Multicompartment micelles from silicone-based triphilic block copolymers

An amphiphilic linear ternary block copolymer was synthesised in three consecutive steps via reversible addition–fragmentation chain transfer polymerisation. Oligo(ethylene glycol) monomethyl ether acrylate was engaged as a hydrophilic building block, while benzyl acrylate and 3-tris(trimethylsiloxy)silyl propyl acrylate served as hydrophobic building blocks. The resulting “triphilic” copolymer consists thus of a hydrophilic (A) and two mutually incompatible “soft” hydrophobic blocks, namely, a lipophilic (B) and a silicone-based (C) block, with all blocks having glass transition temperatures well below 0 °C. The triphilic copolymer self-assembles into spherical multicompartment micellar aggregates in aqueous solution, where the two hydrophobic blocks undergo local phase separation into various ultrastructures as evidenced by cryogenic transmission electron microscopy. Thus, a silicone-based polymer block can replace the hitherto typically employed fluorocarbon-based hydrophobic blocks in triphilic block copolymers for inducing multicompartmentalisation.     

Amphiphilic star-block copolymers and supramolecular transformation of nanogel-like micelles to nanovesicles

Amphiphilic star-block copolymers based on poly(3-hydroxybutyrate) with adamantyl end-functionalization were synthesized via anionic ring-opening polymerization and alkyne-azide "Click Chemistry" coupling. In aqueous medium, the copolymers self-assembled into nanogel-like large compound micelles, and transformed into vesicular nanostructures under the direction of host-guest interaction between the adamantyl end and dimethyl-β-cyclodextrin.     

Multicompartment micelles from star and linear triblock copolymer blends

Dissipative particle dynamics simulations were performed on multicompartment micelles formed by blending star and linear triblock copolymers, in which the influences of blending options and blending ratio as well as copolymer chain compositions were studied systematically. The results show that blending of copolymers with different architectures is a promising strategy to control the morphology and structure of multicompartment micelles. This work revealed several new morphologies of multicompartment micelles by blending star and linear triblock copolymers, and the dynamic processes were elucidated at the molecular level by tracing the motions of copolymer chains. The results of this work provide deep insight into micro/mesoscopic details of the underlying mechanisms, contributing to a more complete understanding of multicompartment micelle formation and structural control.     

Optimization of bioreducible micelles self‐assembled from amphiphilic hyperbranched block copolymers for drug delivery

Dendritic polymers‐based unimolecular micelles with enhanced stability are attractive carriers. However, the preparation of dendrimers or dendrons with higher generation remains substantially synthetic challenge due to the increased steric hindrance, multistep and tedious preparation, and low yields. The adoption of Boltorn H40, a commercially available dendritic polymer of Boltorn family containing multiple hydroxyl groups with various functionalities as a dendrimer‐based starting core template for the generation of hyperbranched polymers, offers a straightforward solution to address this problem. To develop universal strategies toward H40‐based amphiphilic block copolymers, the “grafting from” and “grafting to” approaches were both applied in this study. The reduction‐insensitive block copolymers, H40‐b‐poly(ɛ‐caprolactone)‐b‐poly(oligo(ethylene glycol) monomethyl ether methacrylate) (H40‐b‐PCL‐b‐POEGMA), were synthesized by “grafting from” including sequential ring‐opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The core structure and the polymer composition of the nonreducible amphiphilic hyperbranched block copolymers were optimized toward better properties and performance for drug delivery applications, and H40‐PCL₁₅‐b‐POEGMA₂₃ was screened as the best polymer construct relative to H20‐PCL₁₅‐b‐POEGMA₂₃ and H40‐PCL₁₅‐b‐POEGMA₃₂ in terms of micelle stability and drug loading capacity. Therefore, the reducible H40‐b‐PCL‐SS‐POEGMA with an identical core and polymer composition to that of H40‐PCL₁₅‐b‐POEGMA₂₃ was further prepared by “grafting to” using click coupling between H40‐PCL‐azide and P(OEGMA)‐alkyne. The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX‐loaded reducible micelles of H40‐PCL₁₅‐SS‐POEGMA₂₃ produced greater cytotoxicity in cancer cells than in normal cells and macrophages, therefore, are promising carriers for anticancer drug delivery. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1383–1394     

Bioreducible unimolecular micelles based on amphiphilic multiarm hyperbranched copolymers for triggered drug release

