Y-shaped Block Copolymers Research Articles

A Thermal-Responsive Y-Shaped Miktoarm Amphiphilic Block Copolymer Composed of Poly(ε-caprolactone) and Poly(N-isopropylacrylamide) as a Nano-micellar Carrier for Anti-cancer Drugs

A thermal-responsive Y-shaped amphiphilic block copolymer, namely poly(N-isopropylacrylamide-block-[poly(e-caprolactone)]2 (PNIPAAm-b-PCL2), was synthesized through the combination of atom transfer radical polymerization (ATRP) and ring-opening polymerization (ROP) techniques, and its potential as smart anti-cancer drug delivery system was investigated preliminary. The fabricated polymers were characterized using FTIR and 1H NMR spectroscopy, and GPC analysis. The self-assembly behavior of the fabricated PNIPAAm-b-PCL2 copolymer under thermal stimuli was investigated using dynamic light scattering and UV–Vis spectroscopy. The lower critical solution temperature of the synthesized PNIPAAm-b-PCL2 was found to be 39–41°C. The doxorubicin hydrochloride loading and encapsulation capacities of the fabricated PNIPAAm-b-PCL2 were calculated to be 62 ± 3%, and 75 ± 4%, respectively; the drug release value was up to 46.5% during 40 h at 37°C and up to 88% at 40°C.

Design, Synthesis, and Application of a Difunctional Y-Shaped Surface-Tethered Photoinitiator.

Mixed homopolymer brushes have unique interfacial properties that can be exploited for both fundamental studies and applications in technology. Herein, the synthesis of a new catechol-based biomimetic Y-shaped binary photoinitiator (Y-photoinitiator) and its applications for surface modification with polymer brushes through both "grafting to" and "grafting from" strategies are reported. The "leg" of the Y consists of a catechol group as surface anchoring moiety. The arms are photoinitiator moieties that can be "addressed" independent of each other by radiation of different wavelengths. Using ultraviolet and visible light successively, each arm of the Y-photoinitiator was activated, thereby allowing the synthesis of Y-shaped block copolymer brushes with dissimilar polymer chains. The suitability of the Y-photoinitiator for surface modification was first investigated using N-vinylpyrrolidone and styrene as the model monomers for successive UV-photoiniferter-mediated polymerization and visible-light-induced polymerization, respectively. Switching of the wetting properties of the Y-shaped block copolymer brush poly( N-vinylpyrrolidone)- block-poly(styrene) (PVP- b-PS)-grafted surfaces by contact with different solvents was also investigated. To further exploit this novel Y-photoinitiator for the preparation of functional interfaces, Y-shaped block copolymer brushes poly(1-(2-methacryloyloxyhexyl)-3-methylimidazolium bromide)- block-poly( N-vinylpyrrolidone- co-glycidyl methacrylate) (PIL(Br)- b-P(NVP- co-GMA)) were also prepared and subsequently functionalized with the cell-adhesive arginine-glycine-aspartic acid (RGD) peptides by reaction with the glycidyl groups (PILPNG-RGD). The PILPNG-RGD grafted surfaces showed excellent cell-adhesive, bacteriostatic, and bactericidal properties. Thus, it can be concluded that further exploitation of this novel Y-photoinitiator for graft polymerization should allow the preparation of a wide range of functional interfaces with tailored properties.

Y-shaped copolymers of poly(ethylene glycol)-poly(ε-caprolactone) with ketal bond as the branchpoint for drug delivery

In this study, a Y-shaped amphiphilic block copolymer consisting of hydrophilic poly(ethylene glycol) (mPEG) and two poly(ε-caprolactone) (PCL) as the hydrophobic arms with a ketal linker was synthesized (mPEG-Ketal-(PCL)2). The structure of the copolymer with different compositions was characterized by 1H NMR, gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). The amphiphilic property endows the copolymer with the ability to be self-assembled into micelles for encapsulating anticancer drug doxorubicin (DOX), and the effect of copolymer with different PCL length on drug loading properties were tested. The morphology, size, pH responsiveness, drug release profile and in vitro anticancer activity of the DOX loaded micelles were also studied. In vitro drug release studies showed that over 50% of the DOX was released at pH 5.0 in 24 h because of hydrolysis of ketal linker in the copolymers. The confocal laser microscopy and flow cytometry experiments showed that the DOX-loaded micelles could be effectively internalized by Hela cells, the ketal bond in the backbone was broken in acid endo/lysosomal compartments and triggered the fast release of DOX. The in vitro antitumor efficacy of the DOX loaded mPEG-Ketal-(PCL)2 micelles was better than that of non-pH sensitive ones. In vivo studies showed that the mPEG-Ketal-(PCL)2 micelles enhanced the DOX blood circulation time and had good tumor-targeting efficiency.

