Organobase‐Catalyzed Synthesis of Multiarm Star Polylactide With Hyperbranched Poly(ethylene glycol) as the Core

Multiarm star copolymers consisting of the polyether‐polyol hyperbranched poly(ethylene glycol) (hbPEG) as core and poly(L ‐lactide) (PLLA) arms are synthesized via the organobase‐ catalyzed ring‐opening polymerization of lactide using hbPEG as a multifunctional macroinitiator. Star copolymers with high molecular weights up to 792 000 g mol^?1 are prepared. Detailed 2D NMR analysis provides evidence for the attachment of the PLLA arms to the core and reveals that the adjustment of the monomer/initiator ratio enables control of the arm length. Size exclusion chromatography measurements show narrow molecular weight distributions. Thermal analysis reveals a lower glass transition temperature, melting point, and degree of crystallization for the star‐shaped polylactides compared to linear polylactide.     

Synthesis and characterization of hetero-arm star copolymers

Hetero-arm star copolymers are constituted of a central core carrying branches of two kinds. The two-stage synthesis of such polymer species involves an arm-first step and a core-first step: A linear anionic living polystyrene precursor was used to initiate the polymerization of a small amount of divinylbenzene, yielding star-shaped polystyrene bearing living sites inside the cores; in a second stage these sites were used to initiate the polymerization of another monomer — butyl methacrylate —, more electrophilic than styrene. This second step results in the formation of a new set of branches originating from the same polydivinylbenzene cores. The star polystyrenes, and the hetero-arm star copolymers were characterized adequately, and their molecular weights were found to be in satisfactory agreement with expectation. The presence of some remaining linear precursor in the star polymer samples is discussed thoroughly on the basis of a detailed computerized analysis of the size exclusion chromatograms of both the star polystyrene samples and the hetero-arm star copolymers.     

Poly(2-vinylpyridine)-based star-shaped polymers. Synthesis of heteroarm star (AnBn) and star-block (AB)n copolymers

Heteroarm star copolymers bearing poly(2-vinylpyridine) and polystyrene arms (A_nB_n type) were synthesized by a three-step anionic polymerization method. Polystyrene arms are synthesized first, and they are used to initiate the polymerization of a small amount of divinylbenzene, yielding polystyrene star molecules bearing a number of active sites within its cores. In a subsequent step poly(2-vinylpyridine) arms are growing from the cores. Poly(2-vinylpyridine)-block-poly(tert-butyl acrylate) star block copolymers [(AB)_n type] were also prepared using the same synthetic route. In this case, short polystyryllithium is used to build grafted poly(DVB) cores. These living plurifunctional initiators can easily polymerize 2-vinylpyridine and subsequently tert-butyl acrylate, yielding star molecules bearing diblock copolymers as arms. The short polystyrene grafts of the core can be neglected and the star molecules are considered of the (AB)_n type. These star polymers have been characterized adequately and shown to exhibit rather well-defined structures. The advantages and the drawbacks of the method are discussed.     

Solution Self‐Assembly of Poly(ferrocenylphenylphosphine)‐block‐polydimethylsiloxane: Formation of Spherical Micelles with an Organometallic Poly(ferrocenylphenylphosphine) Core

The novel organometallic‐inorganic diblock copolymer, poly(ferrocenylphenylphosphine)‐block‐polydimethylsiloxane (PFP‐b‐PDMS), with narrow molecular weight distribution has been synthesized by living anionic polymerization through sequential monomer addition. These block copolymers self‐assemble into “star‐like” spherical micelles in hexane with a dense organometallic PFP core surrounded by a swollen corona of the PDMS chains. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to characterize these micellar aggregates. It was found that the block copolymer micelles have a relatively narrow core size distribution, but an overall broader distribution of hydrodynamic size in hexane. Significantly, the preparation method of the micelle solution was also found to have an influence on the size and size distribution of the resulting micellar structures.     

Multi‐arm star block copolymers based on ε‐caprolactone with hyperbranched polyglycerol core

Multi‐arm star block copolymers based on ε‐caprolactone have been prepared by a core‐first approach using propoxylated hyperbranched polyglycerol P(G₅₂PO₃) as a polyfunctional initiator. Various monomer/initiator ratios were employed in the Sn‐catalyzed polymerization in order to vary the length of the caprolactone arms (DP_n(arm) = 10 to 50). The molecular weights of the block copolymers were in good aggreement with the calculated values. Careful NMR analysis revealed that the monomer/initiator ratio not only controls the arm length, but also influences the degree of functionalization. Poly(ε‐CL) stars with 52 arms and absolute molecular weights between 69 200 and 360 400 g/mol have been prepared. SEC measurements showed that the narrow polydispersity of the core molecule (M_w/M_n = 1.24) could be maintained upon block copolymerization. The resulting star polymers exhibited polydispersities between 1.21 and 1.33.     

