Combining Ring-Opening Multibranching and RAFT Polymerization: Multifunctional Linear–Hyperbranched Block Copolymers via Hyperbranched Macro-Chain-Transfer Agents

The synthesis of a hyperbranched macro-chain-transfer agent for RAFT polymerization of functional methacrylate or methacrylamide monomers was achieved by selectively attaching one single CTA onto hyperbranched polyglycerol dendron analogues. The combination of ring-opening multibranching polymerization of glycidol and subsequent RAFT polymerization of the hyperbranched macro-chain-transfer agents created a new route to a variety of multifunctional linear–hyperbranched block topologies. All linear–hyperbranched block copolymers could be synthesized with controlled molecular weight (<i>M</i>_n = 3.2–43.7 kg/mol) and low polydispersity (PDI = 1.15–1.34). As first examples for this universal approach, we present block copolymer syntheses with thermoresponsive methacrylate (tri­(ethylene glycol) methyl ether methacrylate) and biocompatible methacrylamide (2-hydroxypropylmethacrylamide). Because of the presence of dithiobenzoate esters at the end of each linear polymer chain end, selective end-group modification with functional methanethiosulfonates for bioconjugation to proteins (via the biotin–avidin interaction) or drugs (and dyes as model compounds, respectively) could be achieved. This expands the scope of this class of polymer architectures and renders the obtained multifunctional linear–hyperbranched block copolymers applicable as topologically advanced polymeric drug delivery systems

Conducting Polymer with Orthogonal Catechol and Disulfide Anchor Groups for the Assembly of Inorganic Nanostructures

To combine several inorganic components with organic material in a controlled special and permanent manner still remains a difficult issue. Two specifically functionalized block copolymers were synthesized separately and combined in a second step. A heterofunctional poly­(ethylene glycol) (PEG) block copolymer bearing a single amino unit, a short PEG spacer, and multiple catechol functionalities was obtained via anionic ring-opening polymerization (AROP). Using the reversible addition–fragmentation chain transfer (RAFT) radical polymerization technique, a semiconducting block copolymer with carbazole side groups was obtained. The second polyacrylate block contained reactive ester groups and was polymerized onto this hole conducting block. By substitution of the reactive esters with the amino functional PEG-catechol block copolymer and cysteamine methyl disulfide, a hole conducting polymer material with two orthogonal anchor groups for the coating of CdSe QDs, and also for TiO₂, was obtained. TEM images show that upon coating of both materials we were able to obtain QDs homogeneously distributed at the surface of TiO₂ nanoparticles. This spatial assembly is a consequence of the special directing features of the copolymer, possessing two orthogonal anchor groups combined in one material

Interaction of pHPMA–pLMA Copolymers with Human Blood Serum and Its Components

Immediately after administration, polymer therapeutics are exposed to complex biological media like blood which may influence and alter their physicochemical properties due to interactions with proteins or serum components. Among such interactions those leading to larger sized aggregates can be sensitively detected by dynamic light scattering (DLS) as a pre <i>in vivo</i> screening method. Random copolymers from <i>N</i>-(2-hydroxypropyl)­methacrylamide and lauryl methacrylate p­(HPMA-<i>co</i>-LMA) and copolymers loaded with the model drug domperidone were characterized by DLS in isotonic salt solution and in blood serum. The bare amphiphilic copolymer micelles (<i>R</i>_h = 30 nm in isotonic salt solution) formed large aggregates in serum of over 100 nm radius which were shown to originate from interactions with very low density lipoproteins (VLDLs). Encapsulation of the hydrophobic drug domperidone resulted, at first, in drug–copolymer formulations with larger hydrodynamic radii (39 nm < <i>R</i>_h < 49 nm) which, however, did not induce aggregate formation in human serum. Since p­(HPMA-<i>co</i>-LMA) copolymers were demonstrated to have a high potential for drug delivery into the brain, the knowledge of serum–copolymer interactions provides a better understanding of their function in the biological context

A Minimal Hydrophobicity Is Needed To Employ Amphiphilic p(HPMA)-co-p(LMA) Random Copolymers in Membrane Research