Linear, Y-shaped, and H-shaped amphiphilic azobenzene copolymers: Facile synthesis and topological effect on self-assembly and photoresponsive property

Novel linear (AB-type), Y-shaped (AB2-type), and H-shaped (B2AB2-type) amphiphilic block copolymers of poly(ethylene glycol) (PEG) with polymer containing azobenzene chromophores (PAzo) were successfully synthesized by the head-to-tail acyclic diene metathesis (ADMET) polymerization. Three types of acrylate functional ADMET chain stoppers were first prepared through the Michael addition reaction and esterification. Then, a series of amphiphilic copolymers were obtained via through ADMET polymerization of azobenzene-functionalized asymmetric α,ω-diene monomer using the as-prepared PEGs with acrylate end groups as macromolecular chain stoppers. Finally, the amphiphilic copolymers could spontaneously self-assemble into spherical nanoparticles in an aqueous medium. In view of the photoresponsive blocks of PAzo, the solution photochemical properties of the solution and the sizes of these spherical aggregates can be manipulated by changing the parameters such as UV and visible lights. The differences in structure of the copolymers induced profound effects on photoresponsive performance.

A comparative study of linear, Y-shaped and linear-dendritic methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) block copolymers for doxorubicin delivery in vitro and in vivo

The linear, Y-shaped, and linear-dendritic block copolymers of methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) (MPEG-b-PAMAM-b-PGA) with one, two, four, and eight PGA arms but similar MPEG/PGA weight ratios (W/W) (named as P1PA, P2PA, P4PA and P8PA, respectively) were synthesized and comparatively investigated for doxorubicin hydrochloride (DOX) delivery. All the obtained block copolymers were highly biocompatible and could efficiently load DOX into nanoparticles (NPs) through electrostatic interaction. The NPs formed by linear (P1PA) or Y-shaped (P2PA) block copolymers and DOX were spherically shaped with smaller sizes, while the NPs formed from linear-dendritic block copolymers (P4PA and P8PA) were irregular in shape and larger in size. The P1PA/DOX and P2PA/DOX NPs exhibited better DOX protection and slower DOX release profile. However, cell cytotoxicity assays indicated that all the DOX-loaded NPs exhibited similar cytotoxicities with free DOX, indicating effective DOX release after cellular uptake. The NPs from linear and Y-shaped block copolymers greatly extended the blood circulation time, and displayed more accumulation in tumor site and less accumulation in the liver and kidney compared with the linear-dendritic counterparts. In addition, the P1PA/DOX and P2PA/DOX NPs also exhibited higher anti-tumor efficacy and less toxicity than the other DOX formulations. All these results indicated that the linear and Y-shaped MPEG-b-PAMAM-b-PGA block copolymers displayed better DOX delivery ability in anti-tumor treatment than the linear-dendritic copolymers. Statement of SignificancePolymeric NPs derived from block copolymers have emerged as effective vehicles for drug delivery. However, the majority of the researches in this field have involved simple linear block copolymers and there are very few comparative studies on the self-assembly, in vitro, and in vivo drug delivery by the block copolymers with similar composition but different architectures. In this study, a series of linear, Y-shaped, and linear-dendritic polypeptide-based block copolymers were prepared and thoroughly investigated for DOX delivery. These block polymers loaded DOX into NPs with different sizes and morphologies, and exhibited different anti-tumor capabilities both in vitro and in vivo. The results indicated that the architecture of the block copolymers played an important role in their drug delivery behaviors.

