Linear-dendritic Block Copolymers Research Articles

Colloidal inverse bicontinuous cubic membranes of block copolymers with tunable surface functional groups.

Analogous to the complex membranes found in cellular organelles, such as the endoplasmic reticulum, the inverse cubic mesophases of lipids and their colloidal forms (cubosomes) possess internal networks of water channels arranged in crystalline order, which provide a unique nanospace for membrane-protein crystallization and guest encapsulation. Polymeric analogues of cubosomes formed by the direct self-assembly of block copolymers in solution could provide new polymeric mesoporous materials with a three-dimensionally organized internal maze of large water channels. Here we report the self-assembly of amphiphilic dendritic-linear block copolymers into polymer cubosomes in aqueous solution. The presence of precisely defined bulky dendritic blocks drives the block copolymers to form spontaneously highly curved bilayers in aqueous solution. This results in the formation of colloidal inverse bicontinuous cubic mesophases. The internal networks of water channels provide a high surface area with tunable surface functional groups that can serve as anchoring points for large guests such as proteins and enzymes.

Supramolecular Dendritic Polymers: From Synthesis to Applications

CONSPECTUS: Supramolecular dendritic polymers (SDPs), which perfectly combine the advantages of dendritic polymers with those of supramolecular polymers, are a novel class of non-covalently bonded, highly branched macromolecules with three-dimensional globular topology. Because of their dynamic/reversible nature, unique topological structure, and exceptional physical/chemical properties (e.g., low viscosity, high solubility, and a large number of functional terminal groups), SDPs have attracted increasing attention in recent years in both academic and industrial fields. In particular, the reversibility of non-covalent interactions endows SDPs with the ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, such as pH, temperature, light, stress, and redox agents, which further provides a flexible and robust platform for designing and developing smart supramolecular polymeric materials and functional supramolecular devices. The existing SDPs can be systematically classified into the following six major types according to their topological features: supramolecular dendrimers, supramolecular dendronized polymers, supramolecular hyperbranched polymers, supramolecular linear-dendritic block copolymers, supramolecular dendritic-dendritic block copolymers, and supramolecular dendritic multiarm copolymers. These different types of SDPs possess distinct morphologies, unique architectures, and specific functions. Benefiting from their versatile topological structures as well as stimuli-responsive properties, SDPs have displayed not only unique characteristics or advantages in supramolecular self-assembly behaviors (e.g., controllable morphologies, specific performance, and facile functionalization) but also great potential to be promising candidates in various fields. In this Account, we summarize the recent progress in the synthesis, functionalization, and self-assembly of SDPs as well as their potential applications in a wide range of fields. A variety of synthetic methods using non-covalent interactions have been established to prepare different types of SDPs based on varied mono- or multifunctionalized building blocks (e.g., monomer, dendron, dendrimer, and hyperbranched polymer) with homo- or heterocomplementary units. In addition, SDPs can be further endowed with excellent functionalities by employing different modification approaches involving terminal, focal-point, and backbone modification. Similar to conventional dendritic polymers, SDPs can self-assemble into diverse supramolecular structures such as micelles, vesicles, fibers, nanorings, tubes, and many hierarchical structures. Finally, we highlight some typical examples of recent applications of SDP-based systems in biomedical fields (e.g., controlled drug/gene/protein delivery, bioimaging, and biomimetic chemistry), nanotechnology (e.g., nanoreactors, catalysis, and molecular imprinting), and functional materials. The current research on SDPs is still at the very early stage, and much more work needs to be done. We anticipate that future studies of SDPs will focus on developing multifunctional, hierarchical supramolecular materials toward their practical applications by utilization of cooperative non-covalent interactions.

Responsive Linear‐Dendritic Block Copolymers

The combination of dendritic and linear polymeric structures in the same macromolecule opens up new possibilities for the design of block copolymers and for applications of functional polymers that have self-assembly properties. There are three main strategies for the synthesis of linear-dendritic block copolymers (LDBCs) and, in particular, the emergence of click chemistry has made the coupling of preformed blocks one of the most efficient ways of obtaining libraries of LDBCs. In these materials, the periphery of the dendron can be precisely functionalised to obtain functional LDBCs with self-assembly properties of interest in different technological areas. The incorporation of stimuli-responsive moieties gives rise to smart materials that are generally processed as self-assemblies of amphiphilic LDBCs with a morphology that can be controlled by an external stimulus. Particular emphasis is placed on light-responsive LDBCs. Furthermore, a brief review of the biomedical or materials science applications of LDBCs is presented.

