Four-arm Star Polymers Research Articles

Construction and evaluation of novel αvβ3 integrin ligand-conjugated ultrasmall star polymer micelles targeted glomerular podocytes through GFB permeation

As glomerular cells, podocytes are the last line of defense for glomerular filtration barriers (GFB) and play a critical role in chronic kidney disease (CKD). Podocyte-targeted drug delivery is a promising direction in the treatment of CKD. In this study, we constructed four-arm star polymers conjugated with a novel linear RWrNM peptide. And poly ε-caprolactone (PCL) hydrophobic core and brush poly (2-hydroxyethyl methacrylate) (PHEMA) hydrophilic shell were synthesized by ROP and SET LRP polymerization. The PHEMA modified by succinic anhydride was coupled with the novel linear RWrNM peptide, and then the PCL hydrophobic core was loaded with dexamethasone acetate (Dexac) to form micelles with stable dimensions. Our findings showed that the novel micelles had an ultrasmall particle size of 16–30 nm. We, for the first time, showed that the specific affinity of the novel linear RWrNM peptide to primary podocytes (24.9 ± 1.7 times of the free RhB uptake) through the αvβ3 integrin receptor mediation was comparable to that of B16F10 cells (24.4 ± 1.2 times of the free RhB uptake). In vivo studies showed that the novel ultrasmall micelles possessed a significant kidney-targeted effect, excellent podocyte colocalization effect, and GFB permeability at 49%–60 % in normal SD rats. Besides, the novel ultrasmall micelles decreased the plasma elimination half-life of Dexac to 1.62–2.09 h and showed good safety in vitro and in vivo. Both in vitro and in vivo results demonstrated the novel ultrasmall micelles could be used as a promising drug delivery strategy for actively targeted therapy of CKD.

Smart micelles self-assembled from four-arm star polymers as potential drug carriers for pH-triggered DOX release

A series of amphiphilic four-arm star polymers poly(e-caprolactone)-b-poly(2-(diethylamino)ethylmethacrylate) (4AS-PCL-b-PDMAEMA) were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The molecular structures of the copolymers were confirmed with 1H NMR, FT-IR and gel permeation chromatography (GPC). The critical micelle concentration (CMC) values of the star polymers in aqueous solution were extremely low (3.0–4.1 mg/L).In aqueous solution, the copolymers self-assemble into blank and doxorubicin (DOX)-loaded micelles with an average size of 56–150 nm measured by scanning electron microscopy (SEM) and dynamic light scattering (DLS), which consist of outer shell with blocks PDMAEMA and inner core with blocks PCL. The core block PCL was used to contain drug molecules and shell block PDMAEMA could protonize responding to acidic condition. The in vitro release behavior showed that the micelle structure remains basically unchanged, and the drug cumulative release was only 24.5% at pH 7.4, and at pH 5.0, PDMAEMA is protonated and the micelles swell, which accelerates the release rate of DOX and the cumulative release is higher than pH 7.4. Through the semi-empirical model, the mechanism of drug release process was analyzed, and the mechanism of drug release from polymer micelles was further explored. The in vitro cytotoxicity indicated that the 4AS-PCL-b-PDMAEMA materials had low toxicity, but the DOX-loaded micelles had an obvious inhibitory effect on the HepG2 cells. The results indicate the four-arm star polymers 4AS-PCL-b-PDMAEMA may be a potential drug carriers for pH-triggered DOX release.

Anomalous Confinement Slows Surface Fluctuations of Star Polymer Melt Films.

The unusually large film thickness at which confinement effects manifest themselves in surface fluctuations of unentangled four-arm star polymers has been defined using film thicknesses from 10Rg to 107Rg. For 15k four-arm star polystyrene (SPS), confinement appears at a thickness between 112 nm (40Rg) and 72 nm (26Rg), which is remarkably larger than the thicknesses at which confinement appears for unentangled 6k linear (<15 nm, <7Rg) and 6k and 14k cyclic (24 and 22 nm, respectively) polystyrenes. Data for 15k star films can be rationalized using a two-layer model with a 17 nm (6Rg) thick highly viscous layer at the substrate, which is significantly thicker than the 1Rg thick "irreversibly adsorbed" layer. For a 29 nm (10Rg) thick film, more striking confinement occurs due to the combined influence of both interfaces. These results underscore the extraordinary role long-chain branching plays in dictating surface fluctuations of thin films.

