Polymer Chemistry Blog

The synthesis of highly hemo- and cytocompatible zwitterionic 2-oxazoline-based poly(sulfobetaine)s and poly(carboxybetaine)s, which demonstrate beneficial anticoagulant activity, has been reported by Schubert et al.

The polymers were obtained by thiol–ene photoaddition of a tertiary amine-containing thiol onto an alkene-containing precursor copoly(2-oxazoline), followed by betainization with 1,3-propansultone and β-propiolactone. The polymers and their intermediates were characterized by means of 1H NMR spectroscopy and size exclusion chromatography. The influence of the zwitterionic polymers on the aggregation and hemolysis of erythrocytes, the whole blood viscosity, the platelet and complement activation as well as the blood coagulation has been studied in detail. In addition, the cytotoxicity of the materials has been evaluated.

It was found that the zwitterionic POx show no negative interactions with blood. Moreover, anticoagulant activity via the intrinsic and/or the common coagulation pathway was observed. The high hemocompatibility and the low cytotoxicity as well as the beneficial anticoagulant activity of the presented zwitterionic poly(2-oxazoline)s demonstrate their potential for the use in biomedical applications.

Zwitterionic poly(2-oxazoline)s as promising candidates for blood contacting applications by Lutz Tauhardt, David Pretzel, Kristian Kempe, Michael Gottschaldt, Dirk Pohlers and  Ulrich S. Schubert Polym. Chem. 2014, 5, 5751-5764.

Remzi Becer is a web-writer and advisory board member for Polymer Chemistry. He is currently a Senior Lecturer in Materials Science and the director of the Polymer Science and Nanotechnology masters programme at Queen Mary, University of London. Visit www.becergroup.com for more information!

Albumin-based drug delivery has been demonstrated to be useful for achieving improved cancer therapy, largely due to its passive target toward tumor via the enhanced permeability and retention effect and the increased demand for albumin by tumor cells as source of energy and amino acids. However, albumin lacks not only the active mechanism to overcome the cell membrane barrier, but also the ability to penetrate into tumor tissues. Herein, a cell-penetrating albumin-based delivery strategy was developed, in which a cell-penetrating peptide was chemically conjugated to albumin in order to enhance the efficiency of intracellular delivery and tumor penetration. Doxorubicin (DOX) molecules were loaded into the carrier via cleavable disulfide bonds, which are responsive to the highly reducing environment in the cytosol of tumor cells, thus archiving prodrug-type targeted drug release. The cell-penetrating albumin–DOX conjugates displayed significantly higher antitumor activity than DOX. More interestingly, the conjugates also efficiently killed the drug-resistant tumor cells, in sharp contrast to the ineffective DOX. The studies with human xenograft tumors in nude mice further demonstrated the enhanced antitumor efficacy and reduced side effects of the cell-penetrating albumin-assisted DOX delivery strategy, indicating the promise of this delivery system.

The ring-opening polymerization of cyclic ketene acetals (CKAs) by controlled radical mechanisms represents an alternative route for the synthesis of aliphatic polyesters. For the first time, 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) and 2-methylene-4-phenyl-1,3-dioxolane (MPDL) were homopolymerized by nitroxide mediated polymerization (NMP), from the commercially available SG1-based BlocBuilder MA alkoxyamine. Various experimental conditions (i.e., reaction temperature, nature of solvent, and nature of the alkyl initiating radical) were varied to determine the optimized conditions in terms of polymerization kinetics and living character of the final polymer. Chain-end extensions from either PS-SG1 or PBMDO-SG1 were also performed in order to furnish PS-b-PBMDO and PBMDO-b-PS, respectively, thus demonstrating the synthesis of block copolymers comprising a CKA block. In order to have a better insight into the polymerization mechanism, the occurrence of side reactions was analyzed by ³¹P NMR spectroscopy and ESI-MS. It was supposed that the ketal-based macroradical could be irreversibly trapped by nitroxide and thus the corresponding macroalkoxyamine decomposed by CO–N bond dissociation. DFT calculations as well as PREDICI modeling were also undertaken in order to support this hypothesis.

2-Methacryloyloxyethyl-phosphorylcholine (MPC) polymers are zwitterionic in character and are widely used in a range of biomedical devices. The availability of facile polymerization approaches has allowed the synthesis of well-defined MPC polymers, which are now used as delivery carriers for in vitro and in vivo applications. Although biocompatibility testing has extensively been performed on insoluble MPC-based materials, to the best of our knowledge, there are no reports on the hemocompatibility of soluble MPC polymers. Therefore, in this work, linear and hyperbranched MPC polymers of varying molecular weights are synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization. The polymers produced are studied for their blood compatibility, as a function of their molecular weights and structures (linear versus hyperbranched). The hemocompatibility studies including clot formation, complement and platelet activation, and hemolysis indicate that linear and hyperbranched MPC polymers are blood compatible. The remarkable difference in erythrocyte aggregation in the presence of linear and branched MPC polymers indicates the importance of the branched polymer architecture.