Co-delivery of doxorubicin and paclitaxel with linear-dendritic block copolymer for enhanced anti-cancer efficacy

A series of well-defined amphiphilic linear-dendritic block copolymers (telodendrimers, MPEG-b-PAMAM-cholesterol) with 1,2,4 or 8 cholesteryl groups (named as P1, P2, P4, P8, respectively) were synthesized. Their chemical structures were characterized with 1H NMR and mass spectrum (MALDI-TOF MS). The telodendrimers could self-assemble into micelles in aqueous solution, and encapsulate chemotherapeutic drug doxorubicin (DOX) and paclitaxel (PTX) for combination therapy. All the telodendrimers could encapsulate DOX with similar capability. However, their drug-loading capability of PTX is increased with the increasing number of cholesteryl groups. P8 exhibited much higher PTX loading efficiency than its counterparts. Thus, P8 was selected for further application of drug delivery in the paper. The drug-loading micellar nanoparticles (NPs) of P8 were spherical in shape and their diameters were less than 150 nm which were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). In vitro drug release experiment demonstrated that P8 exhibited a controlled release manner for both DOX and PTX, and the two drugs were released simultaneously. In vitro cytotoxicity experiment further demonstrated that the co-delivery of DOX and PTX in P8 exhibited better anti-cancer efficiency than the delivery systems encapsulated with single drug (DOX or PTX). This indicates a synergistic effect. The co-delivery system showed potential in future anti-cancer treatment.

New Morphologies and Phase Transitions of Rod–Coil Dendritic–Linear Block Copolymers Depending on Dendron Generation and Preparation Procedure

Amphiphilic rod–coil dendritic–linear block copolymers PEG(Gm)-b-PMPCS (where m is the number of dendron generation, and m = 1, 2, 3) composed of a semirigid Percec-type dendron with hydrophilic poly(ethylene glycol) (PEG) tails and a rod-like mesogen-jacketed liquid crystalline polymer, poly{2,5-bis[(4′-methoxy-phenyl)oxycarbonyl]styrene} (PMPCS), were successfully prepared. The self-assembled structures undergo a transition from vesicles through large compound vesicles (LCVs) to short cylindrical micelles with increasing dendron generation. PEG(G2)-b-PMPCS forms stable LCVs with porous surfaces of a narrow size distribution in a mixed solvent of tetrahydrofuran and water. The formation mechanism of the supramolecular structure with nano- and microsized scales is studied through changing the rate of water addition. It is composed of two steps: morphological transformation and vesicles fusion or differentiation. Vesicles are precursors for LCVs regardless of what the initial morphology is. However, the fi...

Light Responsive Vesicles Based on Linear–Dendritic Block Copolymers Using Azobenzene–Aliphatic Codendrons

We report on the synthesis and characterization of a series of amphiphilic linear–dendritic block copolymers (LDBCs) as well as their self-assembly in water. The LDBCs are composed of a 2000 g/mol poly(ethylene glycol) (PEG) linear segment linked to the fourth generation of a 2,2-di(hydroxymethyl)propionic acid (bis-MPA)-based dendron containing 4-isobutyloxyazobenzene units (AZO) and hydrocarbon chains (C18) randomly connected to the periphery of the dendron. TEM and cryo-TEM images show that all the LDBCs form stable vesicles in water. The influence of AZO/C18 ratio in the photoresponse of the self-assemblies has been assessed as well as the encapsulation of both hydrophilic (Rhodamine B) and hydrophobic (Nile Red) fluorescent probes and the use of light as an external stimulus to trigger the release of the probes. The results show that by diluting the azobenzene content at the periphery of the dendron, the trans-to-cis photoisomerization rate can be substantially accelerated and the light-induced release activity can be tuned being the vesicles with a 50/50 AZO/C18 ratio the ones suffering the most significant changes upon irradiation.