Topological Structure of Networks Formed from Symmetric Four-Arm Precursors

Gels formed by coupling two different four-arm star polymers lead to polymer networks with high strength and low spatial heterogeneity. However, like all real polymer networks, these materials contain topological defects which affect their properties. In this study, kinetic graph theory and Monte Carlo simulation are used to investigate the structure and cyclic defects formed via A–B type end-linking of symmetric tetra-arm star polymer precursors. While loops constituting of odd number of junctions are forbidden by precursor chemistry, the amount and the correlation of secondary loops are found to increase with decreasing precursor concentration. This suppresses gelation, and the delay of gel point is quantitatively predicted by the topological simulations. Furthermore, comparison with network formed with asymmetric bifunctional–tetrafunctional precursors revealed that the behavior of loops consisting of 2n junctions in the symmetric system is analogous to the behavior of loops consisting of n junctions i...

Self-Assembly of Telechelic Tyrosine End-Capped PEO Star Polymers in Aqueous Solution.

We investigate the self-assembly of two telechelic star polymer-peptide conjugates based on poly(ethylene oxide) (PEO) four-arm star polymers capped with oligotyrosine. The conjugates were prepared via N-carboxy anhydride-mediated ring-opening polymerization from PEO star polymer macroinitiators. Self-assembly occurs above a critical aggregation concentration determined via fluorescence probe assays. Peptide conformation was examined using circular dichroism spectroscopy. The structure of self-assembled aggregates was probed using small-angle X-ray scattering and cryogenic transmission electron microscopy. In contrast to previous studies on linear telechelic PEO-oligotyrosine conjugates that show self-assembly into β-sheet fibrils, the star architecture suppresses fibril formation and micelles are generally observed instead, a small population of fibrils only being observed upon pH adjustment. Hydrogelation is also suppressed by the polymer star architecture. These peptide-functionalized star polymer solutions are cytocompatible at sufficiently low concentration. These systems present tyrosine at high density and may be useful in the development of future enzyme or pH-responsive biomaterials.

A dual crosslinked self-healing system: Supramolecular and covalent network formation of four-arm star polymers

Restoration of large volume damage together with mechanical stability of self-healing polymers requires fast and efficient reversible crosslinking processes together with the presence of a static network. We investigate four-arm star polymers as a dual self-healing material, equipped with hydrogen bonding moieties and azide endgroups applicable for crosslinking based on “click” cycloaddition reaction (CuAAC). The concepts takes advantage of additional supramolecular network formation due to supramolecular cluster formation. To this effect four-arm star poly(isobutylene)s were prepared via living carbocationic polymerization (LCCP) in combination with simple endgroup transformation steps and microwave-assisted click-chemistry to introduce thymine moieties as supramolecular tie points. Four-arm star thymine-telechelic PIB was obtained as a tough rubbery material as proven via melt-rheology and SAXS measurements with clusters of ≈10 hydrogen bonding moieties resulting in a self-healing response at room temperature. To enable the design of a doubly crosslinked self-healing system, four-arm star PIBs bearing an average of 1.7 azide groups and 2.3 thymine endgroups/polymer were crosslinked with a three-arm star alkyne-telechelic PIB. A weakly crosslinked covalent network reinforced by supramolecular hydrogen bonding interactions was obtained in which “click”-crosslinking reduces the number of clustered hydrogen bonds from ≈10 to ≈8. Macroscopic self-healing studies of the double covalent and supramolecular network structure revealed fast and multiple self-healing at 20 °C within 24 h. The now designable four-arm star polymers enabled the design of a highly efficient self-healing system based on double network formation due to “click”-crosslinking and supramolecular cluster formation.

