Synthesis of an Amphiphilic β‑Turn Mimetic Polymer Conjugate

A new biomimetic polymer containing a beta-turn mimetic element (<b>1</b>) was synthesized, using a combination of living carbocationic polymerization (LCCP), amidation, and “click” chemistry. Two different α-ω-functionalized polyisobutylenes (PIBs <b>3</b> and <b>5</b>) bearing either an alkyne group (PIB <b>3</b>) or a primary amine group (PIB <b>5</b>) were directly synthesized via LCCP. The linking of the two PIB strands with the closely positioned carboxyl/azido moieties of a β-turn dipeptide (BTD) <b>2</b> was achieved via a sequence of amidation reaction and the Cu^I-mediated azide/alkyne “click” reaction. By means of size exclusion chromatography (SEC), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), NMR spectroscopy, and LC/MALDI-TOF MS, a detailed structural proof of the β-turn mimetic PIB conjugate (<b>1</b>) was possible

Monitoring ROMP Crossover Chemistry via ESI-TOF MS

We report on the ESI-TOF MS investigation of oligomerization and co-oligomerization reactions via ring-opening metathesis polymerization of noncharged monomers. Thus, the monomers <b>1</b>–<b>4</b> ((±)<i>endo</i>,<i>exo</i>-bicyclo­[2,2,1]­hept-5-ene-2,3-dicarboxylic acid-bis-<i>O</i>-methyl ester (<b>1</b>), <i>exo</i>-<i>N</i>-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-10-oxa-4-azatricyclodec-8-ene-3,5-dione (<b>2</b>), 3-methyl-3-phenylcyclopropene (<b>3</b>), and (±)<i>endo</i>,<i>exo</i>-bicyclo­[2,2,1]­hept-5-ene-2,3-dicarboxylic acid-bis-<i>O</i>-2,2,6,6-tetramethylpiperidinoxyl ester (<b>4</b>)) were investigated with the catalysts <b>5</b>–<b>8</b> (Grubbs catalyst first generation (<b>5</b>), Grubbs catalyst third generation (<b>6</b>), Umicore M1 (<b>7</b>), and Umicore M3 (<b>8</b>)) with respect to their crossover chemistries. Monomers <b>1</b>–<b>4</b> differ in ring size and substitution patterns and allow to study the monomer reactivities in the order of increasing reactivity for monomer <b>3</b> < <b>4</b> ≈ <b>1</b> < <b>2</b>. The measured spectra display a significant difference between the reactions conducted with first- and third-generation catalysts with the main fraction being unreacted catalyst species for the first-generation catalysts <b>5</b> and <b>7</b>, while just a small fraction is composed of oligomer and co-oligomer species. A significant reduction of the amount of the catalyst species and an increase in the fractions of oligomer and co-oligomer species are observed for the third-generation catalysts <b>6</b> and <b>8</b>, in accordance with their higher reactivity as compared to the first-generation catalysts. The highest fraction of co-oligomer species is observed for the crossover reactions <b>1/3</b> and <b>1</b>/<b>4</b>. Propagation of the second monomer, however, is only observed in the combinations <b>1</b>/<b>2</b> and <b>1</b>/<b>4</b> indicative of the higher reactivity of the norbornenes <b>2</b> and <b>4</b> when compared to the cyclopropene <b>3</b>, the latter requiring the addition of hydrochloric acid

Autocatalysis in the Room Temperature Copper(I)-Catalyzed Alkyne–Azide “Click” Cycloaddition of Multivalent Poly(acrylate)s and Poly(isobutylene)s

The concept of self-healing polymers requires fast and efficient cross-linking processes, ideally based on catalytic reactions. We investigate autocatalytic effects in cross-linking processes based on the copper­(I)-catalyzed alkyne–azide “click” cycloaddition reaction (CuAAC), taking advantage of the 1,3-triazole rings formed during the CuAAC-based cross-linking, which act as ligands for subsequent “click”-reactions in turn accelerating the reaction rate of subsequent CuAAC-reactions. Catalysis during the cross-linking reactions of multivalent polymeric alkynes and azides (nine atactic random poly­(propargyl acrylate-<i>co</i>-<i>n</i>-butyl acrylate)­s, <i>M</i>_n = 7000–23400 g/mol) prepared via nitroxide mediated polymerization (NMP) and displaying alkyne-contents ranging from 2.7 mol % to 14.3 mol % per chain were studied via melt-rheology and differential scanning calorimetry (DSC), revealing significant increases of the reaction rate with increasing alkyne-concentrations. A kinetic analysis showed autocatalytic effects (up to a factor of 4.3) now enabling a deeper understanding of the catalysis as well as on the achievement of a “click”-cross-linking concept acting at room temperature. Effects exerted by the molecular weight were investigated by reacting five three-arm-star azido-telechelic poly­(isobutylene)­s (PIB’s) (<i>M</i>_n = 5500–30000 g/mol) and one three-arm-star alkyne-telechelic PIB (<i>M</i>_n = 6300 g/mol) in the cross-linking-reaction, thus linking molecular mobility to changes in CuAAC-reactivity revealing faster network formation with lower molecular weights. The now designable significant autocatalytic effects together with the optimized reaction rate via the lowest molecular weight compounds enabled the design of a new, highly efficient and fast cross-linking system acting at room temperature

