select the most appropriate macromolecule to act as potential molecular carrier of this active compound. The results shows that dendrimers with amine terminal groups (PAMAM-AT G = 3) and dendrimers with carboxylate terminal groups (PAMAM-CT G2.5 and G4.5) produces triazine derivative hydrolysis, even in buffered medium, and are not suitable as carriers. In contrast, dendrimers with neutral end groups (PAMAM-OHT) shows stable association with the active compound, making this dendrimer a possible medium for triazine carriage.     

Curcumin Loaded Dendrimers Specifically Reduce Viability of Glioblastoma Cell Lines

Glioblastoma (GB) is a deadly and aggressive cancer of the CNS. Even with extensive resection and chemoradiotherapy, patient survival is still only 15 months. To maintain growth and proliferation, cancer cells require a high oxidative state. Curcumin, a well-known anti-inflammatory antioxidant, is a potential candidate for treatment of GB. To facilitate efficient delivery of therapeutic doses of curcumin into cells, we encapsulated the drug in surface-modified polyamidoamine (PAMAM) dendrimers. We studied the in vitro effectiveness of a traditional PAMAM dendrimer (100% amine surface, G4 NH₂), surface-modified dendrimer (10% amine and 90% hydroxyl-G4 90/10-Cys), and curcumin (Cur)-encapsulated dendrimer (G4 90/10-Cys-Cur) on three species of glioblastoma cell lines: mouse-GL261, rat-F98, and human-U87. Using an MTT assay for cell viability, we found that G4 90/10-Cys-Cur reduced viability of all three glioblastoma cell lines compared to non-cancerous control cells. Under similar conditions, unencapsulated curcumin was not effective, while the non-modified dendrimer (G4 NH₂) caused significant death of both cancerous and normal cells. By harnessing and optimizing the components of PAMAM dendrimers, we are providing a promising new route for delivering cancer therapeutics. Our results with curcumin suggest that antioxidants are good candidates for treating glioblastoma.     

Designing poly(amido amine) dendrimers containing core diversities by click chemistry of the propargyl focal point poly(amido amine) dendrons

General, fast, efficient, and inexpensive methods for the synthesis of poly (amido amine) (PAMAM) dendrimers having core diversities were elaborated. In all syntheses, the major step involved an inexpensive 1,3‐dipolar cycloaddition reaction between an alkyne and an azide in the presence of Cu(I) species, which is known as the best example of click chemistry. The propargyl‐functionalized PAMAM dendrons are obtained by the divergent approach using propargylamine as an alkyne‐focal point. Three core building blocks, 1,3,5‐tris(azidomethyl)benzene, N,N,N′,N′‐tetra(azidopropylamidoethyl)‐1,2‐diaminoethane, and 4,4′‐(3,5‐bis(azidopropyloxy)benzyloxy)bisphenyl, were designed and synthesized to serve as the azide functionalities for dendrimer growth via click reactions with the alkyne‐dendrons. These three building blocks were employed together with the propargyl‐functionalized PAMAM dendrons in a convergent strategy to synthesize three kinds of PAMAM dendrimers with different core units. This novel and pivotal strategy using an efficient click methodology provides the fast and efficient synthesis of the PAMAM dendrimers with the tailed made core units. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1083–1097, 2008     

Synthesis of conjugates of β-cyclodextrin with polyamidoamine dendrimers and their molecular inclusion interaction with levofloxacin lactate

Polyamidoamine (PAMAM) dendrimers of different generations (G2 and G4) conjugated with β-cyclodextrin (β-CD), PAMAM (G2, G4)-CD, were synthesized using substitution reaction from mono-6-iodine-β-cyclodextrin and PAMAM dendrimers. The resulting molecular structures were characterized by NMR, IR. The molecular interaction between various dendrimers and levofloxacin lactate (LFL) were investigated by monitoring the fluorescence of LFL in the presence of dendrimers in buffer solution (pH 7.4) at 25?°C. It was found that the PAMAM (G2, G4)-CD possesses higher sensitizing ability than that of the corresponding parent dendrimers and natural β-CD, and increases concomitantly with the increases of generation and content of β-CD, suggesting that the PAMAM (G2, G4)-CD possesses stronger inclusion ability with LFL. The possible interaction mechanism between PAMAM-CD and LFL was proposed by ¹H NMR analysis and theoretical calculation. The results show that the LFL molecule is located at the amine end of dendrimer molecule and along the side of cyclodextrin cavities to form supramolecular complexes. Furthermore, results indicate that the main driving force of the complex could be attributed to the electrostatic interactions and hydrogen bonding between LFL and PAMAM-CD, as well as the synergistic effect of intermolecular forces.     

