Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP

Graft-through ring-opening metathesis polymerization (ROMP) using ruthenium N-heterocyclic carbene catalysts has enabled the synthesis of bottle-brush polymers with unprecedented ease and control. Here we report the first bivalent-brush polymers; these materials were prepared by graft-through ROMP of drug-loaded polyethylene-glycol (PEG) based macromonomers (MMs). Anticancer drugs doxorubicin (DOX) and camptothecin (CT) were attached to a norbornene-alkyne-PEG MM via a photocleavable linker. ROMP of either or both drug-loaded MMs generated brush homo- and co-polymers with low polydispersities and defined molecular weights. Release of free DOX and CT from these materials was initiated by exposure to 365 nm light. All of the CT and DOX polymers were at least 10-fold more toxic to human cancer cells after photoinitiated drug release while a copolymer carrying both CT and DOX displayed 30-fold increased toxicity upon irradiation. Graft-through ROMP of drug-loaded macromonomers provides a general method for the systematic study of structure-function relationships for stimuli-responsive polymers in biological systems.     

How good is CuAAC “click” chemistry for polymer coupling reactions?

¹H NMR and SEC analyses are used to investigate the overall efficiency of Copper Catalyzed Azide Alkyne Cycloaddition (CuAAC) “click” coupling reactions between alkyne‐ and azide‐terminated polymers using polystyrene as a model. Quantitative convolution modeling of the entire molecular weight distribution is applied to characterize the outcomes of the functional polymer synthesis reactions (i.e., by atom transfer radical polymerization), as well as the CuAAC coupling reaction. Incomplete functionality of the azide‐terminated polystyrene (∼92%) proves to be the largest factor compromising the efficacy of the CuAAC coupling reaction and is attributed primarily to the loss of terminal bromide functionality during its synthesis. The efficiency of the S_N2 reaction converting bromide to azide was found to be about 99%. After taking into account the influence of non‐functional polymer, we find that, under the reaction conditions used, the efficiency of the CuAAC coupling reaction determined from both techniques is about 94%. These inefficiencies compromise the fidelity and potential utility of CuAAC coupling reactions for the synthesis of hierarchically structured polymers. While CuAAC efficiency is expected to depend on the specific reaction conditions used, the framework described for determining reaction efficiency does provide a means for ultimately optimizing the reaction conditions for CuAAC coupling reactions. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 75–84     

Synthesis and pyrolysis of ABC type miktoarm star copolymers with polystyrene,poly(lactic acid) and poly(ethylene glycol) arms

An ABC type miktoarm star copolymer possessing polystyrene (PS), poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) arms was synthesized by combining Atom Transfer Radical Polymerization (ATRP) and Ring Opening Polymerization (ROP) with two click chemistries, namely thiol–ene and copper catalyzed azide–alkyne cycloaddition (CuAAC). For this purpose, a core 1-(allyloxy)-3-azidopropan-2-ol with allyl and azide functionalities was synthesized in two steps. Then, clickable polymers, polystyrene with thiol functionality (PS–SH) and poly(ethylene glycol) with alkyne functionality (PEG–acetylene) were independently prepared. As the first step of the grafting onto process, PS–SH was thiol–ene clicked onto the core to yield PS–N₃–OH. The second arm was then incorporated onto the core by the Ring Opening Polymerization (ROP) of l-(?)-Lactide (LA) using as PS–N₃–OH initiator and tin(II) 2-ethylhexanoate as catalyst. Finally, alkyne–PEG–acetylene was bonded to the resulting PLA–PS–N₃ using CuAAC click reaction. All intermediates, related polymers at different stages and final PS–PLA–PEG miktoarm star copolymer were characterized by ¹H NMR, FT-IR, SEC and DP-MS analyses. Direct pyrolysis mass spectrometry, (DP-MS) analyses of PS–PLA–PEG and all intermediate polymers indicated that the decomposition of PS and PEG chains occurred almost independently, following the degradation mechanisms of the corresponding homopolymers. On the other hand, during the pyrolysis of PS–PLA–PEG, elimination of H₂O during the decomposition of PEG chains at the early stages of pyrolysis caused hydrolysis of PLA chains and increased the yields of CO₂, CO and units involving unsaturation and/or crosslinked structure.     

