Synthesis,Redox Activity of Rigid Ferrocenyl Dendrimers,and Isolation of Robust Ferricinium and Class‐II Mixed‐Valence Dendrimers

The coupling reactions of ethynylferrocene with trihalogenoarenes do not lead to ethynylferrocenyl arenes that are soluble enough to form the basis of a suitable construction of stiff ferrocenylethynyl arene‐cored dendrimers, which explains the previous lack of reports on stiff ferrocenyl dendrimers. However, rigid ferrocenyl‐terminated dendrimers have been synthesized from 1,3,5‐tribromo‐ and triiodobenzene through Sonogashira and Negishi reactions with 1,2,3,4,5‐pentamethyl‐1′‐ethylnylferrocene ( 1 a ), according to 1→2 connectivity. With compound 1 a , the construction of a soluble dendrimer ( 10 a ) that contained 12 ethynylpentamethylferrocenyl termini was achieved. Stiff dendrimer 10 a shows a single, reversible cyclic voltammetry (CV) wave (with adsorption), which disfavors the hopping heterogeneous electron‐transfer mechanism that is postulated for redox‐terminated dendrimers that contain flexible tethers. The selectivity of these Sonogashira reactions allows the synthesis of an arene‐cored dendron ( 2 c ) that contains both ethynylferrocenyl and 1,2,3,4,5‐pentamethyl‐ferrocenylethynyl redox groups, thus leading to the construction of a dendrimer ( 7 c ) that contains both types of differently substituted ferrocenyl groups with two well‐separated reversible CV waves. Upon selective oxidation, this mixed dendrimer ( 7 c ) leads to a class‐II mixed‐valence dendrimer, 7 c [PF₆]₃, as shown by Mössbauer spectroscopy, whereas oxidation of the related fully pentamethylferrocenylated dendrimer ( 7 a ) leads to the all‐ferricinium dendrimer, 7 a [PF₆]₆.     

Multifunctional triazolylferrocenyl Janus dendron: Nanoparticle stabilizer,smart drug carrier and supramolecular nanoreactor

Owing to their unique broken symmetry, amphiphilic Janus dendrimers and dendons provide fascinating properties for material, biological, pharmaceutical and biomedical applications. The integration of various organometallic moieties into these macromolecules will further offer the opportunity to form complex and intelligent architectures and materials. Here, we report a novel, simple and multifunctional Janus dendron containing redox‐reversible hydrophobic ferrocene (Fc) unit, complexing‐effective 1,2,3‐triazole ligand and biocompatible hydrophilic triethylene glycol termini. Silver and gold nanoparticles were firstly successfully prepared by using the Janus dendron as the reducing agent of Au(III) and Ag(I), and the stabilizer of the corresponding nanoparticles. The redox response of the Fc moiety was then employed to trigger the release of model drug, rhodamine B, encapsulated in supramolecular micelles formed by the self‐assembly of the Janus dendron. Finally, the precise and excellent metal‐complexing ability of the triazole group in this dendron was fully utilized to stabilize a water‐soluble Cu(I) catalyst, forming supramolecular nanoreactors for the catalysis of the copper(I)‐catalyzed azide alkyne cycloaddition click reaction in only water. The multifunctional characteristics of this dendron highlight the potential for organometallic Janus dendrimers and dendrons in the fields of functional materials and nanomedicines.     

Cationic Vesicles Based on Amphiphilic Pillar[5]arene Capped with Ferrocenium: A Redox‐Responsive System for Drug/siRNA Co‐Delivery

A novel ferrocenium capped amphiphilic pillar[5]arene (FCAP) was synthesized and self‐assembled to cationic vesicles in aqueous solution. The cationic vesicles, displaying low cytotoxicity and significant redox‐responsive behavior due to the redox equilibrium between ferrocenium cations and ferrocenyl groups, allow building an ideal glutathione (GSH)‐responsive drug/siRNA co‐delivery system for rapid drug release and gene transfection in cancer cells in which higher GSH concentration exists. This is the first report of redox‐responsive vesicles assembled from pillararenes for drug/siRNA co‐delivery; besides enhancing the bioavailability of drugs for cancer cells and reducing the adverse side effects for normal cells, these systems can also overcome the drug resistance of cancer cells. This work presents a good example of rational design for an effective stimuli‐responsive drug/siRNA co‐delivery system.     

