Solvent‐Induced Structural Transition of Self‐Assembled Dipeptide: From Organogels to Microcrystals

Organogels that are self‐assembled from simple peptide molecules are an interesting class of nano‐ and mesoscale soft matter with simplicity and functionality. Investigating the precise roles of the organic solvents and their effects on stabilization of the formed organogel is an important topic for the development of low‐molecular‐weight gelators. We report the structural transition of an organogel self‐assembled from a single dipeptide building block, diphenylalanine (L ‐Phe‐L ‐Phe, FF), in toluene into a flower‐like microcrystal merely by introducing ethanol as a co‐solvent; this provides deeper insights into the phase transition between mesostable gels and thermodynamically stable microcrystals. Multiple characterization techniques were used to reveal the transitions. The results indicate that there are different molecular‐packing modes formed in the gels and in the microcrystals. Further studies show that the co‐solvent, ethanol, which has a higher polarity than toluene, might be involved in the formation of hydrogen bonds during molecular self‐assembly of the dipeptide in mixed solvents, thus leading to the transition of organogels into microcrystals. The structural transformation modulated by the co‐solvent might have a potential implication in controllable molecular self‐assembly.     

Secondary‐Structure‐Driven Self‐Assembly of Reactive Polypept(o)ides: Controlling Size,Shape, and Function of Core Cross‐Linked Nanostructures

Achieving precise control over the morphology and function of polymeric nanostructures during self‐assembly remains a challenge in materials as well as biomedical science, especially when independent control over particle properties is desired. Herein, we report on nanostructures derived from amphiphilic block copolypept(o)ides by secondary‐structure‐directed self‐assembly, presenting a strategy to adjust core polarity and function separately from particle preparation in a bioreversible manner. The peptide‐inherent process of secondary‐structure formation allows for the synthesis of spherical and worm‐like core‐cross‐linked architectures from the same block copolymer, introducing a simple yet powerful approach to versatile peptide‐based core–shell nanostructures.     

Covalent Self‐Assembly and One‐Step Photocrosslinking of Tyrosine‐Rich Oligopeptides to Form Diverse Nanostructures

We present covalently self‐assembled peptide hollow nanocapsule and peptide lamella. These biomimetic dityrosine peptide nanostructures are synthesized by one‐step photopolymerization of a tyrosine‐rich short peptide without the aid of a template. This simple approach offers direct synthesis of fluorescent peptide nanocages and free‐standing thin films. The simple crosslinked peptide lamella films provide robust mechanical properties with an elastic modulus of approximately 30 GPa and a hardness of 740 MPa. These nanostructures also allow for the design of peptidosomes. The approach taken here represents a rare example of covalent self‐assembly of short peptides into nano‐objects, which may be useful as microcompartments and separation membranes.     

Dispersion RAFT polymerization of 4‐vinylpyridine in toluene mediated with the macro‐RAFT agent of polystyrene dithiobenzoate: Effect of the macro‐RAFT agent chain length and growth of the block copolymer nano‐objects

The dispersion reversible addition‐fragmentation chain transfer (RAFT) polymerization of 4‐vinylpyridine in toluene in the presence of the polystyrene dithiobenzoate (PS‐CTA) macro‐RAFT agent with different chain length is discussed. The RAFT polymerization undergoes an initial slow homogeneous polymerization and a subsequent fast heterogeneous one. The RAFT polymerization rate is dependent on the PS‐CTA chain length, and short PS‐CTA generally leads to fast RAFT polymerization. The dispersion RAFT polymerization induces the self‐assembly of the in situ synthesized polystyrene‐b‐poly(4‐vinylpyridine) block copolymer into highly concentrated block copolymer nano‐objects. The PS‐CTA chain length exerts great influence on the particle nucleation and the size and morphology of the block copolymer nano‐objects. It is found, short PS‐CTA leads to fast particle nucleation and tends to produce large‐sized vesicles or large‐compound micelles, and long PS‐CTA leads to formation of small‐sized nanospheres. Comparison between the polymerization‐induced self‐assembly and self‐assembly of block copolymer in the block‐selective solvent is made, and the great difference between the two methods is demonstrated. The present study is anticipated to be useful to reveal the chain extension and the particle growth of block copolymer during the RAFT polymerization under dispersion condition. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Nano‐emulsion use for the synthesis of polyaniline nano‐grains or nano‐fibers