Because a polymer environment might be milder than a detergent micelle, amphiphilic polymers have attracted attention as alternatives to detergents in membrane biochemistry. The polymer poly­[<i>N</i>-(2-hydroxypropyl)-methacrylamid] [p­(HPMA)] has recently been modified with hydrophobic lauryl methacrylate (LMA) moieties, resulting in the synthesis of amphiphilic p­(HPMA)-co-p­(LMA) polymers. p­(HPMA)-co-p­(LMA) polymers with a LMA content of 5 or 15% have unstable hydrophobic cores. This, on one hand, promotes interactions of the hydrophobic LMA moieties with membranes, resulting in membrane rupture, but at the same time prevents formation of a hydrophobic, membrane mimetic environment that is sufficiently stable for the incorporation of transmembrane proteins. On the other hand, the p­(HPMA)-co-p­(LMA) polymer with a LMA content of 25% forms a stable hydrophobic core structure, which prevents hydrophobic interactions with membrane lipids but allows stable incorporation of membrane proteins. On the basis of our data, it becomes obvious that amphiphilic polymers have to have threshold hydrophobicities should an application in membrane protein research be anticipated

Aggregation Behavior of Amphiphilic p(HPMA)-<i>co</i>-p(LMA) Copolymers Studied by FCS and EPR Spectroscopy

A combined study of fluorescence correlation spectroscopy and electron paramagnetic resonance spectroscopy gave a unique picture of p­(HPMA)-<i>co</i>-p­(LMA) copolymers in aqueous solutions, ranging from the size of micelles and aggregates to the composition of the interior of these self-assembled systems. P­(HPMA)-<i>co</i>-p­(LMA) copolymers have shown high potential as brain drug delivery systems, and a detailed study of their physicochemical properties can help to elucidate their mechanism of action. Applying two complementary techniques, we found that the self-assembly behavior as well as the strength of hydrophobic attraction of the amphiphilic copolymers can be tuned by the hydrophobic LMA content or the presence of hydrophobic molecules or domains. Studies on the dependence of the hydrophobic lauryl side chain content on the aggregation behavior revealed that above 5 mol % laury side-chain copolymers self-assemble into intrachain micelles and larger aggregates. Above this critical alkyl chain content, p­(HPMA)-<i>co</i>-p­(LMA) copolymers can solubilize the model drug domperidone and exhibit the tendency to interact with model cell membranes

Linear-Hyperbranched Graft-Copolymers via <i>Grafting-to</i> Strategy Based on Hyperbranched Dendron Analogues and Reactive Ester Polymers

The synthesis of hyperbranched polyglycerol dendron analogues with precisely one focal amino functionality (H₂N-<i>hb</i>PG) and their use for the synthesis of linear-hyperbranched graft-copolymers in a grafting-to approach is reported. By use of <i>N</i>,<i>N</i>-dibenzyl tris­(hydroxylmethyl) aminomethane as a novel initiator for the ring-opening multibranching polymerization of glycidol, dendron analogues with one focal amino functionality of molecular weights ranging from 500 to 15000 g mol^–1 and narrow to moderate polydispersities (<i>M</i>_w/<i>M</i>_n = 1.2–1.9) were synthesized, as confirmed by NMR and SEC. After removal of the benzyl protective groups, the accessibility and selective transformation of the focal amino group was demonstrated by NMR and MALDI–ToF MS. H₂N-<i>hb</i>PG was then selectively grafted to a linear reactive ester polymer backbone, poly­(pentafluorophenol methacrylate) (PPFPMA), to obtain linear polymers with highly branched side chains of high molecular weights (<i>M</i>_n > 126 kg mol^–1) and low polydispersities (<i>M</i>_w/<i>M</i>_n = 1.1–1.3), as shown by SEC. Successful attachment of the hyperbranched polyether structure to the linear backbone was confirmed by ¹⁹F NMR and fluorescence spectroscopy. The modular approach introduced bears some analogy to the convergent dendrimer synthesis and describes the first linear-hyperbranched graft-copolymers prepared in a <i>grafting-to</i> approach, resulting in hyperbranched brush-type polymers with the highest molecular weight reported to date

Design, Synthesis, and Use of Y‑Shaped ATRP/NMP Surface Tethered Initiator

Heterogeneous polymer brushes on surfaces can be easily formed from a binary initiator on a silicon oxide substrate where two different types of polymers can be grown side-by-side. Herein, we designed a new Y-shaped binary initiator using straightforward chemistry for “grafting from” polymer brushes. This initiator synthesis takes advantage of the Passerini reaction, a multicomponent reaction combining two initiator sites and one surface linking site. This Y-shaped binary initiator can be synthesized in three steps with a higher yield than other similar initiators reported in the literature, and can be performed on a multigram scale. We were able to attach the initiator to a silicon oxide substrate and successfully grow polymer brushes from both initiators (separately and in combination), confirmed by NEXAFS, AFM, and contact angle