Stability of star-shaped RAFT polystyrenes under mechanical and thermal stress

Well-defined three-arm and four-arm star polymers designed via a Z-group approach carrying trithiocarbonate functionalities at the core are prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization featuring molecular weights of Mn,SEC = 156 kDa, Đ = 1.16 (3-arm) and Mn,SEC = 162 kDa, Đ = 1.15 (4-arm) based on multi-angle laser light scattering (MALLS) detection, respectively. The star-shaped polystyrenes are subjected (in bulk) to thermal stress in the temperature range between 140 and 200 °C from 10 minutes up to 96 h. The thermally treated 3-arm and 4-arm star polymers are analyzed via size exclusion chromatography (SEC) to quantify the degradation process at variable temperatures as a function of time under an argon atmosphere. Cleavage rate coefficients of the star polymers are deduced as a function of temperature, resulting in activation parameters for the cleavage process, i.e. Ea = 131 kJ mol−1; A = 3.93 × 1011 s−1 (Mn,SEC = 156 kDa, Đ = 1.16, 3-arm star) and Ea, = 134 kJ mol−1; A = 9.13 × 1011 s−1 (Mn,SEC = 162 kDa, Đ = 1.15, 4-arm star), respectively. Processing of the star-shaped polymers is mimicked via a small scale counter rotating twin screw extrusion to achieve nonlinear shear and elongation flow under pressure. Furthermore, a rheological assessment via the linear shear deformation region (small amplitude oscillatory shear, SAOS) allows for a correlation of the processing conditions with the thermal degradation properties of the star polymers in the melt. Zero shear viscosity (η0) as a criterion of the degradation process is measured in the rheometer and correlated to the weight-average molecular weight, Mw.

Synthesis of well-defined 8-shaped polymers by the combination of RAFT polymerization and click reaction

A series of well-defined 8-shaped polymers have been synthesized by the combination of reversible addition–fragmentation chain transfer (RAFT) polymerization and click reaction. Firstly, well-defined, azide-terminated, four-armed star polymers including poly(N,N-dimethylacrylamide) and polystyrene were prepared by RAFT polymerization using pentaerythritoltetrakis(3-(S-(2-azidoethylcarbonoyl)trithiocarbonyl)propanoate) as a chain transfer agent. Then, intramolecular cyclization of the azide-functionalized four-armed precursors was conducted under highly dilution conditions using a bifunctional N,N-bis(2-propargyloxycarbonyl ethyl)-2-hydroxylethyl amine as the linker, affording 8-shaped polymers. FTIR, 1H NMR, GPC, and MLADI-TOF MS analysis confirmed that the coupling reaction proceeded via the cyclization manner.

Kinetics and Mechanisms of Radical-Based Branching/Cross-Linking Reactions in Preformed Polymers Induced by Benzophenone and Bis-Benzophenone Photoinitiators

The general mechanism for photo-cross-linking of preformed polymers is studied by comparing the efficacy of monofunctional benzophenone (BP) and bifunctional bis-benzophenone (BP-BP) photoinitiators for inducing radical chain branching reactions in glassy polystyrene (PS) and rubbery poly(n-butyl acrylate) (PnBA). Upon UV irradiation, macroradicals form and initiate a variety of cross-linking and scission reactions. The kinetics and mechanisms of these macroradical reactions were monitored by gel permeation chromatography (GPC) measurements of changes in the polymer molecular weight distributions. Molecular weight increases are associated with chain branching while decreases in molecular weight are indicative of chain scission. We study the early stages of radical recombination where branching is manifest as the formation of three- and four-arm star polymers that are soluble and can be detected/differentiated by GPC. Branching is observed even in glassy PS; however, the reactions are much faster in rubbery PnBA, consistent with the expected influence of main chain mobility. At equal chromophore equivalents, BP-BP was found to be more efficient than BP for producing macroradicals, primarily due to a lower degree of self-quenching in BP-BP. When added to glassy PS, the higher efficiency of BP-BP did not translate into more chain branching, except at high additive concentration where the probability of BP-BP chain bridging reactions becomes significant, but instead led to a higher degree of main chain scission. The latter result was attributed to the larger distance between chromophores for BP-BP than for BP at equal benzophenone equivalents. In marked contrast, almost no main chain scission was found for either additive in PnBA, and BP-BP proved more effective for promoting chain branching. The susceptibility to main chain scission is found to be dependent upon the location of radical formation by hydrogen abstraction from the polymer. In PS, radicals can form on the chain backbone, and radical scission reactions lead to fragmentation of the polymer chain. In PnBA, radicals form preferentially on the pendant side chains, and radical scission reactions do not lead to main chain breakage. A simple probability-based model was found to capture the salient features of radiation-induced branching in preformed polymers.