We report that nano‐emulsions can be creatively used as a morphology selective synthesis method to prepare not only nano‐grains but also nano‐fibers with high selectivity. Synthesis of the two different morphological materials was demonstrated using polyaniline synthesis as a model case. Polyaniline nano‐grains were synthesized from aniline molecules in nano‐size aqueous droplets as polymerization sites whose droplets were generated by inverse water‐in‐oil nano‐emulsion use, and polyaniline nano‐fibers were synthesized from aniline in aqueous nano‐dimensional channels as polymerization sites whose channels were generated by direct oil‐in‐water nano‐emulsion use containing high population of oil droplets. Using the approaches, we successfully synthesized nano‐fibers of 60 nm diameter with 0.5 µm length and also nano‐grains having diameter of 60–80 nm. The two different polymerization sites of nano‐scale dimension were made by changing the ratio among surfactant, aqueous aniline/HCl solution, and oil, i.e. organic solvent. We found the nano‐fibers synthesized from the channels formed by the direct oil‐in‐water nano‐emulsion have higher bulk electrical conductivity than the nano‐grains which were synthesized from the droplets formed by the inverse water‐in‐oil emulsion. We also found that the emulsion use allows us to use a room temperature synthesis unlike conventional synthesis methods which require to use ice bath temperature. Physical properties of both nano‐fibers and nano‐grains synthesized were characterized by Fourier transform infrared (FTIR), UV–Vis spectra, scanning electron microscopy (SEM), and four probes conductivity measurement. Copyright © 2009 John Wiley & Sons, Ltd.     

Two‐Dimensional Assembly Based on Flow Supramolecular Chemistry: Kinetic Control of Molecular Interactions Under Solvent Diffusion

Self‐assembly of porphyrin molecules can be controlled kinetically to form structures with lengths extending from the nano‐ to the micrometer scale, through a programmed solvent‐diffusion process in designed microflow spaces. Temporal solvent structures generated in the microflow were successfully transcribed into molecular architectures.     

A One‐Pot Chemically Cleavable Bis‐Linker Tether Strategy for the Synthesis of Heterodimeric Peptides

Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time‐consuming, and low yielding. Inspired by the cellular synthesis of pro‐insulin in which the two constituent peptide chains are expressed as a single‐chain precursor separated by a connecting C‐peptide, we have developed a novel chemically cleavable bis‐linker tether which allows the convenient assembly of two peptide chains as a single “pro”‐peptide on the same solid support. Following the peptide cleavage and post‐synthetic modifications, this bis‐linker tether can be removed in one‐step by chemical means. This method was used to synthesize a drug delivery‐cargo conjugate, TAT‐PKCi peptide, and a two‐disulfide bridged heterodimeric peptide, thionin (7‐19)‐(24‐32R), a thionin analogue. To our knowledge, this is the first report of a one‐pot chemically cleavable bis‐linker strategy for the facile synthesis of cross‐bridged two‐chain peptides.     

Self‐Assembly Drug Delivery System Based on Programmable Dendritic Peptide Applied in Multidrug Resistance Tumor Therapy

In recent decades, diverse drug delivery systems (DDS) constructed by self‐assembly of dendritic peptides have shown advantages and improvable potential for cancer treatment. Here, an arginine‐enriched dendritic amphiphilic chimeric peptide CRRK(RRCG(Fmoc))₂ containing multiple thiol groups is programmed to form drug‐loaded nano‐micelles by self‐assembly. With a rational design, the branched hydrophobic groups (Fmoc) of the peptides provide a strong hydrophobic force to prevent the drug from premature release, and the reduction‐sensitive disulfide linkages formed between contiguous peptides can control drug release under reducing stimulation. As expected, specific to multidrug resistance (MDR) tumor cells, the arginine‐enriched peptide/drug (PD) nano‐micelles show accurate nuclear localization ability to prevent the drug being pumped by P‐glycoprotein (P‐gp) in vitro, as well as exhibiting satisfactory efficacy for MDR tumor treatment in vivo. This design successfully realizes stimuli‐responsive drug release aimed at MDR tumor cells via an ingenious sequence arrangement.     

