Dendritic Copolymers Research Articles

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.

Preparation and in vitro pH-responsive drug release of amphiphilic dendritic star-block copolymer complex micelles

Amphiphilic dendritic star-block copolymer PCL-b-PDMAEMA composed of poly(ε-caprolactone) and poly(2-(N,N-dimethylamino)ethyl methacrylate) was synthesized successfully. In an aqueous solution, the copolymer could simultaneously self-assemble into unimolecular micelles and multimolecular mielles with mean diameters of about 28nm and 190nm, respectively. Dynamic light scattering measurements of these copolymer micelles showed bimodal size distribution. in vitro drug release behavior of the complex micelles loading camptothecin indicated that the rate of drug release could be effectively controlled by altering the pH values of the environment. The cytotoxicity assay confirmed the low cytotoxicity of the complex micelles and the significant drug efficacy. The confocal laser scanning microscopy demonstrated that the drug-loaded micelles could penetrate the cell membrane and be internalized into cytoplasm and cell nucleus of HeLa cells. Thus, the pH-responsive dendritic PCL-b-PDMAEMA micelles could be promising drug delivery vehicles for pharmaceutical and biomedical applications.

Impedimetry and microscopy of electrosynthetic poly(propylene imine)-co-polypyrrole conducting dendrimeric star copolymers

A novel generation 2 poly(propylene imine)-co-polypyrrole conducting dendrimeric star copolymer (G2PPI-co-PPy) was synthesised electrochemically by oxidative copolymerization of pyrrole and pyrrole-functionalised dendrimer (G2PPI-2Py) in LiClO4 NMR spectra of G2PPI-2Py gave a new chemical shift at 8.1ppm for N=CH, which confirmed the incorporation of 2-pyrrole aldehyde into the PPI dendrimer structure. Strong FT-IR bands appeared at 1630cm−1 for N=C in the dendrimer moiety and at 729cm−1 for C-H at the α-position of the PPy ring. Electroanalysis of the polymer films deposited on Pt electrode indicated that G2PPI-co-PPy has a lower electrochemical charge transfer resistance (Rct) value compared to PPy. The decrease in Rct is due to the increase in the conjugation length of the polymer as a result of the linking of the highly conjugated PPy to the PPI dendrimer. Bode impedimetric analysis indicates that Pt|G2PPI-co-PPy is a semiconductor with a maximum phase angle shift of 45.3° at 100MHz. The scanning electron microscopy (SEM) image of G2PPI-co-PPy revealed conical PPy structures growing around a spherical core as predicted by the reaction mechanism for the formation of the dendritic star co-polymer.

Enhancing therapeutic effects of docetaxel-loaded dendritic copolymer nanoparticles by co-treatment with autophagy inhibitor on breast cancer.

Dendrimers are synthetic nanocarriers that comprise a highly branched spherical polymer as new, efficient tools for drug delivery. However, the fate of nanocarriers after being internalized into cells has seldom been studied. Docetaxel loaded dendritic copolymer H40-poly(D,L-lactide) nanoparticles, referred to as “DTX-H40-PLA NPs”, were prepared and used as a model to evaluate whether the NPs were sequestered by autophagy and fused with lysosomes. Besides being degraded through the endolysosomal pathway, the DTX-loaded H40-PLA NPs were also sequestered by autophagosomes and degraded through the autolysosomal pathway. DTX-loaded H40-PLA NPs may stop exerting beneficial effects after inducing autophagy of human MCF-7 cancer cells. Co-delivery of autophagy inhibitor such as chloroquine and chemotherapeutic drug DTX by dendritic copolymer NPs greatly enhanced cancer cell killing in vitro, and decreased both the volume and weight of the tumors in severe combined immunodeficient mice. These findings provide valuable evidence for development of nanomedicine such as dendritic copolymer NPs for clinical application.

Determination of the loading and stability of Pd in an arborescent copolymer in ethanol by microplasma-optical emission spectrometry

A novel microplasma-OES system was used to determine the concentration of Pd stabilized by a dendritic (arborescent) copolymer in ethanol.

Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles

Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N′, N-triacetic acid (NOTA, a macrocyclic chelator for 64Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, 64Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than 64Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.

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.

