Efficient synthesis of ionic triblock copolyesters and facile access to charge‐reversal hybrid micelles

Novel carboxyl‐ and amino‐functionalized copolyesters, based on poly(ε‐caprolactone)‐block‐poly(butylene fumarate)‐block‐poly(ε‐caprolactone), were efficiently synthesized via Michael‐type thiol‐ene click chemistry. The resulting amphiphilic copolyesters with controllable molecular weights and abundant positively or negatively charged groups could spontaneously form pH‐sensitive micelles in aqueous solutions, as confirmed by transmission electron microscopy, dynamic light scattering, fluorescence probing technique, and zeta potential analyses. Importantly, charge‐reversal hybrid micelles can be obtained by co‐assembly of carboxyl‐ and amino‐functionalized copolyesters. The surface charges of hybrid micelles reversed rapidly from negative to positive at isoelectric point via protonation of surface carboxyl and amino groups. Interestingly, the hybrid micelles showed apparent pH‐triggered Nile red‐release behavior in acidic condition resembling tumor intracellular environment, which is fairly desirable for drug delivery. Our work indicates that co‐assembly is a facile but efficient way to prepare charge‐reversal micelles, which have great potential to be used as intelligent drug delivery systems for cancer therapy. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1259–1267     

Investigating alternative acidic proteases for H/D exchange coupled to mass spectrometry: Plasmepsin 2 but not plasmepsin 4 is active under quenching conditions

Structural studies of proteins by hydrogen/deuterium exchange coupled to mass spectrometry (DXMS) require the use of proteases working at acidic pH and low temperatures. The spatial resolution of this technique can be improved by combining several acidic proteases, each generating a set of different peptides. Three commercial aspartic proteases are used, namely, pepsin, and proteases XIII and XVIII. However, given their low purity, high enzyme/protein ratios have to be used with proteases XIII and XVIII. In the present work, we investigate the activity of two alternative acidic proteases from Plasmodium falciparum under different pH and temperature conditions. Peptide mapping of four different proteins after digestion with pepsin, plasmepsin 2 (PSM2), and plasmepsin 4 (PSM4) were compared. PSM4 is inactive at pH 2.2 and 0°C, making it unusable for DXMS studies. However, PSM2 showed low but reproducible activity under DXMS conditions. It displayed no substrate specificity and, like pepsin, no strict sequence specificity. Altogether, these results show that PSM2 but not PSM4 is a potential new tool for DXMS studies.     

Novel Peptide‐Shelled Dendrimer with Dramatically Changeable Thermo‐Responsive Character

The preparation of a novel peptide/dendrimer hybrid is reported in which an elastin‐like oligopeptide is successfully assembled onto a poly(amidoamine) dendrimer surface (G4‐ELP), and its unique thermo‐responsive behavior is discussed. As a result, the G4‐ELP is found to exhibit LCST behavior in the pH range 3–10 including physiological temperature range under neutral‐pH conditions. Moreover, cooperative interplay between the folding state of the ELP shell and the ionization state of the dendrimer core enables the G4‐ELP to control its LCST widely by pH variation. This achievement provides a new insight for the design of dual‐responsive materials with a potential in biological applications.

     

Adaptive Chemoenzymatic Microreactors Composed of Inorganic Nanoparticles and Bioinspired Intrinsically Disordered Proteins

The assembly of protein and inorganic nanoparticles represents an attractive approach to generate composite materials with multiple functions. Herein, we functionalize inorganic nanoparticles with intrinsically disordered protein domains associated with the formation of membraneless compartments in cells. These protein sequences, defined as low complexity domains (LCDs), encode intermolecular interactions that drive highly controlled, dynamic self‐assembly in response to environmental changes. We show that the properties of the LCDs can be transferred to inorganic nanoparticles, inducing controlled phase separation that is dynamic and responsive to ionic strength and pH. Specifically, we hybridize magnetic nanoparticles with multi‐domain proteins consisting of LCD domains and a globular enzyme, generating dynamic protein‐composite compartments that locally confine hybrid chemoenzymatic reactions and respond to external magnetic fields and changes in solution conditions.     