Micelle Behavior of Copolymers Composed of Linear and Hyperbranched Blocks in Aqueous Solution

Multi‐arm poly(THF)‐b‐polyglycerol linear‐hyperbranched copolymers consisting of a linear hydrophobic poly(THF) block and a hyperbranched hydrophilic polyglycerol block were synthesized by ring opening polymerization of tetrahydrofuran with silver trifluoromethane sulfonate as a catalyst and the consecutive polymerization of glycidol. Initiators with different geometries that propagated into different numbers of arms (e.g., 1, 2 or 4) were used to investigate the dependence of the micelle properties of the copolymers on the number of arms. The critical micelle concentration (CMC) first decreased and then increased with increasing numbers of arms showing a minimum CMC at an arm number of 2. A minimum CMC was difficult to obtain using multi‐arm block copolymers composed of linear polymers with the small number of arms investigated in this study. DLS showed that the 4‐arm poly(THF)‐b‐polyglycerol copolymer had a micelle size of approximately 83 nm under aqueous conditions, and the micelle size of the copolymers with different numbers of arms was similar. Unimolecular micelles could eventually be obtained using this system by increasing the number of arms, they are considered an ideal drug delivery carrier due to the concentration‐independent stability in the blood stream.

     

Poly(hydroxyl propyl methacrylate)‐b‐Poly(oligo ethylene glycol methacrylate) Thermoresponsive Block Copolymers by RAFT Polymerization

Thermoresponsive amphiphilic poly(hydroxyl propyl methacrylate)‐b‐poly(oligo ethylene glycol methacrylate) block copolymers (PHPMA‐b‐POEGMA) are synthesized by RAFT polymerization, with different compositions and molecular weights. The copolymers are molecularly characterized by size‐exclusion chromophotography, and ¹H NMR spectroscopy. Dynamic light scattering (DLS) and static light scattering (SLS) experiments in aqueous solutions show that the copolymers respond to temperature variations via formation of self‐organized nanoscale aggregates. Aggregate structural characteristics depend on copolymer composition, molecular weight, and ionic strength of the solution. Fluorescence spectroscopy experiments confirm the presence of less hydrophilic domains within the aggregates at higher temperatures. The thermoresponsive behavior of the PHPMA‐b‐POEGMA block copolymers is attributed to the particular solubility characteristics of the hydrophilic, water insoluble PHPMA block that are modulated by the presence of the water soluble POEGMA block.     

Initiators based on poly(ethylene glycol) for starting heterophase polymerizations: generation of block copolymers and new particle morphologies

Radical heterophase polymerizations with poly(ethylene glycol) radicals lead to the formation of block copolymer particles where the block copolymer architecture and the particle morphology depend on the number of radical per poly(ethylene glycol) chain, the radical termination mode, and the polarity of the monomer, respectively. The thermal decomposition of symmetrical poly(ethylene glycol) azo-initiators following the classical recipes of Heitz results in one radical per poly(ethylene glycol) chain whereas the number of radicals can be adjusted between one or two in the redox system poly(ethylene glycol)/cerium ions. The polymerization of styrene results in latex particles with an almost spherical morphology, consisting of block copolymers, only. In case of a methyl methacrylate polymerization the latex morphology depends on the architecture of the block copolymers formed. Heterophase polymerization with poly(ethylene glycol) azoinitiators in oligo(ethylene glycol) (average molecular weight 200 g · mol⁻¹) instead of in water results in particles with random shape and a strongly indented interface which is explained by the surface tension between polymers and solvent being close to zero.     