A novel type of bioreducible amphiphilic multiarm hyperbranched copolymer (H40-star-PLA-SS-PEG) based on Boltorn® H40 core, poly(l-lactide) (PLA) inner-shell, and poly(ethylene glycol) (PEG) outer-shell with disulfide-linkages between the hydrophobic and hydrophilic moieties was developed as unimolecular micelles for controlled drug release triggered by reduction. The obtained H40-star-PLA-SS-PEG was characterized in detail by nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), gel permeation chromatography (GPC), differential scanning calorimeter (DSC), and thermal gravimetric analysis (TGA). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses suggested that H40-star-PLA-SS-PEG formed stable unimolecular micelles in aqueous solution with an average diameter of 19 nm. Interestingly, these micelles aggregated into large particles rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the hydrophilic PEG outer-shell through reductive cleavage of the disulfide bonds. As a hydrophobic anticancer model drug, doxorubicin (DOX) was encapsulated into these reductive unimolecular micelles. In vitro release studies revealed that under the reduction-stimulus, the detachment of PEG outer-shell in DOX-loaded micelles resulted in a rapid drug release. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. Methyl tetrazolium (MTT) assay demonstrated a markedly enhanced drug efficacy of DOX-loaded H40-star-PLA-SS-PEG micelles as compared to free DOX. All of these results show that these bioreducible unimolecular micelles are promising carriers for the triggered intracellular delivery of hydrophobic anticancer drugs.     

Responsive vesicles from the self-assembly of crystalline-coil polyferrocenylsilane-block-poly(ethylene oxide) star-block copolymers

We demonstrate the synthesis and characterization of star‐shaped crystalline‐coil block copolymers with four arms consisting of an inner block of poly(ethylene oxide) and an outer semicrystalline compartment of poly(ferrocenyldimethylsilane), [PEO₅₀‐b‐PFDMS₃₅]₄. The materials were synthesized by transition‐metal‐catalyzed ring‐opening polymerization of dimethylsila[1]ferrocenophane in the presence of silane‐functionalized four‐arm PEO stars as macroinitiators and they exhibited a moderate polydispersity (PDI?1.4). Self‐assembly in mixtures of THF and different alcohols as selective solvents for the PEO block resulted in the formation of semicrystalline vesicles (ethanol, 1‐butanol) or large, rather ill‐defined, spherical structures (methanol). Further, both the rate of addition of the selective co‐solvent and the overall solvent/non‐solvent ratio drastically affected the size and stability of the self‐assembled particles. We could also show that a photoacid generator, as a model for an active substance, can be encapsulated and the UV‐induced generation of HCl resulted in a straightforward degradation of the organometallic vesicles.     

Visible light-responsive micelles formed from dialkoxyanthracene-containing block copolymers

A class of dialkoxyanthracene-containing diblock copolymers is synthesized which possesses visible light-responsivity. These copolymers can self-assemble into a micellar structure in water. Green visible light (540 nm) is able to scissor these anthracene species and cleave the diblock copolymer into two fragments, inducing disassembly of the self-assembled micelles.     

Mixed micelles based on cationic and anionic amphiphilic diblock copolymers containing identical hydrophobic blocks

Through the use of the methods of turbidimetry, UV spectrophotometry, fluorescence spectroscopy, dynamic light scattering, and ultracentrifugation, micelle formation is studied for cationic (polysty-rene-poly-N-ethyl-4-vinylpyridium bromide) and anionic (polystyrene-sodium polyacrylate) diblock copolymers containing identical polystyrene blocks in dilute aqueous saline solutions. Mixing of aqueous dispersions of individual micelles is accompanied by the formation of only insoluble products, which likely are intermicellar interpolyelectrolyte complexes. At the same time, mixing of diblock copolymers in a nonselective solvent and its subsequent gradient replacement with water during suppressed interpolyelectrolyte interactions yields mixed diblock copolymer micelles, which are found to be dispersionally stable in an excess of charged units of any polymer component. The micelles are composed of an insoluble polystyrene core and a mixed interpolyelectrolyte corona, and their hydrodynamic characteristics are controlled by the ratio of charged units in the mixed diblock copolymers. The mixed micelles are found to be able to interact with the macromolecules of a homopolyelectrolyte, sodium poly(styrene sulfonate), in aqueous solutions and form ternary complexes. In this case, depending on the composition of the mixed micelles, ternary complexes can be dispersionally stable or can aggregate and precipitate.     