Application of pH-responsive poly(2-dimethyl-aminoethylmethacrylate)-block-poly(acrylic acid) coatings for the open-tubular capillary electrochromatographic analysis of acidic and basic compounds

A new type of stimuli-responsive polymeric (SRP) coating has been prepared for use in open tubular capillary electrochromatography (OT-CEC), by grafting poly(2-dimethylaminoethylmethacrylate)-block-poly(acrylic acid) (PDMAEMA-b-PAA) as a Y-shaped block copolymer with two dissimilar chain compositions onto the inner walls of aminopropyl-modified silica capillaries. The grafting process introduced weakly charged functional groups from the PAA and PDMAEMA, enabling the generation of electroendosmotic flow with magnitude and direction adjustable by changing the pH of the running buffer electrolyte. This stimuli-responsive PDMAEMA-b-PAA block copolymer was found to provide excellent resolution of various acidic and basic compounds, leading to efficient analyte separation. When operated in the OT-CEC mode, separation selectivities could be readily manipulated via differential contributions from chromatographic and electrophoretic mechanisms, simply by changing the pH or the ionic strength of the running buffer electrolyte.

Synthesis of Y-shaped amphiphilic copolymers by macromolecular azo coupling reaction

The synthesis of well-defined AB2 Y-shaped amphiphilic block copolymers by macromolecular azo coupling reaction is reported.

Synthesis and Characterization of Biodegradable Amphiphilic Star and Y-Shaped Block Copolymers as Potential Carriers for Vinorelbine

Two amphiphilic block copolymers using hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic poly(ethylene glycol) (PEG) were successfully synthesized. One of them is an (A-b-B)4 type star polymer [(PCL-b-PEG)4] and the other one is a Y-shaped PEG–(PCL)2. A star-shaped polymer (PCL-b-PEG)4 was prepared by ring-opening polymerization (ROP) of ε-caprolactone continued by click reaction of (PCL-azide)4 and PEG-alkyne. The synthesis of Y-shaped PEG–(PCL)2 block copolymer was carried out via Diels-Alder click reaction of a furan protected maleimide end-functionalized PEG (PEG-MI) with an anthracene end-functionalized PCL following the ROP of ε-caprolactone. The characterization of micelles is carried out using both materials in aqueous media as drug delivery vehicles, which showed satisfying results and enhanced the cytotoxic effect of the anti-cancer drug vinorelbine (VLB). However, micelles consisted of Y-shaped unimers were found to be more convenient for delivery of hydrophobic drugs such as VLB because they formed in lower concentration, carrying a higher amount of drugs and owing a monomodal distribution. We concluded that the free tails of hydrophobic chains in Y-shaped block copolymer facilitate the assembly of amphiphilic material in water to form micelles.

Y-shaped block copolymer (methoxy-poly(ethylene glycol))2-b-poly(l-glutamic acid): preparation, self-assembly, and use as drug carriers

The nano polymer drugs based on Y-shaped block copolymer mPEG2-PGA show a great potential on the treatment for solid tumors.

The structures of thin layer formed by microphase separation of grafted Y-shaped block copolymers in solutions

We study the structure formation of grafted Y-shaped block copolymers in solutions via dissipative particle dynamics simulations. We systematically examine how the solvent quality, the grafting density, and the incompatibility between polymer blocks affect the morphology of the grafted layer. The layer thickness and the lateral domain size and inhomogeneity of the layer structures are analyzed. A power law, hlayer ~ σ(n), is found between the layer thickness (hlayer) and the grafting density (σ), which shows three regimes, i.e., the brushes regime, the crossover regime, and the mushrooms regime. In the brushes regime, we also find that the exponent n is dependent on the grafting densities and solvent conditions, regardless of the incompatibility between the polymer blocks. In the mushrooms and the crossover regime, a variety of surface structures can be observed, such as mixed micelles, internally segregated micelles, hamburger micelles, segmented wormlike micelles, and dumbbell micelles. The stripe-like structure formed in the brushes regime is investigated in detail. The simulation results are in good agreement with theoretical predictions and experimental observations, and can be helpful for the surface structure design of functional materials.