Orthogonal Modification of Polymers via Thio–Bromo “Click” Reaction and Supramolecular Chemistry: An Easy Method Toward Head-to-Tail Self-Assembled Supramolecular Polymers

Heterotelechelic poly­(<i>n</i>-butyl acrylate)­s (P<i>n</i>BuA) bearing two different and complementing supramolecular groups (namely, barbiturate (Ba) and the Hamilton wedge (HW)) at their α-end and ω-end (Ba–P<i>n</i>BuA–HW) were prepared by a combination of the reversible addition–fragmentation chain transfer (RAFT) process and the thio–bromo click reaction. The successful synthesis of the heterotelechelic H-bonding polymer Ba–P<i>n</i>BuA–HW (<i>M</i>_n,NMR = 7700 g/mol, <i>M</i>_n,SEC = 7500 g/mol, PDI = 1.25) was proven by a combination of ¹H NMR and MALDI-TOF mass spectrometry. Self-assembly of the resulting heterotelechelic H-bonding polymers (Ba–P<i>n</i>BuA–HW) in a head-to-tail fashion driven by multiple H-bondings in solution and in the bulk was proven by temperature-dependent ¹H NMR, concentration-dependent DOSY NMR studies, and rheological measurements

Hydrogen-Bonded Polymer Nanomedicine with AIE Characteristic for Intelligent Cancer Therapy

One of the major goals of biomedical science is to pioneer advanced strategies toward precise and smart medicine. Hydrogen-bonding (H-bonding) assembly incorporated with an aggregation-induced emission (AIE) capability can serve as a powerful tool for developing supramolecular nanomedicine with clear tumor imaging and smart therapeutic performance. We here report a H-bonded polymeric nanoformulation with an AIE characteristic toward smart antitumor therapy. To do so, we first design a structurally novel tetraphenylethylene (TPE)-based H-bonding theranostic prodrug, TPE-(FUA)4, characterized by four chemotherapeutic fluorouracil-1-acetic acid (FUA) moieties arched to the TPE core. A six-arm star-shaped amphiphilic polymer vehicle, P(DAP-co-OEGEA)6, is prepared, bearing hydrophilic and biocompatible POEGEA (poly(oligo (ethylene glycol) ethyl acrylate) segments, along with a hydrophobic and H-bonding PDAP (poly(diaminopyridine acrylamide)) segment. Thanks to the establishment of the DAP/FUA H-bonding association, incorporating the TPE-(FUA)4 prodrug to the P(DAP-co-OEGEA)6 vehicle can yield H-bond cross-linked nanoparticles with interpenetrating networks. For the first time, AIE luminogens are interwoven into a six-arm star-shaped polymer via an intrinsic H-bonding array of the chemotherapeutic agent FUA, thus imposing an effective restriction of TPE molecular rotations. Concomitantly, encapsulated photothermal agent (IR780) via a hydrophobic interaction facilitates the formation of nanoassemblies, TPE-(FUA)4/IR780@P(DAP-co-OEGEA)6, featuring synergistic cancer chemo/photothermal therapy (CT/PTT). Our study can contribute a practical solution to fulfill biomedical requirements with a conductive advance in precision nanomedicine

Crystallization of Supramolecular Pseudoblock Copolymers

Because of the presence of supramolecular bonds, the crystallization process of supramolecular pseudoblock copolymers (SPBCP) is more complex in comparison to conventional covalently bonded block copolymers (BCP). Thus, supramolecular binding motives included on the polymer chain-ends display additional dynamic effects as well as possible nuclei for the crystallization. In this article we systematically study nonisothermal crystallization processes in SPBCP’s consisting of a crystallizable poly­(ε-caprolactone) (PCL) connected via triple hydrogen bonds to either a short alkyl-modified 2,4-diaminotriazine, or bound to a large block of amorphous poly­(isobutylene) (PIB). The crystallization of the PCL is studied with both groups acting as supramolecular barriers for the crystallization process, either during nucleation or during crystal growth. A strong influence of the short alkyl-modified 2,4-diaminotriazine barrier on the crystallization temperature of the PCL compared to the control sample devoid of this compound is observed. In contrast, the large polymer block (PIB) acting as a barrier causes a strong decrease of the crystallization temperature and fractionated crystallization of SPBCP consisting of smaller PCL-chains is observed

Phase Changes in Mixed Lipid/Polymer Membranes by Multivalent Nanoparticle Recognition