Amphiphilic and hydrophobic surface patterns generated from hyperbranched fluoropolymer/linear polymer networks: Minimally adhesive coatings via the crosslinking of hyperbranched fluoropolymers

Hyperbranched fluoropolymers (HBFPs), based on benzyl ether linkages and having a large number of pentafluorophenyl chain ends, were crosslinked by a reaction with diamino-terminated poly(ethylene glycol) (PEG) or diamino-terminated poly(dimethyl siloxane) (PDMS) to form hyperbranched–linear copolymer networks of different compositions, structures, and properties. The crosslinking reactions involved the nucleophilic aromatic substitution of the pentafluorophenyl para-fluorines of HBFP by the amine functionalities of the respective telechelic linear segments. The contact angles, differential scanning calorimetry, thermogravimetric analysis, tensile measurements, and atomic force microscopy (AFM) were used to characterize the resulting network film samples. The surface wettability of the crosslinked materials was affected by the nature and amount of the linear polymer crosslinking agent employed. Amphiphilic polymer networks were formed by the incorporation of diamino-terminated PEG as a crosslinker, whereas diamino-terminated PDMS produced polymer networks of a hydrophobic character. The mechanical properties improved upon crosslinking, as measured by tensile testing. The mechanical integrity of the films was also found to improve upon crosslinking, as measured by AFM machining protocols. The AFM images revealed topographical morphologies that appeared to be the result of phase segregation of HBFP from PEG or PDMS; the dimensions of the phase-segregated domains were dependent on the stoichiometry of HBFP to the linear polymer and the thickness of the coating. As the content of PEG increased, fouling by human fibrinogen, used as a model protein, decreased. Further studies are in progress to determine the effects of the surface composition, morphology, and topography on the biofouling characteristics. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3531–3540, 2003     

Graft copolymers from star‐shaped and hyperbranched polystyrene macromonomers

Branched polystyrene macromonomers were synthesized by the slow addition of a stoichiometric amount of either 4‐(chlorodimethylsilyl)styrene or vinylbenzyl chloride as a coupling agent to living polystyryllithium. Star‐shaped macromonomers were produced by the addition of the coupling agent alone, and hyperbranched macromonomers resulted from the addition of the coupling agent along with styrene monomer. Star and hyperbranched graft copolymers were produced by the copolymerization of the macromonomers with styrene and methyl methacrylate. The copolymers were characterized by gel permeation chromatography coupled with multi‐angle laser light scattering, ¹H NMR spectroscopy, and Soxhlet extraction to determine that the macromonomers were incorporated in high yields into the copolymers. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3547–3555, 2001     

Time-dependent shrinkage of polymeric micelles of amphiphilic block copolymers containing semirigid oligocholate hydrophobes

Alkyne-derivatized poly(ethylene glycol) (M.W. 5000) was coupled to several azide-terminated oligocholates by the click reaction to form amphiphilic block copolymers. A copolymer with a cholate hexamer as the hydrophobic block formed polymeric micelles that shrank by ~50% over a period of 10 h at 25°C. Shrinkage was faster and more dramatic at 35°C. Shortening the oligocholate by two units or inserting a 4-aminobutyroyl spacer in the hexacholate eliminated or diminished the shrinkage. Metastable aggregates were proposed to form when the block copolymers began to aggregate in water. The large hydrophobic surface, awkward shape, rigidity, and facial amphiphilicity of the cholate repeat unit and the long chain made it difficult for the oligocholates to adjust within the micellar core. As the oligocholates rearranged to maximize hydrophobic interactions and hydrogen-bonding while minimizing conformational strain, the polymeric micelles became more compact over time.     

Multilayer onion-like vesicles self-assembled from amphiphilic hyperbranched multiarm copolymers via simulation

Multilayer onion-like vesicles are valuable in cell mimics and biomedicine fields. However, as an excellent self-assembly precursor, the formation of multilayer onion-like vesicles by the self-assembly of hyperbranched multiarm copolymers (HMCs) were not reported due to the complex self-assembly dynamics. In this article, the self-assembly behavior of multilayer onion-like vesicles from HMCs was systematically investigated using dissipative particle dynamics simulation. The formation conditions for different kinds of vesicles were disclosed through the construction of the morphological phase diagram. Moreover, the formation mechanisms of the onion-like vesicles with different layers were revealed. We observed that it is the fusion mechanism in low concentrations and the molecular rearrangement mechanism in high concentrations. For low concentration, the law between the number of the membrane layers and the morphology of the aggregates in the fusion process was disclosed. Meanwhile, the membrane of the onion-like vesicles self-assembled from HMCs is monolayer structure and the thickness of each layer is decreased in sequence from inside to outside. The current observations have important guiding significance for its application in drug delivery systems.     