Synthesis and characterization of calixarene-based poly(ε-caprolactone) stars catalyzed by yttrium complex

Two calixarene derivatives (2a, 2b) have been synthesized and used as macro-initiators to prepare star-shaped poly(e-caprolactone)s (SPCLs) via controlled ringopening polymerization of e-caprolactone in the presence of yttrium tris(2,6-di-tert-butyl-4-methylphenolate) [Y(DBMP)3]. The molecular weight of SPCLs was characterized by end group 1H-NMR analyses and size-exclusion chromatography (SEC). The results indicate that SPCLs based on a calix[4]arene derivative (2a) are well-defined four-arm star polymers with reasonably narrow molecular weight distributions in the given molecular weight range, while SPCLs based on a calix[6]arene derivative (2b) are star polymers with not so defined structures. Differential scanning calorimetry (DSC) analyses suggest that the maximal melting point, the crystallization temperature and the degree of crystallinity of SPCLs increases with the increasing molecular weight and are lower than those of the liner poly(e-caprolactone) (LPCL) counterpart. Furthermore, polarized optical microscopy (POM) indicates that SPCL exhibits irregular spherulites with poor morphology and slower crystallization rate, whereas LPCL shows fast crystallization rate and good spherulitic morphology.

Synthesis of Photocleavable Linear Macromonomers by ATRP and Star Macromonomers by a Tandem ATRP−Click Reaction: Precursors to Photodegradable Model Networks

Atom transfer radical polymerization (ATRP) and the copper-catalyzed azide−alkyne cycloaddition (CuAAC) were utilized for the synthesis of photodegradable polymeric materials by two complementary schemes. Linear azido-telechelic macromonomers possessing a photocleavable functionality at the center were synthesized by ATRP and subsequent end-group modification. These macromonomers were cross-linked with a tetrafunctional alkyne by CuAAC to form insoluble materials which degraded upon exposure to UV light of 350 nm to yield soluble star polymer products of defined molecular weight. Complementary to this approach, four-armed star polymers possessing photocleavable arms and terminal azides were prepared by a novel one-pot CuAAC/ATRP reaction followed by end-group modification. These star polymers were cross-linked with a linear, bifunctional alkyne to yield insoluble materials which, upon exposure to UV light, degraded to yield linear polymers of defined molecular weight.

Reversible Addition Fragmentation Chain Transfer (RAFT) Polymerization of Methyl Acrylate: Detailed Structural Investigation via Coupled Size Exclusion Chromatography−Electrospray Ionization Mass Spectrometry (SEC−ESI-MS)

The on-line coupling of size exclusion chromatography (SEC) with electrospray ionization mass spectrometry (ESI-MS) was applied to study the polymeric product spectrum generated by the (strongly rate retarded) 2,2‘-azobisisobutyronitrile (AIBN) and 1,1‘-azobis(cyclohexanecarbonitrile) (ACHCN) initiated, cumyl dithiobenzoate (CDB) mediated methyl acrylate (MA) polymerization in detail. Products corresponding to the polymeric reversible addition fragmentation chain transfer (RAFT) agent and the combination and disproportionation termination products (with both cumyl, cyanocyclohexyl, and cyanoisopropyl end groups) along with a product stream arising from an oxidation process of the polymeric RAFT agent yielding sulfines and thioesters could be clearly identified. Termination products associated with the intermediate radical, that is, three- or four-armed star polymers, were not present. There is a degree of ambiguity over the disproportionation product of the macroRAFT radical. The experiments suggest that either the RAFT intermediate disproportionation product or the actual RAFT intermediate radical is present in the ESI-MS spectrum.