N‐Boc‐Protected 1,2‐Diphenylethylenediamine‐Based Dendritic Organogels with Multiple‐Stimulus‐Responsive Properties

A new class of poly(benzyl ether) dendrimers, decorated in their cores with N‐Boc‐protected 1,2‐diphenylethylenediamine groups, were synthesized and fully characterized. It was found that the gelation capability of these dendrimers was highly dependent on dendrimer generation, and the second‐generation dendrimer (R,R)‐G₂DPENBoc proved to be a highly efficient organogelator. A number of experiments (SEM, TEM, FTIR spectroscopy, ¹H NMR spectroscopy, rheological measurements, UV/Vis absorption spectroscopy, CD, and XRD) revealed that these dendritic molecules self‐assembled into elastically interpenetrating one‐dimensional nanostructures in organogels. The hydrogen bonding, π–π, and solvophobic interactions were found to be the main driving forces for formation of the gels. Most interestingly, these dendritic organogels exhibited smart multiple‐stimulus‐responsive behavior upon exposure to environmental stimuli such as temperature, anions, and mechanical stress.     

Synthesis,characterization, and properties of tunable thermosensitive amphiphilic dendrimer‐star copolymers with Y‐shaped arms

Novel and well‐defined amphiphilic dendrimer‐star copolymer poly(ε‐caprolactone)‐block‐(poly(2‐(2‐methoxyethoxy)ethylmethacrylate‐co‐oligo(ethylene glycol) methacrylate))₂ with Y‐shaped arms were synthesized by the combination of ring‐opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The investigation of thermal properties and the analysis of crystalline morphology indicate that the high‐branched structure of dendrimer‐star copolymers with Y‐shaped arms and the presence of amorphous P(MEO₂MA‐co‐OEGMA) segments together led to the complete destruction of crystallinity of the PCL segments in the dendrimer‐star copolymer. In addition, the hydrophilicity–hydrophobicity transition of the dendrimer‐star copolymer film can be achieved by altering the external temperatures. The amphiphilic copolymers can self‐assemble into spherical nanomicelles in water. Because the lower critical solution temperature of the copolymers can be adjusted by varying the ratio of MEO₂MA and OEGMA, the tunable thermosensitive properties can be observed by transmittance, dynamic laser light scattering, and transmission electron microscopy (TEM). The release rate of model drug chlorambucil from the micelles can be effectively controlled by changing the external temperatures, which indicates that these unique high‐branched amphiphilic copolymers have the potential applications in biomedical field. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Self‐assembly of a new class of amphiphilic poly(amidoamine) dendrimers and their electrochemical properties

Amphiphilic poly(amidoamine) (PAMAM) dendrimers consisting of a hydrophilic dendrimer core and hydrophobic aromatic dansyl or 1‐(naphthalenyl)‐2‐phenyldiazene (NPD) shells have been synthesized. These amphiphilic dendrimers from the zero generation to the third generation self‐assemble into vesicular aggregates in water. The self‐assembly behavior of these dendrimers strongly depends on their generations. The generation dependence has been further investigated by an exploration of their electrochemical properties. For the PAMAM–NPD aggregates, the photoisomerization process leads to a change in the aggregate size. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5512–5519, 2005     