Thermal and spectral stability of electroluminescent hyperbranched copolymers containing tetraphenylthiophene‐quinoline‐triphenylamine moieties

Fluorescent hyperbranched copolymers (HB‐x, x = 1–4) with inherent tetraphenylthiophene, triphenylamine (TPA) and quinoline (Qu) moieties were prepared to study the influence of the TPA branching point on the thermal and the spectral stability. All the HB‐x copolymers exhibited high glass transition temperatures (T_gs = 245–315 °C) with the detected values increasing with the increasing branching TPA content in the HB‐x. The solid HB‐x films possess high emission efficiency with the resulting quantum yields (?_Fs) in the ranges of 0.72–0.74. More importantly, the HB‐x copolymers and the derived light‐emitting devices exhibit high photoluminescence (PL) and electroluminescence (EL) stability towards thermal annealing at temperatures higher than 200 °C. After annealing at 200 °C (or 300 °C), no change was observed in the respective PL and EL spectra of HB‐1 (or HB‐4) copolymers. The spectral stability was found to correlate with T_g and with the highest branching density, HB‐4 copolymer possesses the highest thermal stability among all HB‐xs and show no EL spectral change after annealing at 300 °C for 4 h. The results indicate that all the branched HB‐x copolymers are promising candidates for the polymer light‐emitting diodes due to their high quantum yield and spectral stability. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Bioreducible micelles and hydrogels with tunable properties from multi-armed biodegradable copolymers

Multi-armed biodegradable block copolymers with a bioreducible core mPCL-b-PEO were for the first time synthesized by thiol-yne click chemistry. They self-assembled into bioreducible micelles and hydrogels in aqueous solution, which demonstrated tunable size, mechanical and drug-release properties.     

Novel thermoplastic elastomers. I. Synthesis and characterization of star-block copolymers of PSt-b-PIB arms emanating from cyclosiloxane cores

The synthesis and characterization of novel thermoplastic elastomers consisting of multiple polystyrene-b-polyisobutylene (PSt-b-PIB) arms emanating from cyclosiloxane cores is described. The synthesis involved the sequential living cationic block copolymerization of styrene (St) and isobutylene (IB), followed by quantitative allylic end-functionalization of the living PSt-b-PIB⁺ to produce PSt-b-PIB CH₂ CHCH₂ prearms, and finally linking by hydrosilation of these prearms with Si H-containing cyclosiloxanes (e.g., 2,4,6,8,10,12-hexamethylcyclohexasiloxane, D). Two types of star-blocks, namely primary and higher-order star-blocks, were prepared: Primary star-blocks containing 3–9 PSt-b-PIB arms were obtained by using various cyclosiloxanes (D to D) and a close to exact stoichiometry between the Si H and allyl groups, [Si H]/[CC] ∼ 1, in the essential absence of moisture ([H₂O] ∼ 100 ppm). Higher-order star-blocks consisting of 13–24 PSt-b-PIB arms radiating from complex coupled cyclosiloxanes were prepared by the use of Si H/allyl ratios significantly larger than unity ([Si H]/[CC] = 2–3) in the presence of controlled amounts of moisture ([H₂O] ∼ 600 ppm). Reaction conditions (temperature, concentration, stoichiometry, solvent nature, catalyst concentration, etc.) for efficient syntheses have been developed. The products were characterized by 200 and 600 MHz ¹H-NMR spectroscopy and triple-detector (RI, UV, LLS) GPC. The microstructure of the condensed cores in the higher-order star-blocks was studied by 2D-NMR (HMQC) spectroscopy, and the number of cyclosiloxane rings in the cores (i.e., the content (wt %) of cores in the star-blocks) was determined. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 2997–3012, 1998     

Temperature- and pH-responsive unimolecular micelles with a hydrophobic hyperbranched core

The dendritic unimolecular polymeric micelles with a hydrophobic dendritic polyester (Boltorn H40) as the core and the grafted biocompatible poly(N, N-diethylacrylamide)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDEAAM-b-PDMAEMA) as the shell were synthesized by successive reversible addition–fragmentation transfer (RAFT) polymerization of N, N-diethylacrylamide (DEAAM) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) monomers. Laser light scattering studies indicated that the resulting unimolecular polymeric micelles H40–PDEAAM–PDMAEMA with double stimuli-responsive shells exhibited a reversible two-stage phase transition behavior. The effect of varying the block length of PDMAEMA on the thermosensitivity of unimolecular polymeric micelles was studied. With an increase in the outer corona length of PDMAEMA, the temperature range of phase transition for the inner shell PDEAAM would become broad. As pH decreased to 2, the high hydrophilic PDMAEMA blocks with high protonation were independent of temperature, and the size of unimolecular polymeric micelles increased due to the extended-chain conformation of outer layer. The internal core cavities of the unimolecular polymeric micelles exhibited a great potential of loading guest molecules according to the analysis of pyrene probe fluorescence spectra.