pH‐responsive squeezing polysaccharidic nanogels for efficient docetaxel delivery

In this study, we report pH‐responsive polysaccharidic nanogels comprising starch grafted with 3‐(diethylamino)propylamine (DEAP, as an inner soft nanogel core) and poly(ethylene glycol) (PEG, as an outer hydrophilic nanogel shell). Here, the DEAP moieties (pK_b ~ pH 7.0) enhance the lipophilicity of the nanogel core at pH 7.4, improving the loading efficiency of an antitumor model drug (docetaxel [DTX]) in the core. However, the DEAP moieties could be protonated below pH 7.0, resulting in the mediation of ion‐dipole interactions with hydroxyl groups abundant in starch backbone. This event causes the electrostatic condensation of the nanogel core and enables the acceleration of drug release by squeezing of the core. We demonstrated that the nanogels selectively release the drug given a weakly acidic pH stimulus. These drug release trends are reversible with changes in pH. As a result, the nanogels are able to efficiently reduce MDA‐MB‐231 tumor cell population in acidic pH environments.     

Complex micelles formed from two diblock copolymers for applications in controlled drug release

Double‐responsive core‐shell‐corona complex micelles for applications in drug release were formed from self‐assembly of two diblock copolymers PtBA‐b‐ PNIPAM and PtBA‐b‐P4VP. The two diblock copolymers coaggregated into core‐shell complex micelles in acidic water with the hydrophobic PtBA blocks as the common core and soluble PNIPAM/P4VP blocks as the mixed shell. Increasing temperature or pH value, the micelles converted into core‐shell‐corona micelles because of the collapse of PNIPAM or P4VP blocks as the inner shell and soluble P4VP or PNIPAM chains stretching outside as the outer corona. The anti‐inflammation drug naproxen (NAP) was loaded as the model drug in micelles in acidic water and released because of the ionization of NAP in alkaline solutions. Compared with pure core‐shell micelles, release of NAP from core‐shell‐corona complex micelles avoided the burst diffusion and the release rate is more easily controlled by tuning the composition of the mixtures or by adjusting the pH of the medium. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1804–1810, 2009     

Dendrimer complexes: Fine control of metal assembly in macromolecules

New phenylazomethine dendrimers have been developed, with each dendrimer having a unique single structure. From ultraviolet–visible absorption spectra, we determined that stannous chloride added to dendritic polyphenylaz omethine (DPA) was assembled in a stepwise manner from the core shell to the periphery. The selective binding was achieved by the electron density gradient formed in the dendrimer, and it was confirmed by shell‐selective imine reduction, transmission electron microscopy, and NMR measurements. The complex formation constants of the respective shells were estimated to be considerably different by a simulation analysis of ultraviolet–visible absorption spectra. The reversible assembly and release of iron into and out of the dendrimer were possible by electrochemical oxidation and reduction, respectively. DPA with a porphyrin at the core was found to function as an effective reduction catalyst of carbon dioxide. DPA with aryl amine at the core was demonstrated to function as a hole‐transporting material in electroluminescent devices. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 3719–3727, 2005     

Synthesis and characterization of lipid-polymer hybrid nanoparticles with pH-triggered poly(ethylene glycol) shedding

Novel lipid-polymer hybrid nanoparticles are designed with a poly(ethylene glycol) (PEG) coating that is shed in response to a low pH trigger. This allows the nanoparticles to be stable during systemic circulation and at neutral pH, but destabilize and fuse with lipid membranes in acidic environments. The hybrid nanoparticles consist of a poly(lactic-co-glycolic acid) core with a lipid and lipid-PEG monolayer shell. To make the hybrid nanoparticles pH sensitive, a lipid-(succinate)-mPEG conjugate is synthesized to provide a hydrolyzable PEG stealth layer that is shed off the particle surface at low pH. The pH-sensitivity of the nanoparticles is tunable using the molar concentration of the lipid-(succinate)-mPEG incorporated in the lipid shell of the particles. Possible uses of these pH-sensitive nanoparticles include aggregating in acidic tumor microenvironments, escaping acidified endosomes, or aggregating in deep lung tissue for improved inhalation administration.     