Synthesis and characterization of multi-functional linear-dendritic block copolymer for intracellular delivery of antitumor drugs

A novel amphiphilic linear-dendritic block copolymer, semi-polyamidoamine-b-poly(D,L-lactic acid) (PALA) was synthesized and evaluated for its potential as a drug delivery system in this study. PALA was self-assembled in aqueous solution to form nanomicelles with low critical micelle concentration; antitumor drug docetaxel (DTX) was successfully encapsulated into micelles. The prepared micelles demonstrated pH-induced charge conversion and dimension changes. In vitro drug release suggested susceptibility of DTX-loaded micelles to acidic microenvironment. Hemolysis and cytotoxicity testing also indicated in vitro biocompatibility of PALA. Pharmacokinetic study in rats proved that DTX-loaded PALA micelles enhanced the AUC of DTX and prolonged drug clearance in comparison to conventional DTX injection (Taxotere(®)). It was concluded that self-assembled micelles from linear-dendritic block copolymer PALA demonstrated potential for intracellular delivery of anticancer molecules, and that its safety and efficacy in chemotherapy should be further studied.

Multifunctional Poly(ethylene glycol): Synthesis, Characterization, and Potential Applications of Dendritic–Linear–Dendritic Block Copolymer Hybrids

Emerging dendritic-linear-dendritic (DLD) hybrids that possess synergetic properties of linear and highly functional branched dendritic polymers are becoming important macromolecular scaffolds in f ...

The morphology and fabrication of nanostructured micelle by a novel block copolymer with linear–dendritic structure

We report here a novel approach to fabricate a nanostructured micelle as potential drug carriers and the relationship between the morphological structure and the preparation condition. The polymeric micelle aggregates constructed by self-assembly compose of the poly(ε-caprolactone)/monomethoxy poly(ethylene glycol) linear–dendritic block copolymers. The corresponding copolymers were synthesized by using ring opening polymerization of ε-caprolactone (CL) and a dendritic poly(ether–amide) (DPEA-OH) as an initiator, then coupling with the isocyanate end-capped linear monomethoxy polyethylene glycol. Fluorescence spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were performed to characterize the copolymer micelles. The critical micelle concentration (CMC) was determined to be 1.623mg/L. The hydrodynamic radius (Rh) and the polydispersity index (PDI) are influenced by the concentration of the micelle solutions. The multiple morphologies of the micelle aggregates, including spheres, rob-like dendritic structure and vesicles were observed, which the variety depends on the various preparation conditions. The nanostructured micelles based on the linear–dendritic block copolymer possess the strong thermodynamic stability and the power of solubilization of hydrophobic drug molecules.

Preparation of aqueous polyaniline-vesicle suspensions with class III peroxidases. Comparison between horseradish peroxidase isoenzyme C and soybean peroxidase

AbstractAniline was polymerised enzymatically in aqueous solution at pH = 4.3 and 25°C in the presence of submicrometer-sized vesicles formed from sodium bis(2-ethylhexyl)sulphosuccinate (AOT). H2O2 served as oxidant and the enzyme used was either horseradish peroxidase isoenzyme C (HRPC) or soybean peroxidase (SBP), both being class III peroxidases. From previous studies with HRPC, it is known that stable vesicle suspensions containing the emeraldine salt form of polyaniline (PANI-ES) can be obtained within 1–2 days with a 90–95 % yield, provided that optimal reaction conditions are applied. Unfortunately, HRPC becomes inactivated during polymerisation. In the present study, a linear dendritic block copolymer was added to HRPC, resulting in higher operational enzyme stability; the stabilising effect, however, was too small to afford a substantial decrease in the required amount of enzyme. Moreover, replacing HRPC with SBP was of no advantage, although SBP is known to be more stable towards inactivation by H2O2 than HRPC. By contrast, SBP was found to be much slower in oxidising aniline, and complete inactivation of SBP occurred before all the aniline monomers were oxidised, leading to low yields and the formation of over-oxidised products. The same was observed for HRP isoenzyme A2. Reactions without vesicles indicated that peroxidase inactivation was probably caused by PANI-ES.