Stimuli‐Responsive Y‐Shaped Polymer Brushes Based on Junction‐Point‐Reactive Block Copolymers

A general concept for the preparation of junction-point-reactive, amphiphilic Y-shaped block copolymer brushes for ultrathin polymer films is demonstrated, combining anionic polymerization techniques. The polymer films (1–3 nm) exhibit reversible, stimuli-responsive wetting behavior upon application of different external stimuli (temperature and solvent). Contact angle measurements confirm the reversible hydrophobization with shifts up to 23°. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Bioactive Polymeric Metallosomes Self-Assembled through Block Copolymer–Metal Complexation

Spontaneous formation of polymeric metallosomes with uniform size (~100 nm) was found to occur in aqueous medium through the reaction of an anticancer agent, (1,2-diaminocyclohexane)platinum(II) (DACHPt), with a Y-shaped block copolymer of ω-cholesteroyl-poly(L-glutamic acid) and two-armed poly(ethylene glycol) (PEGasus-PLGA-Chole). Circular dichroism spectrum measurements revealed that the PLGA segment forms an α-helix structure within the metallosomes, suggesting that secondary-structure formation of metallocomplexed PLGA segment may drive the self-assembly of the system into vesicular structure. These metallosomes can encapsulate water-soluble fluorescent macromolecules into their inner aqueous phase and eventually deliver them selectively into tumor tissues in mice, owing to the prolonged blood circulation. Accordingly, fluorescent imaging of the tumor was successfully demonstrated along with an appreciable antitumor activity by DACHPt moieties retained in the vesicular wall of the metallosomes, indicating the potential of metallosomes as multifunctional drug carriers.

Reduction-responsive shell-crosslinked micelles prepared from Y-shaped amphiphilic block copolymers as a drug carrier

Biodegradable Y-shaped amphiphilic block copolymer mPEG-b-PLG-b-(PLA)2 was synthesized and characterized by 1H NMR and FTIR. The amphiphilic property of the copolymer with a mPEG-b-PLG segment as the hydrophilic arm and two PLA segments as the hydrophobic arms endows the copolymer with the ability to form core–shell nanoparticles in aqueous solution. Co-assembly of doxorubicin (Dox) and the block copolymer in selective solvent was carried out to prepare Dox-loaded micelles. The inner-shell (PLG) of the micelle was crosslinked through a carbodiimide coupling method with cystamine as the crosslinker. The crosslinked micelles exhibit reduction-responsive release of Dox and the stability in vitro was much better than non-crosslinked micelles. In acidic release condition, the total amount of Dox released could be increased due to the increased solubility of Dox. The blood clearance of Dox in different form of micelles was studied and the results show that Dox loaded in the crosslinked micelles with PEG5K as the outer shell exhibit the longest blood circulation after intravenous injection.

ABA2-type triblock copolymer composed of PCL and PSt: synthesis and characterization

ABA2-type (Y-shaped) triblock copolymer made from poly(e-caprolactone) (PCL) and polystyrene were synthesized by the combination of enzymatic ring-opening polymerization (eROP) and atom transfer radical polymerization (ATRP). First, CCl3-terminated PCL were synthesized by eROP of e-caprolactone in the presence of initiator 2,2,2-trichloroethanol and biocatalyst Novozyme 435, followed by the esterification of the resulting PCL with 2,2-dichloro acetyl chloride to obtain trifunctional macroinitiator. The well-defined Y-shaped block copolymer was then synthesized by ATRP of styrene. The systems display characteristics of a living radical polymerization as indicated by linear first-order kinetics, linearly increasing molecular weight with conversion, and low polydispersities. The macromolecular structures and composition were characterized by HNMR, GPC, and FTIR. The thermal properties were characterized by differential scanning calorimetry.

Synthesis of Biodegradable Amphiphilic Y-shaped Block Co-polymers via Ring-Opening Polymerization for Drug Delivery

A series of novel Y-shaped biodegradable block co-polymers of poly(ε-caprolactone) (PCL) and poly(ethyl ethylene phosphate) (PEEP) (PCL–(PEEP)2) were synthesized via ring-opening polymerization (ROP) of EEP with bis-hydroxy-functional ROP initiator (init–PCL–(OH)2). The init–PCL–(OH)2 was synthesized by ROP of CL using 4-hydroxybutyl acrylate (HBA) as initiator and L-tartaric acid as catalyst in bulk, and subsequently the resulting vinyl-terminated PCL was end-capped by acetyl chloride, followed by Michael addition using excess diethanolamine. The Y-shaped co-polymers and their intermediates were characterized by 1H-, 13C-, 31P-NMR, FT-IR and gel-permeation chromatography. The results indicated that the molecular weight of the Y-shaped co-polymers increased with the increasing of the molar ratios of EEP to init–PCL–(OH)2 in the feed, while the PCL chain length was kept constant. The amphiphilic block co-polymers could self-assemble into micelles in aqueous solution, which was demonstrated by dynamic light scattering, 1H-NMR and atomic force microscopy. A study of controlled release of indomethacin indicated that the amphiphilic block co-polymers could potentially provide novel vehicles for drug delivery.