Dendritic Molecular Electrochromic Batteries Based on Redox‐Robust Metallocenes

In this Concept article, we summarize and discuss recent reports on dendritic molecular electrochromic batteries. Giant dendrimers containing 3ⁿ⁺² terminal tethers (n=generation number) and terminated by first‐raw late‐transition‐metal metallocenes, permethyl metallocenes and other sandwich complexes were shown to be redox robust. Indeed, they can be oxidized and reduced without decomposition and exist under two stable oxidation states (Fe^III/II, Co^III/II). Thus, a pre‐determined number of electrons (up to 14 000) per dendrimer can be exchanged. Cyclic voltammetry showed a remarkable complete reversibility even up to 14 000 Fe and Co termini in metallodendrimers, indicating fast electron hoping among the redox sites and between dendrimers on a carbon surface covered by arylcarboxylate groups. The dendrimer sizes were measured by dynamic light scattering in solution and by AFM (subsequent to flattening in the condensed state also indicating that these metallodendrimers aggregate to form discrete nanoparticles of dendrimers, as atoms do). The metallodendrimer size varies considerably between the two redox forms due to tether extension of the cationic dendrimers upon oxidation, and a breathing mechanism was shown by atomic and electric force microscopy (AFM and EFM). When the redox potential is very negative, the reduced form is an electron‐reservoir system that can deliver a large number of electrons per dendrimer to various reducible substrates. These systems are thus potential dendritic molecular batteries with two different colors for the two redox forms (electrochromic behavior).     

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     

Synthesis and thermal behavior of Janus dendrimers,part 2

The thermal properties of twelve Janus-type dendrimers up to the second generation were evaluated by termogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Compounds consist of the dendritic bisMPA based polyester moieties, and either 3,4-bis-dodecyloxybenzoic acid, 3,5-bis-dodecyloxybenzoic acid or 3,4,5-tris-dodecyloxybenzoic acid moieties, attached to opposite sides of the pentaerythritol core. The thermal stability of the compounds was evaluated by TGA, displaying onset decomposition temperatures (T_d) at around 250 °C. DSC measurements upon heating and cooling confirmed that OH terminated Janus dendrimers featuring large polarity difference in opposite sides display liquid crystalline phases with exception of 3,5-type G1 dendrimer; while acetonide terminated dendrimers displayed merely melting transitions. Dendrimers having terminal alkyl chains at positions 3,4 or 3,4,5 in aromatic moieties exhibited enantiotropic mesophases. However, the thermal behavior of the dendrimers with 3,5-substitution pattern was different: the 3,5-type G1 dendrimer exhibit a lack of mesomorphic transition, and in the case of the 3,5-type G2 dendrimer, the mesophase was absent in the first heating scan but was observed during the subsequent cooling and heating scans at the rate of 10 °C/min.     

Syntheses and nickel coordination properties of cyclen substituted with mixed stilbene/poly(ethylene glycol) dendritic arms

We synthesized a series of cyclens substituted with mixed stilbene and poly(ethylene glycol) dendritic arms. All dendrimers terminated with different peripheral groups had good solubility in common organic solvents, and dendrimers terminated with ? CO₂H groups (CO₂H‐dendrimers) were also soluble in alkaline solutions. The nickel coordination properties of these dendrimers were investigated in organic solvents. Dendrimers terminated with ? CN groups (CN‐dendrimers) and the second‐generation CO₂H‐dendrimer [(CO₂H)₈L2] could produce pentacoordinated nickel complexes; the third‐generation CO₂H‐dendrimer [(CO₂H)₁₆L3] could form tetra‐ and pentacoordinated nickel complexes, and the nickel complex of the fourth‐generation CO₂H‐dendrimer [(CO₂H)₃₂L4] could not be obtained. This result was due to the fact that the globular surface of (CO₂H)₁₆L3 formed a hydrogen‐bond network that selectively penetrated cations and inhibited the access of anions to the core. The formation of the hydrogen‐bond network was confirmed by Fourier transform infrared, ¹H NMR, and fluorescence data. The CN‐dendrimers could not form hydrogen bonds on the surface, and the first‐ and second‐generation CO₂H‐dendrimers could not form intramolecular hydrogen‐bond networks. Therefore, they had no selectivity for positive nickel ions and negative chloride ions. (CO₂H)₃₂L4 could not produce a nickel complex because it had a crammed backbone structure that could not penetrate nickel and chloride ions. Therefore, it was possible to control the ion access of cations and anions with the hydrogen‐bond network of (CO₂H)₁₆L3. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5414–5428, 2005     