以聚酰胺-胺树形分子为模板制备AgI纳米簇

本文以聚酰胺-胺(PAMAM)树形分子为模板,原位制备AgI纳米簇.系统地研究了AgI纳米簇制备过程中各种反应条件如树形分子端基、反应时间、Ag⁺与PAMAM摩尔比等对AgI纳米簇粒径的影响,分别用紫外-可见光谱、荧光光谱、透射电镜等对所制备的纳米簇进行表征.在相同的条件下,以G4.5-COOH₃为模板较以G5.0-NH₂为模板制备的AgI纳米簇粒径小、分布均匀,这主要取决于G4.5-COOCH₃PAMAM树形分子所起的“内模板”作用.G4.5-COOH₃树形分子浓度为1×10^-5mol/L,Ag⁺与树形分子摩尔比为30:1时所制备的AgI纳米簇的粒径分布均匀、稳定性好,室温避光可稳定存在两个月以上.     

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.     

Enhancement of entrapping ability of dendrimers by a cubic silsesquioxane core

We report that a polyhedral oligomeric silsesquioxane (POSS) core can enhance the entrapping ability of dendrimers. Compared to the G2 PAMAM dendrimer, the G2 POSS-core dendrimer can entrap a larger amount of guest molecules without loss of affinity, and consequently, the water solubility of the entrapped guest molecules can be increased. In addition, we demonstrated that a fluorophore entrapped in the G2 POSS-core dendrimer was prevented from undergoing fluorescence photobleaching.     

Synthesis of dicarboxylate oligosaccharide multilayer terminal functionality upon poly(lysine) dendrimer scaffolding

A reactive three‐layered dendrimer containing carboxyl groups was synthesized by the coupling of dicarboxylic acid and a highly reactive, two‐layered glycopeptide dendrimer. Lactose, maltose, or maltotriose was reacted with the poly(lysine) dendrimer in its third and fourth generations by reductive amination and afforded two‐layered glycolysine dendrimers. The reaction was conducted in a borate buffer (pH 9.0). ¹H NMR, ¹³C NMR, and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry analyses were applied for the determination of the structures of the products. When an excess amount of the oligosaccharide and a long reaction time were used, the degree of substitution increased to 1.5–2.0 against an amino group. For the preparation of highly reactive, multilayered dendrimers for an antigen carrier, C6 hydroxy groups of the oligosaccharides were selectively esterified by adipic acid and suberic acid to give 6‐O‐adipoyl oligosaccharide–poly(lysine) dendrimers and 6‐O‐suberoyl oligosaccharide–poly(lysine) dendrimers. The reactivity of these multilayered dendrimers was examined by a model reaction with phenylalanine ethyl ester. The dendrimer showed high reactivity, providing phenylalanine ethyl ester–dicarboxylate oligosaccharide–poly(lysine) dendrimers with a considerably high proportion of phenylalanine residues. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 3622–3633, 2002     

SiO2–poly(amidoamine) dendrimer inorganic/organic hybrids

SiO₂–poly(amidoamine) (PAMAM) dendrimer hybrids were synthesized via (1) a Michael addition reaction between the dendrimer and 3‐(trimethoxysilyl) propyl acrylate, (2) the dissolution of the formed compound in methanol, and (3) the mixing of the latter solution with a methanol solution of partly hydrolyzed tetraethylorthosilicate (TEOS) and its casting on a glass substrate. ¹H NMR indicated that in the first step, 77% of the secondary amines were converted into tertiary amines when the fourth‐generation dendrimer was employed and 46% were converted when the second‐generation dendrimer was used. The final SiO₂–PAMAM dendrimer hybrids were obtained via the hydrolysis and condensation of the compound obtained via the Michael addition and the methanol solution of partly hydrolyzed TEOS. The compartmentalized structure of the hybrids due to the compartments of the dendrimers could be controlled by changing the dendrimer and the amount of TEOS. Scanning electron microscopy and transmission electron microscopy micrographs provided information about the structure of the hybrids. Like the PAMAM dendrimer, the SiO₂–PAMAM dendrimer hybrids exhibited a high metal ion complexing capacity because of the presence of the compartments of the dendrimer; they can be, however, much more easily handled, and, as demonstrated by thermogravimetric experiments, have much higher thermal resistance. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1443–1449, 2000     

Size‐Tunable Micron‐Bubbles Based on Fluorous–Fluorous Interactions of Perfluorinated Dendritic Polyglycerols

This paper describes the behavior of various generations of polyglycerol dendrimers that contain a perfluorinated shell. The aggregation in organic solvents is based on supramolecular fluorous–fluorous interactions, which can be described by means of ¹⁹F NMR spectroscopy. In order to study the interaction and aggregation phenomena of dendrimers with perfluorinated shell and perfluoro‐tagged guest molecules we investigated [G3.5]‐dendrimer with a perfluorinated shell in the presence of perfluoro‐tagged disperse red. Noteworthy, the interaction intensities varied in an unexpected manner depending on the equivalents of perfluoro‐tagged guest molecules added to the dendrimers in solution which then formed supramolecular complexes based on fluorous–fluorous interactions. We found that these complexes aggregated around residual air in the solvent to form stable micron‐sized bubbles. Their sizes correlated with the interaction intensities measured for certain dendrimer–guest molecule ratios. Degassing of the solutions led to a quasi phase separation between organic and fluorous phase, whereby the dendrimers formed the fluorous phases. Regassing the sample with air afforded bubbles of the initial size again.     