Multistimuli‐Responsive Supramolecular Organogels Formed by Low‐Molecular‐Weight Peptides Bearing Side‐Chain Azobenzene Moieties

This work demonstrates that the incorporation of azobenzene residues into the side chain of low‐molecular‐weight peptides can modulate their self‐assembly process in organic solvents leading to the formation of stimuli responsive physical organogels. The major driving forces for the gelation process are hydrogen bonding and π–π interactions, which can be triggered either by thermal or ultrasound external stimuli, affording materials having virtually the same properties. In addition, a predictive model for gelation of polar protic solvent was developed by using Kamlet–Taft solvent parameters and experimental data. The obtained viscoelastic materials exhibited interconnected multistimuli responsive behaviors including thermal‐, photo‐, chemo‐ and mechanical responses. All of them displayed thermoreversability with gel‐to‐sol transition temperatures established between 33–80 °C and gelation times from minutes to several hours. Structure–property relationship studies of a designed peptide library have demonstrated that the presence and position of the azobenzene residue can be operated as a versatile regulator to reduce the critical gelation concentration and enhance both the thermal stability and mechanical strength of the gels, as demonstrated by comparative dynamic rheology. The presence of N‐Boc protecting group in the peptides showed also a remarkable effect on the formation and properties of the gels. Despite numerous examples of peptide‐based gelators known in the literature, this is the first time in which low‐molecular‐weight peptides bearing side chain azobenzene units are used for the synthesis of “intelligent” supramolecular organogels. Compared with other approaches, this strategy is advantageous in terms of structural flexibility since it is compatible with a free, unprotected amino terminus and allows placement of the chromophore at any position of the peptide sequence.     

Cooperative Self‐Assembly‐Assisted Formation of Monodisperse Optically Active Spherical and Anisotropic Nanoparticles

We report a new method in which spontaneous self‐assembly is employed to synthesize monodisperse polymer nanoparticles with controlled size (<50 nm), shape, tunable functionality, and enhanced solvent and thermal stability. Cooperative noncovalent interactions, such as hydrogen bonding and aromatic π–π stacking, assist self‐assembly of amphiphilic macromolecules (polystyrene‐block‐polyvinylpyridine, PS? PVP) and structure directing agents (SDAs) to form both spherical and anisotropic solid polymer nanoparticles with SDAs residing in the particle core surrounded by the polymers. Through detailed investigations by scanning electron microscopy and transmission electron microscopy (TEM), we have rationalized nanoparticle morphology evolution and dependence on factors such as SDA concentration and PVP size. By keeping the PS chain size constant, the particle morphology progresses from continuous films to spherical particles, and on to cylindrical nanowires or rods with increasing the PVP chain size. The final nanoparticles are very stable and can be redispersed in common solvents to form homogenous solutions and thin films of ordered nanoparticle arrays through solvent evaporation processes. These nanoparticles exhibit tunable fluorescent colors (or emissions) depending on the choices of the central SDAs. Our method is simple and general without requiring complicated synthetic chemistry, stabilizing surfactants, or annealing procedures (e.g., temperature or solvent annealing), making scalable synthesis feasible.     

Polymerization‐induced self‐assembly of block copolymer through dispersion RAFT polymerization in ionic liquid

Polymerization‐induced self‐assembly of block copolymer through dispersion RAFT polymerization has been demonstrated to be a valid method to prepare block copolymer nano‐objects. However, volatile solvents are generally involved in this preparation. Herein, the in situ synthesis of block copolymer nano‐objects of poly(ethylene glycol)‐block‐polystyrene (PEG‐b‐PS) in the ionic liquid of 1‐butyl‐3‐methylimidazolium hexafluorophosphate ([BMIN][PF₆]) through the macro‐RAFT agent mediated dispersion polymerization is investigated. It is found that the dispersion RAFT polymerization of styrene in the ionic liquid of [BMIN][PF₆] runs faster than that in the alcoholic solvent, and the dispersion RAFT polymerization in the ionic liquid affords good control over the molecular weight and the molecular weight distribution of the PEG‐b‐PS diblock copolymer. The morphology of the in situ synthesized PEG‐b‐PS diblock copolymer nano‐objects, e.g., nanospheres and vesicles, in the ionic liquid is dependent on the polymerization degree of the solvophobic block and the concentration of the fed monomer, which is somewhat similar to those in alcoholic solvent. It is anticipated that the dispersion RAFT polymerization in ionic liquid broads a new way to prepare block copolymer nano‐objects. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1517–1525     

Direct Synthesis of a Covalently Self‐Assembled Peptide Nanogel from a Tyrosine‐Rich Peptide Monomer and Its Biomineralized Hybrids

There has been significant progress in the self‐assembly of biological materials, but the one‐step covalent peptide self‐assembly for well‐defined nanostructures is still in its infancy. Inspired by the biological functions of tyrosine, a covalently assembled fluorescent peptide nanogel is developed by a ruthenium‐mediated, one‐step photo‐crosslinking of tyrosine‐rich short peptides under the visible light within 6 minutes. The covalently assembled peptide nanogel is stable in various organic solvents and different pH levels, unlike those made from vulnerable non‐covalent assemblies. The semipermeable peptide nanogel with a high density of redox‐active tyrosine acts as a novel nano‐bioreactor, allowing the formation of uniform metal–peptide hybrids by selective biomineralization under UV irradiation. As such, this peptide nanogel could be useful in the design of novel nanohybrids and peptidosomes possessing functional nanomaterials.     