Tetraphenylsilane‐Cored Star‐Shaped Amphiphilic Block Copolymers for pH‐Responsive Anticancer Drug Delivery

Four‐arm star‐shaped poly[2‐(diethylamino)ethyl methacrylate]‐b‐poly[2‐hydroxyethyl methacrylate]s block copolymers using tetraphenylsilane (TPS) as a core with adjustable arm lengths are synthesized through two‐step atom transfer radical polymerizations. For comparison, a linear block copolymer with similar molecular weight is also prepared. The assembled star‐shaped copolymer micelles exhibit sizes of 102–139 nm and critical micelle concentrations of 1.49–3.93 mg L^?1. Moreover, the bulky and rigid TPS core is advantageous for propping up the four star‐shaped arms to generate large intersegmental space. As a result, the drug‐loading capacity in the micelles is up to 33.97 wt%, much surpassing the linear counterpart (8.92 wt%) and the previously reported star‐shaped copolymers prepared using pentaerythritol as the core. Furthermore, the micelles show sensitive pH‐responsive drug release when the pH changes from 7.4 to 5.0. The in vitro cytotoxicity to Hela cells indicates that the doxorubicin (DOX)‐loaded micelles have similar anticancer activity to the pristine DOX. The combination of excellent micelle stability, high drug‐loading, sensitive pH response, and good anticancer activity endows the copolymers with promising application in drug control delivery for anticancer therapy.     

pH‐Switchable Complexation between Double Hydrophilic Heteroarm Star Copolymers and a Cationic Block Polyelectrolyte

Double hydrophilic heteroarm star copolymers of poly(methacrylic acid) (PMAA) and poly(ethylene oxide) (PEO) were synthesized via atom‐transfer radical polymerization (ATRP) using the “in‐out” method. The synthesis consisted of three steps. Namely, ATRP was applied to the preparation of a star macroinitiator with PEO arms and a cross‐linked core resulting from the polymerization of divinylbenzene (DVB) in the first step, chain extension with tert‐butyl methacrylate (tBMA) under ATRP conditions, and subsequent hydrolysis of the tert‐butyl groups afforded (PEO)_n‐PDVB‐(PMAA)_n heteroarm star copolymers with a cross‐linked microgel core. This novel type of double hydrophilic heteroarm star copolymer can be considered as unimolecular micelles with hybrid coronas. The star copolymers exhibited pH‐dependent solubility in water, being soluble at high pH and insoluble at low pH, due to the formation of hydrogen‐bonded complexes between the PEO and PMAA arms. A mixed solution of the heteroarm star copolymer and a PEO‐b‐PQDMA diblock copolymer, where PQDMA is poly(2‐(dimethylamino)ethyl methacrylate) fully quaternized with methyl iodide, remained stable in the whole pH range, and exhibited an intriguing pH‐switchable complexation behavior accompanied with structural rearrangement.

     

The effect of RAFT-derived cationic block copolymer structure on gene silencing efficiency

In this work a series of ABA tri-block copolymers was prepared from oligo(ethylene glycol) methyl ether methacrylate (OEGMA(475)) and N,N-dimethylaminoethyl methacrylate (DMAEMA) to investigate the effect of polymer composition on cell viability, siRNA uptake, serum stability and gene silencing. Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization was used as the method of polymer synthesis as this technique allows the preparation of well-defined block copolymers with low polydispersity. Eight block copolymers were prepared by systematically varying the central cationic block (DMAEMA) length from 38 to 192 monomer units and the outer hydrophilic block (OEGMA(475)) from 7 to 69 units. The polymers were characterized using size exclusion chromatography and (1)H NMR. Chinese Hamster Ovary-GFP and Human Embryonic Kidney 293 cells were used to assay cell viability while the efficiency of block copolymers to complex with siRNA was evaluated by agarose gel electrophoresis. The ability of the polymer-siRNA complexes to enter into cells and to silence the targeted reporter gene enhanced green fluorescent protein (EGFP) was measured by using a CHO-GFP silencing assay. The length of the central cationic block appears to be the key structural parameter that has a significant effect on cell viability and gene silencing efficiency with block lengths of 110-120 monomer units being the optimum. The ABA block copolymer architecture is also critical with the outer hydrophilic blocks contributing to serum stability and overall efficiency of the polymer as a delivery system.     

Mixed Hyperbranched/Triblock Copolymer Micelle Assemblies: Physicochemical Properties and Potential for Drug Encapsulation

Mixed micelles have numerous advantages while requiring little to no effort in preparation. This study aims to produce mixed micelle nanostructures from a linear triblock copolymer and a hyperbranched random copolymer, and is able to be loaded with the weakly water-soluble drugs curcumin and indomethacin. Different preparation techniques are employed to produce mixed micelles comprised of Pluronic F127 block copolymer, and hyperbranched poly[(ethylene glycol) methyl ether methacrylate-co-lauryl methacrylate], H-[P(OEGMA-co-LMA)], copolymer. Few studies have dabbled in these types of coassemblies, which provides insight into how structural differences of each copolymer can affect the formation of micelles. To determine the properties of the emerging nanostructures in aqueous environments, including their size, homogeneity, and surface charge, different physicochemical techniques are used, such as light scattering and spectroscopic methods. The results reveal that the copolymers combine, and spontaneously self-assemble into mixed micelle-like nanostructures in aqueous environments, whereas both systems of neat and drug-loaded nanostructures exhibit desirable properties such as small average micelle hydrodynamic radii and low size polydispersity indices. The nanostructures that result from the effective encapsulation of curcumin exhibit outstanding stability over 169 days. The fluorescent qualities of curcumin persist after encapsulation, making the novel nanostructures excellent candidates for bioimaging applications.     