Novel ultrafiltration membranes with the least fouling properties for the treatment of veterinary antibiotics in the pharmaceutical wastewater

Dendrimers have received more attention in all fields of research these days. In the present study, polyamidoamine (PAMAM) dendrimers were synthesized on the acrylic ultrafiltration membranes to minimize fouling as an important deficiency in the separation process. The antifouling activity of these dendrimers with different generations (G0‐3) was tested to restrict three macrolides (tylvalosin, tylosin, and tulathromycin) and two pleuromutilins (tiamulin and valnemulin) as veterinary antibiotic drugs with amine groups and positive charges at pH = 7 of the membrane surface. These compounds are risky for human consumption. Due to having several amine functional groups and branches, PAMAM dendrimers can be a great coating agent for antifouling. G3 PAMAM dendrimer‐coated membranes had the best performance (water flux: 130.7 L/m²·h, rejection of tulathromycin: 91.4%, flux recovery ratio: 86.3%). The function of this ultrafiltration process depended on pore size and also charge surface. A significant reduction for irreversible and reversible fouling was observed for this new ultrafiltration membrane (F_ir: 14.5%, F_re: 21.9%). This observation was confirmed by the power law model. Three 5‐hour cycle ultrafiltration processes were carried out for veterinary antibiotic wastewater that showed 3.18% loss of initial water flux (for the third cycle), final cleaning efficiency of 96.82%, and tylvalosin rejection of 94.1%.     

Ester‐ and amide‐terminated dendrimers with alternating amide and ether generations

Ester‐terminated polyamide dendrimers up to the third generation and amide‐terminated polyamide dendrimers of the first generation were synthesized by convergent growth. The Williamson ether synthesis and diphenylphosphoryl azide (DPPA) coupling of amines to carboxylic acids were used for the construction of the dendrimers, having alternate ether and amide generations. The methyl ester‐ and N,N‐diethylamide‐terminated dendrimers were readily soluble in common organic solvents while the N‐methylamide‐ and N‐benzylamide‐terminated dendrimers were soluble only in DMF and DMSO. Both the end and internal amide groups of the N,N‐diethylamide‐terminated dendrimer were reduced by LiAlH₄ to form a polyamine dendrimer. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1533–1543, 2000     

Guest–host chemistry with dendrimers: Stable polymer assemblies by rational design

A new type of guest has been designed and synthesized for the exo‐type supramolecular functionalization of adamantyl‐urea‐terminated poly(propylene imine) dendrimers. This new type of guest motif features a uriedo methane sulfonic acid moiety that binds very selectively to the surfaces of dendrimers via a combination of noncovalent interactions forming well‐defined complexes. The guest–host properties have been examined for a fifth‐generation adamantyl‐urea‐functionalized poly(propylene imine) dendrimer capable of binding 32 guest molecules and for a model host molecule that can bind only one guest molecule. The guest–host chemistry has been studied with ¹H NMR spectroscopy, nuclear Overhauser enhancement spectroscopy NMR spectroscopy, T₁‐relaxation NMR experiments, and IR spectroscopy. The 1:32 ratio with the dendrimer has been confirmed unambiguously from ¹H NMR spectra of the complex after size exclusion chromatography. Competition experiments with guests bearing a carboxylic acid instead of a sulfonic acid in the binding motif have demonstrated that the sulfonic acid has superior binding strength. Also, the importance of a combination of noncovalent interactions has been shown via competition experiments with a guest lacking the uriedo moiety. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3792–3799, 2004     

Low generational polyamidoamine dendrimers to enhance the solubility of folic acid:A‘‘dendritic effect’’investigation

Low generational(G0–G2,G for generation) polyamidoamine(PAMAM) dendrimers were investigated as enhancers to improve the aqueous solubility of folic acid at pH 11 and pH 5.In these two cases,the solubility of folic acid increases with both the dendrimer concentration and generation.However,the solubilization mechanism is different.The electrostatic interaction between the primary amines of dendrimers and the ionized carboxylic groups of folic acid dominates the dissolution process at pH 11 while the increase of the solubility of folic acid at pH 5 is attributed to the hydrophobic encapsulation inside the dendrimer molecules.In addition,for comparison ethylenediamine was used as a small molecule control to examine the ‘‘dendritic effect' in the dendrimer-related solubilization process.Interestingly,PAMAM dendrimers exhibit,at pH 5,a significant superiority over ethylenediamine in enhancing solubility,whereas this ‘‘dendritic effect' cannot be observed under the basic condition.