Zhu et al. applied Cu(II)-mediated atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA) using the concept of thermoregulated phase-transfer catalysis (TRPTC) for an aqueous–organic biphasic system. Activators generated by electron transfer (AGET) ATRP was used to establish the TRPTC ATRP system using 2-cyanoprop-2-yl 1-dithionaphthalate (CPDN) as an alkyl pseudohalide initiator, CuBr₂ as the catalyst and ascorbic acid (AsAc) as the reducing agent. They used a thermoresponsive monofunctional ligand including the dipyridyl group (MPEG-DPA), which enabled the transfer of the catalyst complex into the organic phase from the aqueous phase upon heating, thus achieving homogeneous polymerization; and the catalyst complex could retransfer into the aqueous phase from the organic phase thereby realizing the separation and recycling of the catalyst complex upon cooling. Well-defined PMMA with controlled molecular weight and narrow molecular weight distribution could be obtained by TRPTC ATRP. Furthermore, the polymerization of MMA could be successfully carried out even when the amount of catalyst was reduced to the ppm level. The features of controlled/“living” radical polymerization of MMA were verified by chain end analysis and chain-extension experiments.

Atom transfer radical polymerization of methyl methacrylate with a thermo-responsive ligand: construction of thermoregulated phase-transfer catalysis in an aqueous–organic biphasic system by Jinlong Pan, Lifen Zhang, Liangjiu Bai, Zhengbiao Zhang, Hong Chen, Zhenping Cheng* and Xiulin Zhu*, Polym. Chem., 2013, 4, 2876-2883.

Monomers based on vinylcyclopropane (VCP) have not attracted a lot of attention in polymer chemistry compared to regular vinyl monomers. This is mainly due to the difficulty in synthesizing them and their polymerisation behaviour. Polymerisation of VCP is known to proceed via a 1,2-type or a 1,5-type, i.e. a radical ring opening polymerization (RROP). RROP of VCP can lead to three different isomeric repeating units: two pent-2-enyl units and one cyclobutyl unit. These different polymerization pathways are the reason why VCP derivatives are not frequently used in polymer chemistry.

Theato et al. have demonstrated the synthesis and polymerization of a new reactive vinylcyclopropane monomer, 1-cyano-1-pentafluorophenoxycarbonyl-2-vinylcyclopropane. The obtained polymer contained exclusively the pent-3-enyl repeating unit in the polymer backbone. Taking advantage of activated ester chemistries, post-polymerization modifications with different aliphatic amines have been conducted. All prepared polymers exhibited an upper critical solution temperature (UCST) in ethanol and ethanol–water. It was found that the UCST was directly related to the amide moiety of the polymer. An increased solubility of the polymer in ethanol with the increase of the volume of the aliphatic amide moiety was observed. The reverse effect was found when adding water to the ethanolic solution of the polymer.

Post-polymerization modification of reactive polymers derived from vinylcyclopropane: 1. synthesis and thermo-responsive behaviour by Denis H. Seuyep N., Gerrit A. Luinstra and Patrick Theato Polym. Chem., 2013, 4, 2724-2730.

Facile synthetic and modification procedures of functionalized polymers have been the subject of extensive fundamental and applied research efforts during the last decade. The concept of ‘click’ chemistry induced a transition towards ‘on-demand’ preparation of tailored polymeric systems. The toolbox of research labs is currently loaded with a variety of established ‘click’ reactions, offering ample possibilities for macromolecular design and synthesis. Moreover, the development and valorization of novel polymer materials with a broad range of applications (medicines, electronics, bioconjugation, labeling, etc.) significantly promoted interdisciplinary research. The elaboration of innovative procedures and the combination of existing reactions in multi-step one-pot sequences further exemplify the scientific eagerness to study the possibilities and limitations of ‘click’ chemistry to the full extent.

Filip Du Prez et al. have elaborated a straightforward, isocyanate-free method for the synthesis of functionalized polyurethanes, based on amine–thiol–ene conjugation. Aminolysis of a readily available AB′-urethane monomer, containing both an acrylate (A) and a thiolactone unit (B′), facilitates the preparation of various reactive thiol–acrylates. In situ polymerization via Michael addition proceeds under ambient conditions, yielding polyurethanes with a large variety of chemical functionalities. Side-chain functionality originates from the modular use of different amines, allowing for the introduction of pendent functional groups (e.g. double bond, triple bond, furfuryl, tertiary amine, morpholine) along the polyurethane backbone. Extensive model studies revealed the kinetic profile of this reaction sequence and excluded the occurrence of competing reactions, such as aza-Michael addition and disulfide formation. This mild one-pot reaction requires no additives or external trigger and the obtained polyurethanes remain soluble throughout the process, enabling post-polymerization modification in the same reaction medium.

One-pot, additive-free preparation of functionalized polyurethanes viaamine–thiol–ene conjugation by Pieter Espeel, Fabienne Goethals. Frank Driessen, Le-Thu T. Nguyen and Filip Du Prez, Polym. Chem. 2013, 4, 2449-2456.