Well‐defined thermoresponsive dendritic polyamide/poly(N‐vinylcaprolactam) block copolymers

ABSTRACTThe first‐ and second‐generation well‐defined thermoresponsive amphiphilic linear–dendritic diblock copolymers based on hydrophilic linear poly(N‐vinylcaprolactam) and hydrophobic dendritic aromatic polyamide have been synthesized via reversible addition fragmentation chain transfer polymerization of N‐vinylcaprolactam by employing dendritic chain‐transfer agents possessing a single dithiocarbamate moiety at the focal point. These linear–dendritic copolymers exhibit reversible temperature‐dependent phase transition behaviors in aqueous solution as characterized by turbidity measurements using UV–vis spectroscopy. Their lower critical solution temperatures depend on the generation of the dendritic aromatic polyamides and the concentrations of the copolymer solutions. These amphiphilic copolymers are able to form nanospherical micelles in the aqueous solution as revealed by fluorescent spectroscopy, dynamic light scattering, and transmission electron microscope (TEM). The core–shell structure of micelles has been proved by 1H NMR analyses of the micelles in D2O. The micelles loaded with indomethacin as a model drug showed high‐drug loading capacity and thermoresponsive drug release behavior. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3240–3250

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 ...

Dendritic Block and Dendritic Brush Copolymers through Anionic Macroinimer Approach

Anionic macroinimer is prepared through selective monoaddition of polyisoprenyllithium (PILi) toward 1,3-bis(1-phenylvinyl)benzene (MDDPE) in THF/cyclohexane mixture. The resulting macroinimer, possessing a living anion and a diphenylethylene (DPE) group at the same end of the PI chain, undergoes self-condensing vinyl copolymerization (SCVCP) with styrene after the solvent has been switched from mixture of THF/cyclohexane into pure cyclohexane. Dendritic block copolymers of styrene and isoprene are obtained, in which PI chains are linked to the branch points. The molecular weights of the dendritic products mainly depend on the ratio of monomer to macroinimer, whereas PI chain length has only slight effects. The PI segments are subsequently epoxidized and grafted with PILi or polystyrenyllithium (PSLi) to give dendritic polymer brushes. Both dendritic block copolymers and dendritic polymer brushes show decreased intrinsic viscosities. Dendritic block copolymer of styrene and isoprene undergoes a specially slow process of self-assembly, from unimolecular micelles and intermediate compound micelles to large compound micelles, in mixed solvent (n-heptane/THF = 19/1, v/v). In addition, conversion of large compound micelles into lamellar structure is observed for the first time in self-assembly of dendritically branched polymers.

Synthesis and Properties of Multicleavable Amphiphilic Dendritic Comblike and Toothbrushlike Copolymers Comprising Alternating PEG and PCL Grafts

Facile construction of novel functional dendritic copolymers by combination of self-condensing vinyl polymerization, sequence-controlled copolymerization and RAFT process was presented. RAFT copolymerization of a disulfide-linked polymerizable RAFT agent and equimolar feed ratio of styrenic and maleimidic macromonomers afforded multicleavable AmBn dendritic comblike copolymers with alternating PEG (A) and PCL (B) grafts, and a subsequent chain extension polymerization of styrene, tert-butyl acrylate, methyl methacrylate, and N-isopropylacrylamide gave AmBnCo dendritic toothbrushlike copolymers. (PEG)m(PCL)n copolymers obtained were of adjustable molecular weight, relatively low polydispersity (PDI = 1.10–1.32), variable CTA functionality (fCTA = 4.3–7.5), and similar segment numbers of PEG and PCL grafts, evident from 1H NMR and GPC-MALLS analyses. Their branched architecture was confirmed by (a) reduction-triggered degradation, (b) decreased intrinsic viscosities and Mark–Houwink–Sakurada exponent than their “linear” analogue, and (c) lowered glass transition and melting temperatures and broadened melting range as compared with normal AmBn comblike copolymer. In vitro drug release results revealed that the drug release kinetics of the disulfide-linked AmBn copolymer aggregates was significantly affected by macromolecular architecture, end group and reductive stimulus. These stimuli-responsive and biodegradable dendritic copolymer aggregates had a great potential as controlled delivery vehicles.

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.

Dissipative particle dynamics simulation study on the mechanisms of self-assembly of large multimolecular micelles from amphiphilic dendritic multiarm copolymers