Topology‐Matching Design of an Influenza‐Neutralizing Spiky Nanoparticle‐Based Inhibitor with a Dual Mode of Action

In this study, we demonstrate the concept of “topology‐matching design” for virus inhibitors. With the current knowledge of influenza A virus (IAV), we designed a nanoparticle‐based inhibitor (nano‐inhibitor) that has a matched nanotopology to IAV virions and shows heteromultivalent inhibitory effects on hemagglutinin and neuraminidase. The synthesized nano‐inhibitor can neutralize the viral particle extracellularly and block its attachment and entry to the host cells. The virus replication was significantly reduced by 6 orders of magnitude in the presence of the reverse designed nano‐inhibitors. Even when used 24 hours after the infection, more than 99.999 % inhibition is still achieved, which indicates such a nano‐inhibitor might be a potent antiviral for the treatment of influenza infection.     

Enzyme Degradable Polymersomes from Chitosan‐g‐[poly‐l‐lysine‐block‐ε‐caprolactone] Copolymer

The scope of this study includes the synthesis of chitosan‐g‐[peptide‐poly‐ε‐caprolactone] and its self‐assembly into polymeric vesicles employing the solvent shift method. In this way, well‐defined core–shell structures suitable for encapsulation of drugs are generated. The hydrophobic polycaprolactone side‐chain and the hydrophilic chitosan backbone are linked via an enzyme‐cleavable peptide. The synthetic route involves the functionalization of chitosan with maleimide groups and the preparation of polycaprolactone with alkyne end‐groups. A peptide functionalized with a thiol group on one side and an azide group on the other side is prepared. Thiol‐ene click‐chemistry and azide–alkyne Huisgen cycloaddition are then used to link the chitosan and poly‐ε‐caprolactone chains, respectively, with this peptide. For a preliminary study, poly‐l ‐lysin is a readily available and cleavable peptide that is introduced to investigate the feasibility of the system. The size and shape of the polymersomes are studied by dynamic light scattering and cryo‐scanning electron microscopy. Furthermore, degradability is studied by incubating the polymersomes with two enzymes, trypsin and chitosanase. A dispersion of polymersomes is used to coat titanium plates and to further test the stability against enzymatic degradation.     

Photoinitiated Polymerization‐Induced Self‐Assembly of Glycidyl Methacrylate for the Synthesis of Epoxy‐Functionalized Block Copolymer Nano‐Objects

Herein, a novel photoinitiated polymerization‐induced self‐assembly formulation via photoinitiated reversible addition–fragmentation chain transfer dispersion polymerization of glycidyl methacrylate (PGMA) in ethanol–water at room temperature is reported. It is demonstrated that conducting polymerization‐induced self‐assembly (PISA) at low temperatures is crucial for obtaining colloidal stable PGMA‐based diblock copolymer nano‐objects. Good control is maintained during the photo‐PISA process with a high rate of polymerization. The polymerization can be switched between “ON” and “OFF” in response to visible light. A phase diagram is constructed by varying monomer concentration and degree of polymerization. The PGMA‐based diblock copolymer nano‐objects can be further cross‐linked by using a bifunctional primary amine reagent. Finally, silver nanoparticles are loaded within cross‐linked vesicles via in situ reduction, exhibiting good catalytic properties.

     

Photoinduced Proton‐Transfer Reactions for Mild O‐H Functionalization of Unreactive Alcohols

Hexafluoroisopropanol is typically considered as an unreactive solvent and not as a reagent in organic synthesis. Herein, we report on a mild and efficient photochemical reaction of aryl diazoacetates with hexafluoroisopropanol that enables, under stoichiometric reaction conditions, the synthesis of fluorinated ethers in excellent yield. Mechanistic studies indicate there is a preorganization of hexafluoroisopropanol and the diazoalkane acts as an unreactive hydrogen‐bonding complex. Only after photoexcitation does this complex undergo a protonation‐substitution reaction to the reaction product. Investigations on the applicability of this photochemical transformation show that a broad variety of acidic alcohols can be subjected to this transformation and thus demonstrate the feasibility of this concept for O‐H functionalization reactions (54 examples, up to 98 % yield).     