Effect of poly(dimethylsiloxane)-block-poly(oligo (ethylene glycol) methacrylate) amphiphilic block copolymers on dermal fibroblast viability and proliferation

Abstract

In this work, well-defined poly(dimethylsiloxane)-b-poly(oligo (ethylene glycol) methacrylate) (PDMS-b-POEGMA) amphiphilic block copolymers were synthesized and their effect on human dermal fibroblast were investigated. Anionic ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) were used to synthesis the block copolymers. The molecular weight of synthesized copolymers ranged from 1000 to 2300?Da by changing the number of both PDMS and POEGMA units. It was found that the copolymer having low molecular weight decreased the fibroblast viability and proliferation by inducing apoptosis. It was proved by flow cytometry and TUNEL assay that human dermal fibroblast experienced apoptosis after exposure to synthesized amphiphilic copolymers. The results of this work suggest the use of PDMS-b-POEGMA amphiphilic copolymers with low molecular weight for hypertrophic scars remediation.     

Block copolymer micelles as seed in emulsion polymerization

The size of aggregates formed by poly(acrylic acid)-block-poly(methyl methacrylate) block copolymers was determined and the applicability of these block copolymers as stabilizers in emulsion polymerization was investigated. The analytical methods included transmission electron microscopy, light scattering, and analytical ultracentrifugation. Polymers with a hydrophilic poly(acrylic acid) block of equal or larger size than the hydrophobic poly(methyl methacrylate) block are efficient as stabilizers down to block copolymer-to-monomer ratios of less than 1 wt.-%. From the influence of the block copolymer-to-monomer ratio on the latex particle size, from the relation between the number of block copolymer molecules per latex particle and the aggregation number of the block copolymer micelles, and from fluorescence studies we conclude that micelles consisting of block copolymers with 35 or more hydrophobic MMA units act as a seed in the emulsion polymerization of acrylic and methacrylic monomers.     

Synthesis of new amphiphilic star polymers derived from a hyperbranched macroinitiator by the cationic ‘grafting from’ method

New amphiphilic star polymers possessing a hyperbranched core and hydrophilic graft arms have been prepared. The synthetic strategy involved esterification of the 4,4-bis(4′-hydroxyphenyl)valeric acid based hyperbranched polymer with 3-(chloromethyl)benzoyl chloride to obtain the hyperbranched macroinitiator followed by cationic ring-opening polymerization of 2-methyl-2-oxazoline to give amphiphilic polymers. Exchange of the chloride counter ion with trifluoromethanesulfonate (KCF₃SO₃ or AgCF₃SO₃) or iodide (KI) anions leads to higher polymerization rates. Phenyl 2-(chloromethyl)benzoate was used as a model initiator to study the effect of different coinitiators on the initiator efficiency. KI as a coinitiator yielded 56–86% initiator conversion whereas only 30–37% initiator conversion was achieved with KCF₃SO₃ or AgCF₃SO₃ as coinitiator after quantitative monomer consumption. Photon correlation spectroscopy (PCS) in methanol and chloroform for selected graft copolymers revealed the formation of single star molecules ranging from 22 to 50 nm in diameter.     

Synthesis of methacrylic multi-arm star copolymers by “arm-first” group transfer polymerisation

Methacrylic star polymers were synthesized by the “arm-first” method of star polymer formation by the addition of difunctional monomer, ethylene glycol dimethacrylate, to living linear poly(methyl methacrylate) as prepared by group transfer polymerisation (GTP). The effects of living polymer concentration and ratio of difunctional monomer to living polymer are discussed, and show how macromolecular design and control may be imposed on the number of arms and molecular weight of the star polymer. Diluting the difunctional crosslinking monomer with monomer has been examined with the view to establishing funtionalisation of the star core.     