The self‐assembly over nano‐ to submicro‐length scales in water of a fluorescent julolidine‐labeled amphiphilic random terpolymer

A novel fluorescent‐labeled amphiphilic random terpolymer is synthesized by controlled radical polymerization of a fluorescent molecular rotor monomer, 2‐cyano‐2‐[4‐vinyl(1,1′‐biphenyl)‐4′‐yl]vinyljulolidine, a hydrophilic monomer, poly (ethylene glycol) methyl ether methacrylate, and a hydrophobic monomer, perfluorohexylethyl acrylate. Combined dynamic light scattering and fluorescence emission spectroscopy measurements are used to investigate its self‐assembly in water solution. Self‐assembled nanostructures with a hydrodynamic diameter size D_h of 4 ± 1 nm are detected due to the single‐chain folding of the terpolymer in unimer micelles. The fluorescence emission intensity of the terpolymer in water solution is found to be one order of magnitude higher than that in organic solvents, as a result of the preferential encapsulation of the julolidine co‐units in hydrophobic compartments of the unimer micelles. The temperature dependence of the self‐associative behavior of the amphiphilic terpolymer is also investigated and a critical temperature is identified at which a transition between single‐chain unimer micelles and multi‐chain aggregates (D_h = 400 ± 40 nm) reversibly takes place on heating–cooling cycles. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 797–804     

Ultrasound‐Driven Secondary Self‐Assembly of Amphiphilic β‐Cyclodextrin Dimers

The controlled secondary self‐assembly of amphiphilic molecules in solution is theoretically and practically significant in amphiphilic molecular applications. An amphiphilic β‐cyclodextrin (β‐CD) dimer, namely LA‐(CD)₂, has been synthesized, wherein one lithocholic acid (LA) unit is hydrophobic and two β‐CD units are hydrophilic. In an aqueous solution at room temperature, LA‐(CD)₂ self‐assembles into spherical micelles without ultrasonication. The primary micelles dissociates and then secondarily form self‐assemblies with branched structures under ultrasonication. The branched aggregates revert to primary micelles at high temperature. The ultrasound‐driven secondary self‐assembly is confirmed by transmission electron microscopy, dynamic light scattering, ¹H NMR spectroscopy, and Cu²⁺‐responsive experiments. Furthermore, 2D NOESY NMR and UV/Vis spectroscopy results indicate that the formation of the primary micelles is driven by hydrophilic–hydrophobic interactions, whereas host–guest interactions promote the formation of the secondary assemblies. Additionally, ultrasonication is shown to be able to effectively destroy the primary hydrophilic–hydrophobic balances while enhancing the host–guest interaction between the LA and β‐CD moieties at room temperature.     

Morphology‐Controlled Self‐Assembly of an Organic/Inorganic Hybrid Porphyrin Derivative Containing Polyhedral Oligomeric Silsesquioxane (POSS)

An organic/inorganic hybrid porphyrin derivative, namely, metal‐free tetrakisphenyl porphyrin–polyhedral oligomeric silsesquioxanes (H₂TPP‐POSS) was synthesized by azide–alkyne click chemistry. The self‐assembly behavior of H₂TPP‐POSS was systematically studied in CHCl₃ at different concentrations and in solvents with different polarities. Novel nanovesicles could be obtained through the self‐assembly of H₂TPP‐POSS in CHCl₃ at a concentration lower than 10^?4 m. Diffuse microrods formed at a concentration higher than 10^?4 M . Additionally, the polarity of the solvent also greatly influenced the assembled morphologies, and a series of assembled morphologies, including crescent‐shaped micelles, spherical micelles, doughnut‐shaped vesicles, and ordered square sheets, could form in solvents with different polarities.     