Double-Hydrophilic Block Copolymer as an Effective and Environmentally Friendly Inhibitor for Phosphate and Carbonate Scales in Cooling Water Systems

AbstractIn this paper, a series of linear-dendritic block copolymers allyloxy poly(ethylene glycol) polyglycerol (APEG-PG-(OH)n) copolymer, was synthesized by anionic polymerization of glycerol using allyloxy poly(ethylene glycol) (APEG). The polymers were characterized by FT-IR and 1H NMR. The polymers were tested as novel environment-friendly inhibitors for industrial cooling water circulation. The performance of AA/APEG-PG-(OH)n on inhibition of calcium phosphate and calcium carbonate precipitation was studied by static scale inhibition tests. It was shown that AA/APEG-PG-(OH)n exhibited excellent ability to control inorganic minerals, with approximately 99 % calcium phosphate inhibition and 85 % calcium carbonate inhibition at levels of 4 and 10 mg/L AA/APEG-PG-(OH)n, respectively. The effect on formation of calcium phosphate and calcium carbonate was investigated with combination of scanning electronic microscopy (SEM), transmission electron microscopy (TEM), X-ray powder diffraction (XRD) analysis, respectively.

Solvent-induced hierarchical self-assembly of amphiphilic PEG(Gm)-b-PS dendritic-linear block copolymers

The self-assembly of dendritic-linear block copolymers PEG(Gm)-b-PS (where m is the generation number, and m = 1, 2, 3) of different generations with similar hydrophilic weight fractions in aqueous media was studied. With the increasing generation number, the self-assembled aggregates transform from polydisperse vesicles to a mixture of cylindrical micelles with a few vesicles. Turbidity measurements, transmission electron microscopy, and scanning electron microscopy were used to explore the effect of the solvent on the aggregation process in mixtures of tetrahydrofuran–water. Depending on the content of water added, many intermediate structures like large compound vesicles with porous surfaces or combined morphologies from vesicles and cylindrical micelles could be found. In situ monitoring of the intermediate structures provided mechanistic insights regarding their formation processes. For PEG(G1)-b-PS and PEG(G2)-b-PS, the results showed that the fusion and fission processes occur during the addition of water. The fusion process is composed of two steps. First, the vesicles contact and adhere to each other. Second, they rearrange to form larger structures. In the fission process, the large structures are distorted or elongated at first, and then they transform into smaller vesicles. For PEG(G3)-b-PS, only the adhesion and separation processes were detected, without further fusion and fission. Comparing the aggregation processes induced by solvent of samples with different dendron generations, we propose that it is easy for the fusion process to take place between vesicles and difficult between vesicles and cylindrical micelles.

Light induced molecular release from vesicles based on amphiphilic linear-dendritic block copolymers

We report on the synthesis and characterization of new amphiphilic linear-dendritic block copolymers (LDBCs) as well as their self-assembly in water to form polymeric vesicles. We have also investigated the encapsulation of both hydrophilic and hydrophobic fluorescent probes by these stimuli-responsive polymeric vesicles and the use of light as an external stimulus to trigger the release of the probes. The LDBCs are composed of a 2000 g mol−1 poly(ethylene glycol) (PEG) linear segment linked to a fourth generation 2,2-di(hydroxymethyl)propionic acid (bis-MPA) based dendron with 4-isobutyloxyazobenzene units at the periphery. By tuning the chemical structure of the azobenzene moieties, a specific LDBC has been identified that forms stable vesicles in water as it is clearly revealed by TEM and Cryo-TEM images. Encapsulation of both hydrophobic and hydrophilic molecules by these vesicular self-assemblies has been investigated by fluorescence analysis as well as the release of the loaded probes triggered by low intensity UV illumination, which is related to trans-to-cis isomerisation of the azobenzene moieties. Thus, the potential of these photo-responsive vesicles as light-responsive nanocarriers is demonstrated.

Enhanced bioactivity of internally functionalized cationic dendrimers with PEG cores.