Polymersome‐forming amphiphilic glycosylated polymers: Synthesis and characterization

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

V‐shaped graft copolymers via triple click reactions: Diels–alder,copper‐catalyzed azide–alkyne cycloaddition,and nitroxide radical coupling

We report here a simple and universal synthetic pathway covering triple click reactions, Diels–Alder, copper‐catalyzed azide–alkyne cycloaddition (CuAAC), and nitroxide radical coupling (NRC), to prepare well‐defined graft copolymers with V‐shaped side chains. The Diels–Alder click reaction between the furan protected‐maleimide‐terminated poly(ethylene glycol) (PEG) and a trifunctional core ( 1 ) carrying an anthracene, alkyne, and bromide was carried out to yield the corresponding α‐alkyne‐ and α‐bromide‐terminated PEG (PEG‐alkyne/Br) in toluene at 110 °C. Subsequently, the polystyrene or polyoxanorbornene with pendant azide functionality as a main backbone is reacted with the PEG‐alkyne/Br and 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO)‐terminated poly(ε‐caprolactone) using the CuAAC and NRC reactions in a one‐pot fashion in N,N′‐dimethylformamide at room temperature to result in the target V‐shaped graft copolymers. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 4667–4674     

Chain-growth polymerization of azide–alkyne difunctional monomer: Synthesis of star polymer with linear polytriazole arms from a core

This article reports a chain-growth coupling polymerization of AB difunctional monomer via copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction for synthesis of star polymers. Unlike our previously reported CuAAC polymerization of AB _n (n ≥ 2) monomers that spontaneously demonstrated a chain-growth mechanism in synthesis of hyperbranched polymer, the homopolymerization of AB monomer showed a common but less desired step-growth mechanism as the triazole groups aligned in a linear chain could not effectively confine the Cu catalyst in the polymer species. In contrast, the use of polytriazole-based core molecules that contained multiple azido groups successfully switched the polymerization of AB monomers into chain-growth mechanism and produced 3-arm star polymers and multi-arm hyperstar polymers with linear increase of polymer molecular weight with conversion and narrow molecular weight distribution, for example, M_w/M_n ~ 1.05. When acid-degradable hyperbranched polymeric core was used, the obtained hyperstar polymers could be easily degraded under acidic environment, producing linear degraded arms with defined polydispersity. © 2019 Wiley Periodicals, Inc. J. Polym. Sci. 2020 , 58, 84–90     

One-pot synthesis of hybrid multifunctional silica nanoparticles with tunable coating by click chemistry in reverse w/o microemulsion

Multifunctional hybrid silica nanoparticles with a fluorescent core and tunable organic or polymeric shell can easily be prepared by a sol-gel process followed by 1,3 dipolar cycloaddition (CuAAC) in the same reverse quaternary W/O microemulsion. Compared to a classical multistep process, this one-pot synthesis reduces greatly the number of purification steps and avoids aggregation phenomena. The confinement of reactants inside the micellar system gives rise to a noticeable increase of the CuAAC reaction rate. In addition, using simultaneously two different substrates for CuAAC on silica allows us to obtain directly multifunctional hybrid nanoparticles displaying a double grafting without any separation or purification steps except the final recovery by centrifugation, which opens the door to a tunable coating of the nanoparticles. Particularly, the hydrophilic-lipophilic balance of the coating can be adjusted by implementing the pertinent MPEG:dodecyl azide ratio. As an application, the great versatility of this strategy has been proved by the one-pot synthesis of fluorescent silica nanoparticles with a PEG coating and encapsulating silver clusters.     

Star polymers by photoinduced copper‐catalyzed azide–alkyne cycloaddition click chemistry

Well‐defined star polymers consisting of tri‐, tetra‐, or octa‐arms have been prepared via coupling‐onto strategy using photoinduced copper(I)‐catalyzed 1,3‐dipolar cycloaddition click reaction. An azide end‐functionalized polystyrene and poly(methyl methacrylate), and an alkyne end‐functionalized poly(ε‐caprolactone) as the integrating arms of the star polymers are prepared by the combination of controlled polymerization and nucleophilic substitution reactions; whereas, multifunctional cores containing either azide or alkyne functionalities were synthesized in quantitatively via etherification and ring‐opening reactions. By using photoinduced copper‐catalyzed azide–alkyne cycloaddition (CuAAC) click reaction, reactive linear polymers are simply attached onto multifunctional cores to form corresponding star polymers via coupling‐onto methodology. The chromatographic, spectroscopic, and thermal analyses have clearly demonstrated that successful star formations can be obtained via photoinduced CuAAC click reaction. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1687–1695     

Chain‐Growth Click Polymerization of AB2 Monomers for the Formation of Hyperbranched Polymers with Low Polydispersities in a One‐Pot Process