Selective addressing of membrane components in complex membrane mixtures is important for many biological processes. The present paper investigates the recognition between multivalent surface functionalized nanoparticles (NPs) and amphiphilic block copolymers (BCPs), which are successfully incorporated into lipid membranes. The concept involves the supramolecular recognition between hybrid membranes (composed of a mixture of a lipid (DPPC or DOPC), an amphiphilic triazine-functionalized block copolymer TRI-PEO₁₃-<i>b</i>-PIB₈₃ (BCP <b>2</b>), and nonfunctionalized BCPs (PEO₁₇-<i>b</i>-PIB₈₇ BCP <b>1</b>)) with multivalent (water-soluble) nanoparticles able to recognize the triazine end group of the BCP <b>2</b> at the membrane surface via supramolecular hydrogen bonds. CdSe-NPs bearing long PEO₄₇-thymine (THY) polymer chains on their surface specifically interacted with the 2,4-diaminotriazine (TRI) moiety of BCP <b>2</b> embedded within hybrid lipid/BCP mono- or bilayers. Experiments with GUVs from a mixture of DPPC/BCP <b>2</b> confirm selective supramolecular recognition between the THY-functionalized NPs and the TRI-functionalized polymers, finally resulting in the selective removal of BCP <b>2</b> from the hybrid vesicle membrane as proven via facetation of the originally round and smooth vesicles. GUVs (composed of DOPC/BCP <b>2</b>) show that a selective removal of the polymer component from the fluid hybrid membrane results in destruction of hybrid vesicles via membrane rupture. Adsorption experiments with mixed monolayers from lipids with either BCP <b>2</b> or BCP <b>1</b> (nonfunctionalized) reveal that the THY-functionalized NPs specifically recognize BCP <b>2</b> at the air/water interface by inducing significantly higher changes in the surface pressure when compared to monolayers from nonspecifically interacting lipid/BCP <b>1</b> mixtures. Thus, recognition of multivalent NPs with specific membrane components of hybrid lipid/BCP mono- and bilayers proves the selective removal of BCPs from mixed membranes, in turn inducing membrane rupture. Such recognition events display high potential in controlling permeability and fluidity of membranes (e.g., in pharmaceutics)

2D-LC/SEC-(MALDI-TOF)-MS Characterization of Symmetric and Nonsymmetric Biocompatible PEO_<i>m</i>–PIB–PEO_<i>n</i> Block Copolymers

Complex copolymer mixtures can be directly analyzed via multidimensional chromatographic techniques after successful synthesis. High-performance liquid chromatography coupled to size exclusion chromatography (LC/SEC) revealed detailed information on the chemical composition, polymeric structure, and molar mass distribution of copolymer mixtures, in particular of symmetric and nonsymmetric α-TEO-ω-PEO telechelic PIB copolymers. A series of azide/alkyne “click” reactions after living polymerization reactions were used to prepare the either symmetric or nonsymmetric PIB–PEO-based triblock copolymers of the general structure (PEO_<i>n</i>–PIB–PEO_<i>m</i> BCPs (with <i>n</i> = 3; <i>m</i> = 3, 12, or 17)). In order to demonstrate the efficiency of the “click” reaction and thus the purity of the final triblock copolymers, the critical conditions of the PIB-homopolymers (<i>M</i>_n = 3–30 kg mol^–1) in the isocratic elution mode (LCCC) were investigated. Thus, it was possible to separate the final polymers from their intermediates using a reversed-phase Atlantis-RP C18 column as stationary phase and a mixture of methyl-<i>tert</i>-butyl ether/methanol (85.34/14.66 (w/w)) as mobile phase. On the basis of the PEO segment length and overall hydrophobicity of the BCPs, we observed a complete separation of the stepwise “click” products. Finally, direct coupling of the 2D-LC/SEC to (MALDI-TOF) mass spectrometric techniques allowed a clear identification of all reaction steps proving the structure of the final symmetric and nonsymmetric triblock copolymers

Nanostructure and Rheology of Hydrogen-Bonding Telechelic Polymers in the Melt: From Micellar Liquids and Solids to Supramolecular Gels

Polymers with hydrogen-bonding groups in the melt state often combine the ability to form specific supramolecular bonds with a tendency for unspecific aggregation and microphase separation. Using a combination of small-angle X-ray scattering and shear spectroscopy, we present a study of structure formation and rheological properties of such a case, an exemplary series of telechelic polyisobutylenes, functionalized with hydrogen-bonding end groups. Unspecific interaction between hydrogen-bonding groups leads to the formation of micelles. For monofunctional samples, we observe ordering at lower temperatures, induced by a temperature dependent concentration of the micelles. The rheological properties of these systems can be mapped to the behavior of a concentrated colloidal fluid or solid. For bifunctional polymers with complementary hydrogen-bonding groups, interaction between micellar aggregates leads to network formation and solidlike properties at lower temperatures induced by gelation without ordering. Only in this case the supramolecular bonds directly determine the rheological properties