Hybrid dendritic-linear block copolymers based on a 4-arm poly(ethylene glycol) (PEG) core were synthesized using an accelerated AB2/CD2 dendritic growth approach through orthogonal amine/epoxy and thiol-yne chemistries. The biological activity of these 4-arm and the corresponding 2-arm hybrid dendrimers revealed an enhanced, dendritic effect with an exponential increase in cell internalization concomitant with increasing amine end groups and low cytotoxicity. Furthermore, the ability of these hybrid dendrimers to induce endosomal escape combined with their facile and efficient synthesis makes them attractive platforms for gene transfection. The 4-arm-based dendrimer showed significantly improved DNA binding and gene transfection capabilities in comparison with the 2-arm derivative. These results combined with the MD simulation indicate a significant effect of both the topology of the PEG core and the multivalency of these hybrid macromolecules on their DNA binding and delivery capablities.

Photoresponsive Polymersomes Formed by Amphiphilic Linear–Dendritic Block Copolymers: Generation-Dependent Aggregation Behavior

Azobenzene-containing linear–dendritic block copolymers (LDBC) with varied generation numbers were synthesized recently. This photosensitive LDBC consists of a linear solvophilic block (R) and solvophilic dendrons of which the periphery is attached with a solvophobic coil–rod diblock (B–Y). The self-assembly and its photoresponsive transformation are explored by dissipative particle dynamics. Dependent on the generation number, polymer concentration, block lengths, and π–π interaction between rod blocks, the aggregate exhibits a rich variety of morphological conformations, including spherical micelle, worm-like micelle, cylindrical micelle, hamburger-like micelle, nanosheet, nanobowl, and vesicle. In general, polymersomes take shape for LDBCs with large generation number while nanofibers and nanosheets develop for LDBCs with small generation number. Upon UV illumination, the photoinduced trans-to-cis isomerization of azobenzene takes place and the membrane becomes distorted, wrinkled, and even ruptured. A...

Azobenzene-containing linear–dendritic block copolymers prepared by sequential ATRP and click chemistry

A series of light responsive linear–dendritic BCs consisting of a liquid crystalline aliphatic polyester dendron functionalized with sixteen 4-cyanoazobenzene moieties linked to a linear block of poly(methyl methacrylate), poly(ethyl methacrylate) or poly(styrene) have been investigated. The linear block was synthesis by atom transfer radical polymerization using an alkyne terminated initiator and was coupled to dendron with an azido group at the focal point by a Huisgen's 1,3-dipolar cycloaddition. The effectiveness of the coupling reaction and purity of the block copolymers was asserted by chromatographic and spectroscopic techniques as well as their thermal behaviour was studied by thermogravimetric analysis, differential scanning calorimetry and optical microscopy. Morphology, optical properties and photoinduced response of these block copolymers have also been evaluated.

Effects of Dendron Generation and Salt Concentration on Phase Structures of Dendritic–Linear Block Copolymers with a Semirigid Dendron Containing PEG Tails

We prepared a series of dendritic–linear block copolymers (DLBCPs) bearing a semirigid Percec-type dendron with ionophilic poly(ethylene glycol) (PEG) tails and a polystyrene (PS) linear polymer by nitroxide-mediated living radical polymerization (NMRP). As the DLBCPs are connected by an ester linkage, through hydrolysis the molecular weights of the DLBCPs were precisely characterized by gel permeation chromatography and MALDI-TOF MS. Differential scanning calorimetry, small-angle X-ray scattering, and transmission electron microscopy were used to investigate the phase behaviors of the DLBCPs. Results show that the PEG tails of the semirigid dendron display a cold crystallization peak and a melting peak during the second heating process, while for the neat DLBCPs, the crystallization of the PEG tails is completely inhibited, and only the glass transition temperature (Tg) of the PS block is observed. However, Tg of the dendron block can be observed by complexing the DLBCPs with LiCF3SO3, suggesting that mi...