Hyperbranched polymers are important soft nanomaterials but robust synthetic methods with which the polymer structures can be easily controlled have rarely been reported. For the first time, we present a one‐pot one‐batch synthesis of polytriazole‐based hyperbranched polymers with both low polydispersity and a high degree of branching (DB) using a copper‐catalyzed azide–alkyne cycloaddition (CuAAC) polymerization. The use of a trifunctional AB₂ monomer that contains one alkyne and two azide groups ensures that all Cu catalysts are bound to polytriazole polymers at low monomer conversion. Subsequent CuAAC polymerization displayed the features of a “living” chain‐growth mechanism with a linear increase in molecular weight with conversion and clean chain extension for repeated monomer additions. Furthermore, the triazole group in a linear (L) monomer unit complexed Cu^I, which catalyzed a faster reaction of the second azide group to quickly convert the L unit into a dendritic unit, producing hyperbranched polymers with DB=0.83.     

A Simple Post-Polymerization Modification Method for Controlling Side-Chain Information in Digital Polymers

A three-step post-polymerization modification method was developed for the design of digitally encoded poly(phosphodiester)s with controllable side groups. Sequence-defined precursors were synthesized, either manually on polystyrene resins or automatically on controlled pore glass supports, using two phosphoramidite monomers containing either terminal alkynes or triisopropylsilyl (TIPS) protected alkyne side groups. Afterwards, these polymers were modified by stepwise copper-catalyzed azide–alkyne cycloaddition (CuAAC). The terminal alkynes were first reacted with a model azide compound, and after removal of the TIPS groups, the remaining alkynes were reacted with another organic azide. This simple method allows for quantitative side-chain modification, thus opening up interesting avenues for the preparation of a wide variety of digital polymers.     

Quadruple click reactions for the synthesis of cysteine‐terminated linear multiblock copolymers

Synthesis of cysteine‐terminated linear polystyrene (PS)‐b‐poly(ε‐caprolactone) (PCL)‐b‐poly(methyl methacrylate) (PMMA)/or poly(tert‐butyl acrylate)(PtBA)‐b‐poly(ethylene glycol) (PEG) copolymers was carried out using sequential quadruple click reactions including thiol‐ene, copper‐catalyzed azide–alkyne cycloaddition (CuAAC), Diels–Alder, and nitroxide radical coupling (NRC) reactions. N‐acetyl‐L ‐cysteine methyl ester was first clicked with α‐allyl‐ω‐azide‐terminated PS via thiol‐ene reaction to create α‐cysteine‐ω‐azide‐terminated PS. Subsequent CuAAC reaction with PCL, followed by the introduction of the PMMA/or PtBA and PEG blocks via Diels–Alder and NRC, respectively, yielded final cysteine‐terminated multiblock copolymers. By ¹H NMR spectroscopy, the DP_ns of the blocks in the final multiblock copolymers were found to be close to those of the related polymer precursors, indicating that highly efficient click reactions occurred for polymer–polymer coupling. Successful quadruple click reactions were also confirmed by gel permeation chromatography. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

End‐group functionalization and postpolymerization modification of helical poly(isocyanide)s

This contribution presents the synthesis of helical alkyne‐terminated polymers using a functionalized Nickel complex to initiate the polymerization of menthylphenyl isocyanides. The resulting polymers display low dispersities and controlled molecular weights. Copper‐catalyzed azide/alkyne cycloadditions (CuAAC) are performed to attach various azide‐containing compounds to the polymer termini. After azido‐phosphonate moiety attachment the polymer displays a signal at 25.4 ppm in the ³¹P NMR spectrum demonstrating successful end‐group functionalization. End‐group functionalization of a fluorescent dye allows to determine the functionalization yield as 89% (±8). Successful ligation of an azide‐functionalized peptide sequence (M_KLA = 1547 g/mol) increases the M_n from 5100 for the parent polymer to 6700 for the bioconjugate as visualized by GPC chromatography. Analysis by CD spectroscopy confirms that the helical conformation of the poly(isocyanide) block in the peptide–polymer conjugate is maintained after postpolymerization modification. These results demonstrate an easy, generalizable, and versatile strategy toward mono‐telechelic helical polymers. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2766–2773     

Combining aminocyanine dyes with polyamide dendrons: a promising strategy for imaging in the near-infrared region

Cyanine dyes are known for their fluorescence in the near-IR (NIR) region, which is desirable for biological applications. We report the synthesis of a series of aminocyanine dyes containing terminal functional groups such as acid, azide, and cyclooctyne groups for further functionalization through, for example, click chemistry. These aminocyanine dyes can be attached to polyfunctional dendrons by copper-catalyzed azide alkyne cycloaddition (CuAAC), strain-promoted azide alkyne cycloaddition (SPAAC), peptide coupling, or direct S(NR)1 reactions. The resulting dendron-dye conjugates were obtained in high yields and displayed high chemical stability and photostability. The optical properties of the new compounds were studied by UV/Vis and fluorescence spectroscopy. All compounds show large Stokes shifts and strong fluorescence in the NIR region with high quantum yields, which are optimal properties for in vivo optical imaging.     