Multifunctional ATRP initiators: Synthesis of four-arm star homopolymers of methyl methacrylate and graft copolymers of polystyrene and poly(t-butyl methacrylate)

Tetrakis bromomethyl benzene was used as a tetrafunctional initiator in the synthesis of four-armed star polymers of methyl methacrylate via atom transfer radical polymerization (ATRP) with a CuBr/2,2 bipyridine catalytic system and benzene as a solvent. Relatively low polydispersities were achieved, and the experimental molecular weights were in agreement with the theoretical ones. A combination of 2,2,6,6-tetramethyl piperidine-N-oxyl-mediated free-radical polymerization and ATRP was used to synthesize various graft copolymers with polystyrene backbones and poly(t-butyl methacrylate) grafts. In this case, the backbone was produced with a 2,2,6,6-tetramethyl piperidine-N-oxyl-mediated stable free-radical polymerization process from the copolymerization of styrene and p-(chloromethyl) styrene. This polychloromethylated polymer was used as an ATRP multifunctional initiator for t-butyl methacrylate polymerization, giving the desired graft copolymers.

Linking reactions of living polymers with bromomethylbenzene derivatives: Synthesis and characterization of star homopolymers and graft copolymers with polyelectrolyte branches

Anionic polymerization techniques utilizing 1,2,4,5-tetra(bromomethyl)- benzene as the linking agent were employed for the synthesis of four-arm star polymers with poly(tert-butyl methacrylate) (PtBuMA), poly(methyl methacrylate), poly(tert-butylacrylate) (PtBuA), or poly(2-vinylpyridine) (P2VP) branches. This work was extended through the “grafting onto” method, in combination with anionic polymerization techniques, to synthesize graft copolymers consisting of polystyrene backbones and PtBuA, PtBuMA, or P2VP branches. Postpolymerization reactions were performed to produce graft copolymers with polyelectrolyte branches. Crosslinking reactions were observed in some of the graft materials several months after their preparation. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4337–4350, 1999

Method of determining the degree of branching from the gel permeation chromatogram for star-shaped SBS thermoplastic block copolymers

A novel GPC calculation method has been developed for characterizing star-shaped styrene–butadiene block copolymers (SBS). This method enables us to determine the degree of branching (number of arms per molecule) of the synthesized polymer without the need of a priori measurement of the true molecular weights of the SBS star polymer and its linear polymeric arm. To illustrate the simplicity of this method, nearly monodispersed three-arm and four-arm model star polymers have been purposely synthesized by linking living diblock polymeric arms of the polystyrene-block-polybutadiene type with silicon tetrachloride as the multifunctional linking agent. The good agreement between the degree of branching calculated from the GPC chromatogram and that actually measured by MALL (multiple angle laser light scattering) has corroborated the validity of the calculation method. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 3393–3401, 1997

Phase separation phenomena in aqueous solutions of amphiphilic poly(ethylene oxide) star polymers

Three- and four-armed star polymers with poly(ethylene oxide) arms capped with hydrophobic end-groups were synthesized from nonylphenoxypoly(ethylene glycol)s and well defined tri- and tetraisocyanates. The latter were hydrosilylation products of m-isopropenyl- α, α-dimethylbenzyl isocyanate ( m-TMI). In aqueous solution the arm ends associate, and above a critical star concentration the mixture phase separates into a dilute phase and a condensed gel phase. Their respective polymer concentrations remain constant as long as the two phases coexist, their volume fractions being proportional to the total polymer concentration. Brookfield viscosity measurements confirm the formation of the gel phase which resembles an amphiphilic hydrogel. It exhibits a high affinity for hydrophobic compounds.

Computer simulation of the dynamics of shape fluctuations in uniform star polymers

The dynamics of uniform three- and four-arm star polymers were studied by means of Monte Carlo simulation using the bond fluctuation model originated by Carmesin and Kremer extended to three dimensions. It is found that the relaxation times of the fluctuations of the extensions along the principal axes obey a generalized dynamic scaling relationship. The rigid-body rotations do not relax exponentially but instead show Kohlrausch-Williams-Watts behavior

Behavior of starlike polymers between walls

The behavior of four-armed star polymers between walls is studied via off-lattice Monte Carlo simulations. The molecules consist of a central bead with four arms of five beads each protruding from it. Simulation results for density profiles and global properties are reported for a volume fraction of 0.3 and a wall separation of 16 bead diameters. The behavior of these molecules is found to be similar to that of linear polymers between walls