Core-shell-corona au-micelle composites with a tunable smart hybrid shell

Micelles having a core of polystyrene and a mixed shell of poly(ethylene glycol) and poly(4-vinylpyridine) were formed through self-assembly of a triblock copolymer poly(ethylene glycol)- block-polystyrene- block-poly(4-vinylpyridine) in acidic water (pH 2). Reducing the HAuCl(4)-treated micelle solution leads to the formation of the Au-micelle composites with a core of polystyrene, a hybrid shell of poly(4-vinylpyridine)/Au/poly(ethylene glycol), and a corona of poly(ethylene glycol). The gold nanoparticles with controlled sizes were anchored to poly(4-vinylpyridine) to form the physically cross-linked hybrid shell. In aqueous solution, the hybrid shell is swollen and the swollen degree is sensitive to the pH condition. Under basic conditions, the channel in the hybrid shells of the composite is produced, which renders the composites a good catalytic activity. In addition, the composites also show good stability, unchanged hydrodynamic diameter, and surface plasmon absorption under different pH conditions.     

A Supramolecular Hydrogel Based on Polyglycerol Dendrimer‐Specific Amino Group Recognition

Dendrimer‐based supramolecular hydrogels have gained attention in biomedical fields. While biocompatible dendrimers were used to prepare hydrogels via physical and/or chemical crosslinking, smart functions such as pH and molecular control remain undeveloped. Here, we present polyglycerol dendrimer‐based supramolecular hydrogel formation induced by a specific interaction between the polyglycerol dendrimer and an amino group of glycol chitosan. Gelation was achieved by mixing the two aqueous solutions. Hydrogel formation was controlled by varying the polyglycerol dendrimer generation. The hydrogel showed pH‐dependent swelling; strongly acidic conditions induced degradation via dissociation of the specific interaction. It also showed unique l ‐arginine‐responsive degradation capability due to competitive exchange of the amino groups of glycol chitosan and l ‐arginine. These polyglycerol dendrimer‐based supramolecular characteristics allow multimodal application in smart biomaterials.     

Dendrimer‐Type Peptoid‐Decorated Hexaphenylxylenes and Tetraphenylmethanes: Synthesis and Structure in Solution and in the Gas Phase

Branched organic nanostructures are useful scaffolds that find multiple applications in a variety of fields. Here, we present a novel approach to dendrimer‐like structures. Our design contains a rigid hydrocarbon‐based core (hexaphenylxylylene/tetraethynylphenylmethane) combined with a library of N‐substituted oligoglycines (so‐called peptoids) providing a flexible shell. The use of click chemistry allows rapid assembly of the nanostructures. The possibility of tuning the size and the solubility of this new type of nanostructure will be advantageous for future applications such as heterogeneous catalysis.     

Polystyrene‐Core–Silica‐Shell Hybrid Particles Containing Gold and Magnetic Nanoparticles

Polystyrene‐core–silica‐shell hybrid particles were synthesized by combining the self‐assembly of nanoparticles and the polymer with a silica coating strategy. The core–shell hybrid particles are composed of gold‐nanoparticle‐decorated polystyrene (PS‐AuNP) colloids as the core and silica particles as the shell. PS‐AuNP colloids were generated by the self‐assembly of the PS‐grafted AuNPs. The silica coating improved the thermal stability and dispersibility of the AuNPs. By removing the “free” PS of the core, hollow particles with a hydrophobic cage having a AuNP corona and an inert silica shell were obtained. Also, Fe₃O₄ nanoparticles were encapsulated in the core, which resulted in magnetic core–shell hybrid particles by the same strategy. These particles have potential applications in biomolecular separation and high‐temperature catalysis and as nanoreactors.     