Effect of the molecular structure on the reactivity in a family of tetra-amine compounds derived from Jeffamines

The effect of the molecular structure on the reactivity of four first-generation linear-dendritic block copolymers derived from Jeffamines and bearing amine end groups is presented and discussed. Different parameters were investigated via chemical modifications and nuclear magnetic resonance analysis, showing that chain length, hydrophilic/hydrophobic character, and flexibility of the central oligoether block did not produce any change in the amine moiety reactivity. In contrast, the type of branches and the nature of the amine end groups strongly affected the reactivity in an unusual manner. In fact, the copolymer bearing aromatic amine end groups showed better reactivity than those based on aliphatic counterparts.

A linear-dendritic cationic vector for efficient DNA grasp and delivery

This paper presents an attempt to design an efficient and biocompatible cationic gene vector via structural optimization that favors the efficient utilization of amine groups for DNA condensation. To this end, a linear-dendritic block copolymer of methoxyl-poly(ethylene glycol)-dendritic polyglycerol-graft-tris(2-aminoethyl)amine (mPEG-DPG-g-TAEA) was prepared with specially designed multiple functions including strong DNA affinity, endosomal buffering and expected serum-tolerance. Based on the transfection in serum-free and serum-conditioned media, the influences of the polymer structures including the degree of polymerization of DPG and TAEA substitution degree were explored. As compared to polyethylenimine (Mw=5kDa) (PEI5k) with similar molecular weight and higher amine density, mPEG-DPG-g-TAEA displayed comparably high DNA affinity due to the special linear-dendritic architecture. Consequently, at very low N/P ratio, mPEG-DPG-g-TAEA vectors could mediate efficient in vitro luciferase expression at levels that are comparable with or even superior to the commercially available Lipofectamine™ 2000, while being apparently higher than PEI5k. The designed vectors exhibit considerably higher cell biocompatibility and better resistance against bovine serum albumin adsorption than PEI5k. The stability of the complexes on coincubation with heparin was found to be largely dependent on the polymer structure. As concluded from the comparative transfection study in the absence/presence of chloroquine, it is likely that the polycation itself could produce endosomal buffering. This linear-dendritic vector shows promising potential for the application of gene delivery.

Self-assembled hierarchical structure evolution of azobenzene-containing linear-dendritic liquid crystalline block copolymers

In this paper, the phase behaviors and self-assembled structures of a series of liquid crystalline linear-dendritic block copolymers (LDBCs) in the bulk state have been systematically investigated in combination with DSC, POM, SAXS, WAXS, and TEM. The LDBCs consist of a linear poly(ethylene glycol) (PEG) block (degree of polymerization, DP = 49) and dendritic polyamidoamine (PAMAM) segments of generation G0 to G3, functionalized with photoactive azobenzene mesogenic units bearing an octyloxy tail and a flexible ten-methylene spacer (AZO). An unprecedented hierarchical structure evolution with increasing dendron generation has been demonstrated for this series of azobenzene-containing LDBCs in bulk. Well-defined lamellar structures are formed for liquid crystalline LDBCs of G0, G1, and G2 with only a slight change in layer spacing between 12.2 and 13.0 nm. A simple lamellar structure is generated by mPEG-G0-(AZO)2, while tetragonal-within-lamellar and lamellar-within-lamellar hierarchical structures are created in mPEG-G1-(AZO)4 and mPEG-G2-(AZO)8, respectively, due to further suborganization between PAMAM and AZO segments within the dendritic blocks. For the highest generation copolymer investigated in this work, mPEG-G3-(AZO)16, the structure changes dramatically from lamellar for lower generations into rectangular columnar with lattice parameters a = 8.5 nm and b = 6.5 nm or higher temperature disordered columnar mesophases. The introduction of the alkyloxy tail in the azobenzene mesogenic unit is of crucial importance for constructing such hierarchical structures. Moreover, those complex lamellar mesophases transform into micellar or network cubic structures upon cooling to ambient solidification temperature with PEG crystallization showing a complete inverse phase change tendency in virtue of the curvature effect as a result of the specific linear-dendritic architecture. Very interestingly, the films of azobenzene-containing liquid crystalline LDBCs exhibit generation/morphology dependent photophysical characteristics, which may afford a convenient way for designing and fine-tuning novel optical storage materials.