Folate‐Conjugated Poly(N‐(2‐hydroxypropyl) methacrylamide)‐block‐Poly(benzyl methacrylate): Synthesis,Self‐Assembly,and Drug Release

Well‐defined amphiphilic diblock copolymers of poly(N‐(2‐hydroxypropyl)methacrylamide)‐block‐poly(benzyl methacrylate) (PHPMA‐b‐PBnMA) are synthesized using reversible addition–fragmentation chain transfer polymerization. The terminal dithiobenzoate groups are converted into carboxylic acids. The copolymers self‐assemble into micelles with a PBnMA core and PHPMA shell. Their mean size is <30 nm, and can be regulated by the length of the hydrophilic chain. The compatibility between the hydrophobic segment and the drug doxorubicin (DOX) affords more interaction of the cores with DOX. Fluorescence spectra are used to determine the critical micelle concentration of the folate‐conjugated amphiphilic block copolymer. Dynamic light scattering measurements reveal the stability of the micelles with or without DOX. Drug release experiments show that the DOX‐loaded micelles are stable under simulated circulation conditions and the DOX can be quickly released under acidic endosome pH.     

Statistical Copolymers Comprising Bio-Based Aromatic Methacrylate Segments and Their Influence on the Glass Transition Temperature

Synthesis of statistical copolymers is described from bio-based 4-(4-methacryloyloxyphenyl)butan-2-one ( 1 ) with an aliphatic methacrylate, such as n-butyl methacrylate ( 2 ), N,N-(dimethylamino)ethyl methacrylate ( 3 ), and lauryl methacrylate ( 4 ), using mostly dimethyl sulfoxide as solvent in the free radical polymerization. Though 4  is insoluble in dimethyl sulfoxide, diethyl carbonate is the preferred solvent for the copolymerization using this monomer although both yield and molecular weight are lower even for poly(4-(4-methacryloyloxyphenyl)butan-2-one) than using dimethyl sulfoxide as solvent. ¹H NMR spectroscopic analysis gives information about the content on the monomer segments in all copolymers. Furthermore, elementary analysis additionally supports the results obtained for the copolymers made from 1  and 3 . As shown by the copolymerization diagrams and the copolymerization parameters, the copolymerization of 1 with 2 is a nearly ideal copolymerization using short polymerization time (20 min). Extending the polymerization time results in slight deviation from an ideal copolymerization. Furthermore, the glass transition temperature of the copolymers determined by DSC and calculated using both the Fox equation and the Gibbs-DiMarzio equation show the strong influence of the copolymer composition. As expected, the glass transition temperature increases with increasing content on aromatic segments in the copolymer that may be interesting for application in coatings and adhesives, respectively.     

Free radical “grafting from” hyperbranched polyesters based on polymeric azo initiators

Aromatic and aliphatic hyperbranched polyesters were prepared by AB₂ polycondensation process. The highly branched, functional structure of these polymers leads to excellent solubility in combination with low solution viscosities. Varied numbers of the functional groups of the hyperbranched structures were modified with azo functions which are able to initiate free radical polymerization. An increase in temperature in the presence of the vinyl monomers methyl methacrylate (MMA), butyl methacrylate (BMA), styrene (S), or acrylamide (AA) results in “grafting from” the hyperbranched structure. Using this method several graft products were synthesized with variations in structure, number, and size of the graft arms. Gel-permeation chromatography (GPC) with universal calibration and viscosity measurements indicate a strong influence of the hyperbranched core on the properties of the graft product. It was possible to control the phase behavior of the graft products from two phases to homogeneous by the ratio hyperbranched polyester: grafted monomer. The film forming properties which are very poor for unmodified hyperbranched polyester were improved by grafting with linear polymer chains.     

Synthesis and Characterization of Large‐Core Star Polymers and Polymer Networks: Effects of Arm Length and Composition of the Cross‐Linking Mixture

Large‐core star polymers (LCSPs) and polymer networks were prepared using sequential group transfer polymerization (GTP) for the synthesis of linear poly(methyl methacrylate) (polyMMA) arms, followed by their cross‐linking using a mixture of MMA monomer and ethylene glycol dimethacrylate (EGDMA) cross‐linker. High monomer/cross‐linker molar ratios and short arms favored the formation of polymer networks, whereas the opposite conditions favored the formation of LCSPs. LCSPs presented two populations: star polymers and covalently linked star polymer aggregates. The size of the non‐aggregated star polymers, and the size and fraction of the star polymer aggregates passed through a maximum as the amount of the monomer in the cross‐linking mixture increased. The degrees of swelling in tetrahydrofuran (THF) of the networks, the sol fraction extracted from them, and the percentage of linear polymer in the sol fraction increased as the degree of polymerization of the arms increased.