Switchable Hydrolase Based on Reversible Formation of Supramolecular Catalytic Site Using a Self‐Assembling Peptide

The reversible regulation of catalytic activity is a feature found in natural enzymes which is not commonly observed in artificial catalytic systems. Here, we fabricate an artificial hydrolase with pH‐switchable activity, achieved by introducing a catalytic histidine residue at the terminus of a pH‐responsive peptide. The peptide exhibits a conformational transition from random coil to β‐sheet by changing the pH from acidic to alkaline. The β‐sheet self‐assembles to form long fibrils with the hydrophobic edge and histidine residues extending in an ordered array as the catalytic microenvironment, which shows significant esterase activity. Catalytic activity can be reversible switched by pH‐induced assembly/disassembly of the fibrils into random coils. At higher concentrations, the peptide forms a hydrogel which is also catalytically active and maintains its reversible (de‐)activation.     

Design and characterization of Dendrimer of MNPs as a novel,heterogeneous and reusable nanomagnetic organometallic catalyst for one‐pot synthesis of hydroxyl naphthalene‐1,4‐dione derivatives under solvent‐free conditions

A novel super acidic magnetic nanoparticle as catalyst was successfully synthesized. The preparation of this dendrimer sulfonic acid functionalized γ‐Fe₂O₃ magnetic core‐shell silica nanoparticles as a new recoverable and heterogeneous nanocatalyst was described. The new catalyst was characterized using various techniques such as scanning electron microscopy (SEM), energy dispersive spectrum (EDS), and thermo gravimetric synthesis (TGA). Moreover, we have examined the catalytic activity of the catalyst for one‐pot, efficient and facile synthesis of 2‐hydroxy‐1,4‐naphthoquinone derivatives via a three‐component condensation reaction of 2‐hydroxynaphthalene‐1,4‐dione, aromatic aldehydes and aniline derivatives. High yields of products, short reaction times, waste‐free, mild, ambient and solvent‐free reaction conditions are advantages of this protocol. Also, the catalyst can be easily recovered by an external magnetic and reused several times without significant loss of its catalytic activity.     

A water-soluble aromatic dendrimer as a model basis for dual-action drugs

The affinities of two anionic pyrenyl probes for pyridinium high-molecular-mass cations of different topologies—poly(N-ethyl-4-vinylpyridinium bromide) and a water-soluble poly(pyridylphenylene) dendrimer—are studied by the method of fluorescence quenching. The hydrophilic probe carrying three sulfonate groups in a molecule more efficiently interacts with a flexible highly charged linear polycation throughout the studied pH range. The binding of the dendrimer with a relatively hydrophobic probe containing a single carboxyl group is improved by acidification of solutions, and it becomes dominant in weakly acidic solutions. The interaction of DNA with the dendrimer containing the hydrophobic probe has no effect on the formation of the dendriplex and leads to displacement of only a small fraction of the bound probe into solution. Our model studies demonstrate that dual-action dendrimer carriers capable of simultaneous delivery of genetic material and hydrophobic drugs to target cells can be created.     

A polycationic dendrimer as noncovalent support for anionic organometallic complexes

Polycationic dendrimer 1 forms a well-defined, stoichiometric assembly with eight anionic metal complexes; this assembly is successfully applied as a Lewis acidic catalyst which performs comparably to the unsupported metal complex.     

Multivalency by Self‐Assembly: Binding of Concanavalin A to Metallosupramolecular Architectures Decorated with Multiple Carbohydrate Groups

Multiplication of functional units through self‐assembly is a powerful way to new properties and functions. In particular, self‐organization of components decorated with recognition groups leads to multivalent entities, amenable to strong and selective binding with multivalent targets, such as protein receptors. Here we describe an efficient, supramolecular, one‐pot valency multiplication process proceeding through self‐organization of monovalent components into well‐defined, grid‐shaped [2×2] tetranuclear complexes bearing eight sugar residues for multivalent interaction with the tetrameric lectin, concanavalin A (Con A). The grids are stable in water under physiological pH at a relatively high concentration, but dissociate readily at slightly more acidic pH or upon dilution below a certain threshold, in a type of on–off behavior. The carbohydrate‐decorated grids interact strongly and selectively with Con A forming triply supramolecular bio‐hybrid polymeric networks, which lead to a highly specific phase‐separation and quasi‐quantitative precipitation of Con A out of solution. Dramatic effects of valency number on agglutination properties were demonstrated by comparison of grids with divalent carbohydrates of covalent and non‐covalent (L ‐shaped, mononuclear zinc complex) scaffolds. The results presented here provide prototypical illustration of the power of multivalency generation by self‐assembly leading to defined arrays of functional groups and binding patterns.     