Amperometric Detection and Quantification of 8‐Hydroxy‐2′‐deoxyguanosine (8‐OHdG) Using Dendrimer Modified Electrodes

8‐Hydroxy‐2′‐deoxyguanosine (8‐OHdG) detection by high performance liquid chromatography (HPLC) with amperometric detection was studied using a Au electrode modified with different dendrimer based thin films. Gold electrode is thiol‐modified, forming self‐assembled monolayers on which different generation PAMAM dendrimers with terminal functional groups ? COOH and ? NH₂ have been attached using peptidic bonds. Results obtained in synthetic samples show low limits of detection and quantification for 8‐OHdG (1.2×10^?9 and 3.7×10^?9 M respectively), with matrix interference elimination, thus avoiding sample pretreatment. Best results are obtained with electrodes modified with aliphatic amino thiols and 3.5 and 4.5 generation carboxylated dendrimers (Au/AET/DG^3.5 and Au/AET/DG^4.5), demonstrating that these materials constitute a good alternative for 8‐OHdG determination in biological fluids.     

Adaptive Amphiphilic Dendrimer‐Based Nanoassemblies as Robust and Versatile siRNA Delivery Systems

siRNA delivery remains a major challenge in RNAi‐based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self‐assemble into adaptive supramolecular assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addition, this amphiphilic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer‐based adaptive supramolecular assemblies represent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer‐based self‐assembled drug delivery in biomedical applications.     

Self‐Assembly of Amphiphilic Janus Dendrimers into Mechanically Robust Supramolecular Hydrogels for Sustained Drug Release

Compounds that can gelate aqueous solutions offer an intriguing toolbox to create functional hydrogel materials for biomedical applications. Amphiphilic Janus dendrimers with low molecular weights can readily form self‐assembled fibers at very low mass proportion (0.2 wt %) to create supramolecular hydrogels (G′?G′′) with outstanding mechanical properties and storage modulus of G′>1000 Pa. The G′ value and gel melting temperature can be tuned by modulating the position or number of hydrophobic alkyl chains in the dendrimer structure; thus enabling exquisite control over the mesoscale material properties in these molecular assemblies. The gels are formed within seconds by simple injection of ethanol‐solvated dendrimers into an aqueous solution. Cryogenic TEM, small‐angle X‐ray scattering, and SEM were used to confirm the fibrous structure morphology of the gels. Furthermore, the gels can be efficiently loaded with different bioactive cargo, such as active enzymes, peptides, or small‐molecule drugs, to be used for sustained release in drug delivery.     

Topological Effect on the Structure of Self‐Assembled Aggregates from Amphiphilic Macromolecules in Solution

The self‐assembled morphologies of cyclic amphiphiles, which are composed of a long hydrophobic block and a short hydrophilic block, in selective solutions are studied by using a simulated annealing method. The morphological dependence of the aggregates on solvent quality is investigated. The topology effects are studied by comparing results from linear counterparts of the amphiphiles. It is observed that, in addition to spherical micelles, cylindrical micelles, disklike micelles, vesicles, and large compound micelles, muticompartment vesicles with several fluidic cores can be formed by the cyclic systems. The morphologies are regulated by the interaction parameter ε_AS between the hydrophobic block and solvents. Furthermore, it is revealed that the differences of characteristics of the self‐assembled aggregates originate from the difference in architectural constraint. The wide region of forming multicompartment vesicles suggests that cyclic amphiphilic macromolecules could be a suitable candidate for applications to deliver multiple functional components by compartmentalizing different components in different confined space of vesicles.     