Dendritic multiarm copolymers, including dendrimer multiarm copolymers and hyperbranched multiarm copolymers, have shown great potential to be excellent precursors in self-assembly, and many impressive supramolecular structures have been prepared through the solution self-assembly of them. However, the corresponding theoretical studies on the self-assembly mechanism have been greatly lagging behind. Herein, we report the micellization behaviors of amphiphilic dendritic multiarm copolymers with a hydrophobic dendritic core and many hydrophilic arms by dissipative particle dynamics simulations. Both the self-assembly mechanisms and the dynamic self-assembly processes for the formation of unimolecular micelles, microphase-separated small micelles, and large multimolecular micelles have been disclosed through the simulations. Most importantly, the work has proved the large multimolecular micelles are a kind of multimicelle aggregate (MMA) with two formation mechanisms. One is called the unimolecular micelle aggregate (UMA) mechanism, which describes the formation of large multimolecular micelles from direct aggregation of unimolecular micelles; the other is called the small micelle aggregate (SMA) mechanism, which shows that the dendritic multiarm copolymers first self-assemble into small micelles and then the small micelles further aggregate into large multimolecular micelles. In addition, the microphase separation model of the dendritic multiarm copolymers as well as the effects on the formations of UMAs and SMAs are also discussed. These simulation results agree well with experimental observations, and have extended the understanding of the micellization process of dendritic multiarm copolymers.

Linear–dendritic biodegradable block copolymers: from synthesis to application in bionanotechnology

Besides biodegradability and biocompatibility, linear–dendritic biodegradable block copolymers present unique hierarchical self-assembly and multivalent characteristics, making them appealing in stimuli-responsive nanomedicine and hydrogel applications. This minireview highlights the recent progress on linear–dendritic biodegradable block copolymers synthesized via click chemistry, the DNA–/protein–dendritic biohybrids, and their prospects in bionanotechnology.

Synthesis and versatile postpolymerization modification of couplable A(BC)mD heterografted comblike block quaterpolymers

The synthesis and postfunctionalization of A(BC)mD (A = PDMA; B = PEG; C = PCL; D = PNIPAM, PtBA and PMA) comblike block copolymers comprising alkyne and tertiary amino functionalities and alternating PEG and PCL grafts are described. Three-step successive RAFT processes using prop-2-ynyl 4-(benzodithioyl)-4-cyanopentanoate as an original mediator were used to synthesize amphiphilic PDMA(PEG-alt-PCL)mPM (m ≈ 7) heterografted copolymers, in which the PEG and PCL segments were introduced by the alternating copolymerization of styrenic and maleimidic macromonomers. GPC-MALLS and 1H NMR results indicated that the resultant quaterpolymers were of well-controlled molecular weight and relatively low polydispersity (PDI = 1.12–1.25). The combination of end group transformation and the azide–alkyne “click” reaction afforded (A(BC)mD)n (n ≈ 4) comblike-linear multiblock copolymer and (A(BC)mD)x (x ≈ 7) dendritic graft copolymer, and Menschutkin reaction between A(BC)mD copolymer and bromide-functionalized small molecule/macromolecule gave an ion-bearing A′(BC)mD comblike block copolymer and A(BC)mD-graft-E toothbrushlike copolymer, revealing the great potential of postpolymerization modification in novel architecture construction. Preliminary results indicated that the introduction of various functionalities and polymer segments into brushlike copolymers via the quaternization process could affect the chain relaxation and melting behaviors, solubility, and surface wettability of polymer films.

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.

The Investigation of a Linear-Dendrite Copolymeric Nanoparticles As Drug Carriers: ONIOM Study

Linear–dendrite copolymers containing hyper branched poly(citric acid) and linear poly(ethylene glycol) blocks PCA–PEG–PCA are promising nonmaterial to use in nanomedicine. To investigate their potential application in biological systems (especially for drug carries) ONIOM2 calculations were applied to study the nature of particular interactions between drug and the polymeric nanoparticles. Binding energy (BE) and interaction energy (IE) analysis of these complexes allowed the fundamental features of the drug- the Linear– dendritic copolymers interactions to be assessed based on ONIOM method. The results show that they have weak interaction and these complexes have relatively low stability and so PCA-PEG-PCA copolymers can use to as drug delivery.

Preparation of long supramolecular carbon nanotubes

One of the most important characteristics of carbon nanotubes, CNTs, that distinguishes them from other materials and motivates scientists to use them as highly efficient tools in a wide variety of applications, is their one dimensionality, i.e. long length and small diameter. Unfortunately there is strong evidence that long carbon nanotubes show asbestos-like pathology. Herein we report a method to produce supramolecular systems consisting of linear–dendritic copolymers and short CNTs, LDCNTs. In this method, linear–dendritic copolymers with peripheral aromatic groups are used to connect short carbon nanotubes, SCNTs, toward ultra-long and highly flexible carbon nanotubes. The π–π stacking of dendritic blocks of a linear–dendritic copolymer onto the surface of SCNTs is the main driving force to create LDCNTs. Since in the section lengths connections are noncovalent, they can be broken down to SCNTs in biological systems and therefore asbestos-like carcinogenicity of LDCNTs could probably be avoided.

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.