Unimolecular micelle derived from hyperbranched polyethylenimine with well‐defined hybrid shell of poly(ethylene oxide) and polystyrene: A versatile nanocapsule

The synthesis and properties of a macromolecular nanocapsule derived from hyperbranched polyethylenimine (HPEI) with well‐defined hybrid shell of poly(ethylene oxide) monomethyl ether (mPEO) and polystyrene (PS) are described. HPEI is treated in sequence with 4‐glycidol‐2,2,6,6‐tetrametyl‐piperidin‐1‐oxyl, succinic anhydride, mPEO, leading to a HPEI derivative compatible with nitroxide‐mediated living radical polymerization of styrene, thus a macromolecular nanocapsule, HPEI@PEO/PS, is available with a well‐defined and tunable hybrid shell of PEO and PS. Within certain PEO/PS ratio, the nanocapsule is soluble in a number of organic solvents as well as in water. The nanocapsule exists as three layer onion‐like particle (HPEI@PS@PEO) in water, whereas in chloroform it exists as a hybrid shell particle (HPEI@PEO/PS), and the particles generally exist in the form of unimolecular micelle. In a biphasic water/chloroform mixture, the nanocapsule can transfer anionic, water‐soluble guest from an aqueous phase to the chloroform phase; while when dissolved in water, the nanocapsule can efficiently capture both ionic and apolar solutes. Release of the guest can occur under the stimulus of pH or the switch of medium. This is the first example of a unimolecular micelle that can simultaneously deliver both polar and apolar guests. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 681–691, 2010     

Supramolecular Protein Assemblies in the Nucleus of Human Cells

Genetically encoded supramolecular protein assemblies (SMPAs) are induced to form in living cells by combination of distinct self‐assembly properties. A single fusion construct contains genes encoding the heavy chain (H) of human ferritin and the citrine fluorescent protein, the latter exposing a weak dimerization interface, as well as a nuclear localization signal. Upon expression in HeLa cells, in vivo confocal fluorescence and differential interference contrast imaging revealed extended SMPA structures exclusively in the nuclei. Assemblies were typically round and took alveolar, shell‐like, or hybrid structure. Transmission electron microscopy revealed a crystalline packing. Site‐specific mutagenesis of the citrine dimerization interface clarified the mechanism of SMPA formation. The constituent proteins retained their activity in iron binding and fluorescence emission, thus suggesting a general strategy for formation of synthetic cellular bodies with specific biochemical function.     

Electrocatalytic Nanostructured Ferric Tannates: Characterization and Application of a Polyphenol Nanosensor

A novel core–shell hybrid nanomaterial composed of peculiar maghemite nanoparticles (surface‐active maghemite nanoparticles (SAMNs)) as the core and tannic acid (TA) as the shell was developed by self‐assembly of ferric tannates onto the surface of SAMNs by simple incubation in water. The hybrid nanomaterial (SAMN@TA) was characterized by using UV/Vis, FTIR, and Mössbauer spectroscopies, magnetization measurements, and X‐ray powder diffraction, which provide evidence of a drastic reorganization of the iron oxide surface upon reaction with TA and the formation of an outer shell that consists of a cross‐linked network of ferric tannates. According to a Langmuir isotherm analysis, SAMN@TA offers one of most stable iron complexes of TA reported in the literature to date. Moreover, SAMN@TA was characterized by using electrical impedance spectroscopy, voltammetry, and chronoamperometry. The nanostructured ferric tannate interface showed improved conductivity and selective electrocatalytic activity toward the oxidation of polyphenols. Finally, a carbon‐paste electrode modified with SAMN@TA was used for the determination of polyphenols in blueberry extracts by square‐wave voltammetry.