Light‐Induced Reversible Self‐Assembly of Gold Nanoparticles Surface‐Immobilized with Coumarin Ligands

A novel light‐induced reversible self‐assembly (LIRSA) system is based on the reversible photodimerization and photocleavage of coumarin groups on the surface of gold nanoparticles (AuNPs) in THF solution. Facilitated by coumarin groups, light irradiation at 365 nm triggers the stable assembly of monodisperse AuNPs; the resulting self‐assembly system can be disassembled back to the disassembled state by a relatively short exposure to benign UV light. The reversible self‐assembly cycle can be repeated 4 times. A specific concentration range of coumarin ligand and the THF solvent were identified to be the two predominant factors that contribute to the LIRSA of AuNPs. This is the first successful application of reversible photodimerization based on a coumarin derivative in the field of AuNP LIRSA. This LIRSA system may provide unique opportunities for the photoregulated synthesis of many adjustable nanostructures and devices.     

Hybrid organic–inorganic block copolymer nano‐objects from RAFT polymerization‐induced self‐assembly

A simple route to organic–inorganic (O/I) nano‐objects with different morphologies through polymerization‐induced block copolymer self‐assembly is described. The synthetic strategy relies on the chain‐extension of polyhedral oligomeric silsesquioxanes (POSS)‐containing macro‐CTA (PMAiBuPOSS₁₃ and PMAiBuPOSS₁₉) with styrene at 120 °C in octane, a selective solvent of the POSS‐containing block. The polymerization system was proven to afford a plethora of O/I nano‐objects, such as spherical micelles, cylindrical micelles, and vesicles depending on the respective molar masses of the PMAiBuPOSS and polystyrene (PS) blocks. The cooling procedure was also proven to be a crucial step to generate particles with a unique morphology. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4558–4564     

Nano‐amylose‐2,3‐bis(3,5‐dimethylphenylcarbamate)‐silica hybrid sol immobilized on open tubular capillary column for capillary electrochromatography enantioseparation

The chiral organic‐inorganic hybrid materials can exhibit a high loading, and the chiral selector nanoparticles can create efficient stationary phases for open‐tubular capillary electrochromatography (OT‐CEC). Hence, a novel protocol for the preparation of an OT column coated with nano‐amylose‐2,3‐bis(3,5‐dimethylphenylcarbamate) (nano‐ABDMPC)‐silica hybrid sol through in situ layer‐by‐layer self‐assembly method was developed for CEC enantioseparation. By controlling the assembly cycle number of nano‐ABDMPC‐silica hybrid sol, a homogeneous, dense and stable coating was successfully prepared, which was confirmed by SEM and elemental analysis. As the main parameter influencing the chiral separating effect, the nano‐ABDMPC bearing 3‐(triethoxysilyl)propyl residues concentration was investigated. The experimental results showed that 10.0 mg/mL nano‐ABDMPC bearing 3‐(triethoxysilyl)propyl residues coated OT capillary column possessed chiral recognition ability toward the six enantiomers (phenylalanine, tyrosine, tryptophan, phenethyl alcohol, 1‐phenyl‐2‐propanol, and Tröger's base) at some of the different conditions tested. Additionally, the coated OT column revealed adequate repeatability concerning run‐to‐run, day‐to‐day and column‐to‐column. These results demonstrated the promising applicability of nano‐ABDMPC‐silica hybrid sol coated OT column in CEC enantioseparations.     

Copper(II)‐Mediated Self‐Assembly of Hairpin Peptides and Templated Synthesis of CuS Nanowires

The self‐assembly of peptides and proteins under well‐controlled conditions underlies important nanostructuring processes that could be harnessed in practical applications. Herein, the synthesis of a new hairpin peptide containing four histidine residues is reported and the self‐assembly process mediated by metal ions is explored. The work involves the combined use of circular dichroism, NMR spectroscopy, UV/Vis spectroscopy, AFM, and TEM to follow the structural and morphological details of the metal‐coordination‐mediated folding and self‐assembly of the peptide. The results indicate that by forming a tetragonal coordination geometry with four histidine residues, copper(II) ions selectively trigger the peptide to fold and then self‐assemble into nanofibrils. Furthermore, the copper(II)‐bound nanofibrils template the synthesis of CuS nanowires, which display a near‐infrared laser‐induced thermal effect.