Electrochemically Induced Reversible and Irreversible Coupling of Triarylamines

The electrochemical coupling and dimerization behavior of the low molecular compounds triphenylamine (<b>TPA</b>) and 9-phenylcarbazole (<b>PHC</b>) in comparison to tri-<i>p</i>-tolylamine (<i><b>p</b></i><b>-TTA</b>) with para-blocked methyl groups has been investigated in detail. In contrast to the unsubstituted radical cations of <b>TPA</b> and <b>PHC</b>, the radical cations of <i><b>p</b></i><b>-TTA</b> are stable in the radical cation state and do not undergo any further coupling reactions. However, we found that the dicationic state of <i><b>p</b></i><b>-TTA</b> does undergo two different competitive reaction pathways: (1) an irreversible intramolecular coupling reaction which leads to phenylcarbazole moieties and (2) a reversible intermolecular dimerization leading to charged σ-dimers. The σ-dimers become decomposed upon discharging at low potentials (<i>E</i>_pc = −0.97 V vs Fc/Fc⁺) so that the starting monomer <i><b>p</b></i><b>-TTA</b> is partially regenerated. In particular, the reversible dimerization reaction has not been described in literature so far. Polymeric systems containing para-methyl blocked triarylamines in the side chain exhibit similar coupling behavior upon electrochemical doping

Copolymerization of Polythiophene and Sulfur To Improve the Electrochemical Performance in Lithium–Sulfur Batteries

We first report on the copolymerization of sulfur and allyl-terminated poly­(3-hexylthiophene-2,5-diyl) (P3HT) derived by Grignard metathesis polymerization. This copolymerization is enabled by the conversion of sulfur radicals formed by thermolytic cleavage of S₈ rings with allyl end-group. The formation of a C–S bond in the copolymer is characterized by a variety of methods, including NMR spectroscopy, size exclusion chromatography, and near-edge X-ray absorption fine spectroscopy. The <b>S-P3HT</b> copolymer is applied as an additive to sulfur as cathode material in lithium–sulfur batteries and compared to the use of a simple mixture of sulfur and P3HT, in which sulfur and P3HT were not covalently linked. While P3HT is incompatible with elementary sulfur, the new <b>S-P3HT</b> copolymer can be well dispersed in sulfur, at least on the sub-micrometer level. Sulfur batteries containing the <b>S-P3HT</b> copolymer exhibit an enhanced battery performance with respect to the cycling performance at 0.5C (799 mAh g^–1 after 100 cycles for <b>S-P3HT</b> copolymer versus only 544 mAh g^–1 for the simple mixture) and the C-rate performance. This is attributed to the attractive interaction between polysulfides and P3HT hindering the dissolution of polysulfides and the charge transfer (proven by electrochemical impedance spectroscopy) due to the homogeneous incorporation of P3HT into sulfur by covalently linking sulfur and P3HT

Size-Dependent Knockdown Potential of siRNA-Loaded Cationic Nanohydrogel Particles

To overcome the poor pharmacokinetic conditions of short double-stranded RNA molecules in RNA interference therapies, cationic nanohydrogel particles can be considered as alternative safe and stable carriers for oligonucleotide delivery. For understanding key parameters during this process, two different types of well-defined cationic nanohydrogel particles were synthesized, which provided nearly identical physicochemical properties with regards to their material composition and resulting siRNA loading characteristics. Yet, according to the manufacturing process using amphiphilic reactive ester block copolymers of pentafluorophenyl methacrylate (PFPMA) and tri­(ethylene glycol)­methyl ether methacrylate (MEO₃MA) with similar compositions but different molecular weights, the resulting nanohydrogel particles differed in size after cross-linking with spermine (average diameter 40 vs 100 nm). This affected their knockdown potential significantly. Only the 40 nm sized cationic nanogel particles were able to generate moderate gene knockdown levels, which lasted, however, up to 3 days. Interestingly, primary cell uptake and colocalization studies with lysosomal compartments revealed that only these small sized nanogels were able to avoid acidic compartments of endolysosomal uptake pathways, which may contribute to their knockdown ability exclusively. To that respect, this size-dependent intracellular distribution behavior may be considered as an essential key parameter for tuning the knockdown potential of siRNA nanohydrogel particles, which may further contribute to the development of advanced siRNA carrier systems with improved knockdown potential