Facilitating polymer conjugation via combination of RAFT polymerization and activated ester chemistry

The synthesis of block copolymers via polymer conjugation of well‐defined building blocks offers excellent control over the structures obtained, but often several coupling strategies need to be explored to find an efficient one depending on the building blocks. To facilitate the synthesis of polymers with adjustable functional end‐groups for polymer conjugation, we report on the combination of activated ester chemistry with RAFT polymerization using a chain transfer agent (CTA) with a pentafluorophenyl ester (PFP‐CTA), which allows for flexible functionalization of either the CTA prior to polymerization or the obtained polymer after polymerization. Different polymethacrylates, namely PMMA, P(t‐BuMA) and PDEGMEMA, were synthesized with an alkyne‐CTA obtained from the aminolysis of the PFP‐CTA with propargylamine, and the successful incorporation of the alkyne moiety could be shown via ¹H and ¹³C NMR spectroscopy and MALDI TOF MS. Further, the reactive α‐end‐groups of polymers synthesized using the unmodified PFP‐CTA could be converted into azide and alkyne end‐groups after polymerization, and the high functionalization efficiencies could be demonstrated via successful coupling of the resulting polymers via CuAAC. Thus, the PFP‐CTA allows for high combinatory flexibility in polymer synthesis facilitating polymer conjugation as useful method for the synthesis of block copolymers. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

3‐miktoarm star terpolymers using triple click reactions: Diels–Alder,copper‐catalyzed azide‐alkyne cycloaddition,and nitroxide radical coupling reactions

Well‐defined linear furan‐protected maleimide‐terminated poly(ethylene glycol) (PEG‐MI), tetramethylpiperidine‐1‐oxyl‐terminated poly(ε‐caprolactone) (PCL‐TEMPO), and azide‐terminated polystyrene (PS‐N₃) or ‐poly(N‐butyl oxanorbornene imide) (PONB‐N₃) were ligated to an orthogonally functionalized core ( 1 ) in a two‐step reaction mode through triple click reactions. In a first step, Diels–Alder click reaction of PEG‐MI with 1 was performed in toluene at 110 °C for 24 h to afford α‐alkyne‐α‐bromide‐terminated PEG (PEG‐alkyne/Br). As a second step, this precursor was subsequently ligated with the PCL‐TEMPO and PS‐N₃ or PONB‐N₃ in N,N‐dimethylformamide at room temperature for 12 h catalyzed by Cu(0)/Cu(I) through copper‐catalyzed azide‐alkyne cycloaddition and nitroxide radical coupling click reactions, yield resulting ABC miktoarm star polymers in a one‐pot mode. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

ABC type miktoarm star copolymers through combination of controlled polymerization techniques with thiol‐ene and azide‐alkyne click reactions

ABC type miktoarm star copolymer with polystyrene (PS), poly(ε‐caprolactone) (PCL) and poly(ethylene glycol) (PEG) arms was synthesized using controlled polymerization techniques in combination with thiol‐ene and copper catalyzed azide‐alyne “click” reactions (CuAAC) and characterized. For this purpose, 1‐(allyloxy)‐3‐azidopropan‐2‐ol was synthesized as the core component in a one‐step reaction with high yields (96%). Independently, ω‐thiol functionalized polystyrene (PS‐SH) was synthesized in a two‐step protocol with a very narrow molecular weight distribution. The bromo end function of PS obtained by atom transfer radical polymerization was first converted to xanthate function and then reacted with 1, 2‐ethandithiol to yield desired thiol functional polymer (PS‐SH). The obtained polymer was grafted onto the core by thiol‐ene click chemistry. In the following stage, ε‐caprolactone monomer was polymerized from the core by ring opening polymerization (ROP) using tin octoate as catalyst through hydroxyl groups to form the second arm. Finally, PEG‐acetylene, which was simply synthesized by the esterification of Me‐PEG and 5‐pentynoic acid, was clicked onto the core through azide groups present in the structure. The intermediates at various stages and the final miktoarm star copolymer were characterized by ¹H NMR, FTIR, and GPC measurements. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