Self‐Assembly of Fullerene‐Based Janus Particles in Solution: Effects of Molecular Architecture and Solvent

Two molecular Janus particles based on amphiphilic [60]fullerene (C₆₀) derivatives were designed and synthesized by using the regioselective Bingel–Hirsh reaction and the click reaction. These particles contain carboxylic acid functional groups, a hydrophilic fullerene (AC₆₀), and a hydrophobic C₆₀ in different ratios and have distinct molecular architectures: 1:1 (AC₆₀–C₆₀) and 1:2 (AC₆₀–2C₆₀). These molecular Janus particles can self‐assemble in solution to form aggregates with various types of micellar morphology. Whereas vesicular morphology was observed for both AC₆₀–C₆₀ and AC₆₀–2C₆₀ in tetrahydrofuran, in a mixture of N,N‐dimethylformamide (DMF)/water, spherical micelles and cylindrical micelles were observed for AC₆₀–C₆₀ and AC₆₀–2C₆₀, respectively. A mechanism of formation was tentatively proposed based on the effects of molecular architecture and solvent polarity on self‐assembly.     

Attachment of Amine‐ and Maleimide‐Containing Ferrocene Derivatives onto Self‐Assembled Alkanethiol and Alkanedithiol Monolayers: Voltammetric Evaluation of Cross‐Linking Efficiencies and Surface Coverage of Electroactive Groups

Ferrocene derivatives containing primary amines and maleimide groups were attached covalently onto N‐hydrosuccinimidyl (NHS)‐terminated alkanethiol self‐assembled monolayers (SAMs) and SAMs of alkanedithiol. The surface coverage and efficiencies of the two cross‐linking reactions were evaluated with cyclic voltammetry. All the ferrocene derivatives attached onto the alkanethiol or alkanedithiol SAMs exhibit reversible redox waves. The surface coverage of the aminated ferrocene groups was compared to that of N‐hydrosuccinimidyl (NHS)‐terminated alkanethiol SAM. The covalent attachment of β‐ferrocenylethylamine onto a 11,11′‐dithio‐bis(succinimidylundecanoate) SAM yielded an efficiency as high as 63.1%. The cross‐linking efficiency of this reaction was found to increase with the nucleophilicity of the amino groups. SAMs of longer alkyl chains favor the attachment of a greater number of ferrocene derivatives. As for the Michael‐type electrophilic addition between the sulfhydryl groups of the alkanedithiol SAMs and the ferrocenyl maleimide, the cross‐linking efficiencies were found to range from 6.5% to 25.7%, depending on the alkanedithiol chain length. The difference in the efficiencies between the two types of cross‐linking reactions might be partially attributable to the steric hindrance imposed by the SAMs and the relative sizes of the functional groups.     

Polymersome‐forming amphiphilic glycosylated polymers: Synthesis and characterization

Copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) was used to prepare glycosylated polyethylene (PE)–poly(ethylene glycol) (PEG) amphiphilic block copolymers. The synthetic approach involves preparation of alkyne‐terminated PE‐b‐PEG followed by CuAAC reaction with different azide functionalized sugars. The alkyne‐terminated PE‐b‐PEG was prepared by etherification reaction between hydroxyl‐terminated PE‐b‐PEG (M_n ～ 875 g mol^?1) and propargyl bromide and azidoethyl glycosides were prepared by glycosylation of 2‐azidoethanol. Atmospheric pressure solids analysis probe‐mass spectrometry was used as a novel solid state characterization tool to determine the outcome of the CuAAC click reaction and end‐capping of PE‐b‐PEG by the azidoethyl glycoside group. The aqueous solution self‐assembly behavior of these amphiphilic glycosylated polymers was explored by TEM and dye solubilization studies. Carbohydrate‐bearing spherical aggregates with the ability to solubilize a hydrophobic dye were observed. The potential of these amphiphilic glycosylated polymers to self‐assemble via electro‐formation into giant carbohydrate‐bearing polymersomes was also investigated using confocal fluorescence microscopy. An initial bioactivity study of the carbohydrate‐bearing aggregates is furthermore presented. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 5184–5193