双烯化合物类单体合成支化聚合物的支化结构的研究

分别以二乙烯基苯(DVB)、双甲基丙烯酸二缩三乙二醇酯(tri-EGDMA)和1,6-双马来酰亚胺基正己烷(BMIH)为支化单体,采用原子转移自由基聚合合成支化聚苯乙烯;以先核后臂法合成的星状支化聚苯乙烯为参照对合成的支化聚合物的支化形态进行研究.采用气相色谱(GC)、核磁共振氢谱(1H-NMR)和三检测凝胶渗透色谱(TD-SEC)测定了苯乙烯的转化率,聚合物分子量及其分布,特性黏数和均方回转半径.实验结果表明3个支化聚合反应体系内悬垂双键是逐步消耗的,不存在明显的成核过程.反应前期,以形成带有悬垂双键的初级链和轻度支化聚合物为主,聚合物分子量随单体转化率逐步上升;反应后期,悬垂双键聚合导致的分子之间的偶合更加明显,使得聚合物分子量快速上升,合成得到的都是无规支化聚合物.     

N-Alkynyl imides (ynimides): synthesis and use as a variant of highly labile ethynamine

This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with azide followed by hydrazinolysis of the phthaloyl protecting group.     

Tunable Self‐Assembly of Triazole‐Linked Porphyrin–Polymer Conjugates

The convergence of supramolecular chemistry and polymer science offers many powerful approaches for building functional nanostructures with well‐defined dynamic behaviour. Herein we report the efficient “click” synthesis and self‐assembly of AB₂‐ and AB₄‐type multitopic porphyrin–polymer conjugates (PPCs). PPCs were prepared using the copper(I)‐catalysed azide–alkyne cycloaddition (CuAAC) reaction, and consisted of linear polystyrene, poly(butyl acrylate), or poly(tert‐butyl acrylate) arms attached to a zinc(II) porphyrin core via triazole linkages. We exploit the presence of the triazole groups obtained from CuAAC coupling to direct the self‐assembly of the PPCs into short oligomers (2–6 units in length) via intermolecular porphyrinatozinc–triazole coordination. By altering the length and grafting density of the polymer arms, we demonstrate that the association constant of the porphyrinatozinc–triazole complex can be systematically tuned over two orders of magnitude. Self‐assembly of the PPCs also resulted in a 6 K increase in the glass transition temperature of the bulk material compared to a non‐assembling PPC. The modular synthesis and tunable self‐assembly of the triazole‐linked PPCs thus represents a powerful supramolecular platform for building functional nanostructured materials.     

Polymeric dibromomaleimides as extremely efficient disulfide bridging bioconjugation and pegylation agents

A series of dibromomaleimides have been shown to be very efficacious at insertion into peptidic disulfide bonds. This conjugation proceeds with a stoichiometric balance of reagents in buffered solutions in less than 15 min to give discrete products while maintaining the disulfide bridge and thus peptide conformation. The insertion is initiated by disulfide reduction using a water-soluble phosphine, tris(2-carboxyethyl)phosphine (TCEP) which allows for subsequent substitution of the two maleimide bromides by the generated thiols. Reaction of salmon calcitonin (sCT) with 2,3-dibromomaleimide (1.1 excess) in the presence of TCEP (1.1 equiv) in aqueous solution at pH 6.2 gives complete production of a single conjugate which requires no workup. A linear methoxy poly(ethylene glycol) (PEG) was functionalized via a Mitsunobu reaction and used for the successful site-specific and rapid pegylation of sCT. This reaction occurs in 15 min with a small stoichiometry excess of the pegylating agent to give insertion at the disulfide with HPLC showing a single product and MALDI-ToF confirming conjugation. Attempts to use the group in a functional ATRP polymerization initiator led to polymerization inhibition. Thus, in order to prepare a range of functional polymers an indirect route was chosen via both azide and aniline functional initiators which were converted to 2,3-dibromomaleimides via appropriate reactions. For example, the azide functional polymer was reacted via a Huisgen CuAAC click reaction to an alkyne functional 2,3-dibromomaleimide. This new reagent allowed for the synthesis of conjugates of sCT with comb polymers derived from PEG methacrylic monomers which in addition gave appropriate cloud points. This reaction represents a highly efficient polymer conjugation method which circumvents problems of purification which normally arise from having to use large excesses of the conjugate. In addition, the tertiary structure of the peptide is efficiently maintained.