Y-shaped block copolymers of poly(ethylene glycol) and poly( N-isopropylacrylamide) synthesized by ATRP

Novel Y-shaped block copolymers of poly(ethylene glycol) and poly( N-isopropylacrylamide), PEG-b-(PNIPAM) 2, were successfully synthesized through atom transfer radical polymerization (ATRP). A difunctional macroinitiator was prepared by esterification of 2,2-dichloroacetyl chloride with poly(ethylene glycol) monomethyl ether (PEG). The copolymers were obtained via the ATRP of N-isopropylacrylamide (NIPAM) at 30 °C with CuCl/Me 6TREN as a catalyst system and DMF/H 2O (v/v = 3:1) mixture as solvent. The resulting copolymers were characterized by gel permeation chromatography (GPC) and 1H NMR. These block copolymers show controllable molecular weights and narrow molecular weight distributions (PDI < 1.15). Their phase transition temperatures and the corresponding enthalpy changes in aqueous solution were measured by differential scanning calorimetry (DSC). As a result, the phase transition temperature of PEG 45-b-(PNIPAM 55) 2 is higher than that of PNIPAM, however, the corresponding enthalpy change is much lower, indicating the significant influence of the macromolecular composition and architecture on the phase transition.

Synthesis and Property of Y-Shaped Thermoresponsive Block Copolymers

Novel Y-shaped amphiphilic block copolymers of poly(ethylene glycol) and poly(N-isopropylacrylamide), PEG-b-(PNIPAM)2, were successfully synthesized through atom transfer radical polymerization (ATRP). A difunctional macroinitiator was prepared by esterification of 2,2-dichloroacetyl chloride with poly(ethylene glycol) monomethyl ether (PEG). The copolymers were obtained via the ATRP of N-isopropylacrylamide (NIPAM) with CuCl/Me6TREN as catalyst and DMF/H2O (v/v = 3:1) mixture as solvent. The resulting polymers were characterized by gel permeation chromatography (GPC) and 1H NMR. These block copolymers show controllable molecular weights and narrow molecular weight distributions (PDI &lt;1.15). Their phase transition temperatures and enthalpy changes in aqueous solution were measured by differential scanning calorimetry (DSC). The results indicate a significant influence of the macromolecular architecture on the phase transition. This is the first study into the effect of molecular architecture on the phase transition using Y-shaped amphiphilic block copolymer composed of PEG and PNIPAM.

Synthesis of Well-Defined Y-Shaped Zwitterionic Block Copolymers via Atom-Transfer Radical Polymerization

A series of well-defined Y-shaped (AB2-type) zwitterionic block copolymers were synthesized by atom-transfer radical polymerization (ATRP). First, a bishydroxy-functional ATRP initiator was synthesized by esterification of 2-hydroxyethyl acrylate with 2-bromoisobutyryl bromide, followed by Michael addition using excess diethanolamine. 2-(Diethylamino)ethyl methacrylate (DEA) was polymerized via ATRP using this bishydroxy-functional initiator. The bromine end groups of PDEA were then quantitatively removed by radical chain transfer using excess N,N,N‘,N‘ ‘,N‘ ‘-pentamethyldiethylenetriamine (PMDETA). Esterification of the ω-bishydroxyl end groups using excess 2-bromoisobutyryl bromide afforded a PDEA-based ω-bifunctional macroinitiator [PDEA-(Br)2]. A series of Y-shaped zwitterionic PDEA-(PSEMA)2 [PSEMA poly(succinyloxyethyl methacrylate)] block copolymers were synthesized via ATRP of 2-hydroxyethyl methacrylate (HEMA) using this PDEA-(Br)2 macroinitiator, followed by reacting the HEMA hydroxyl groups with...

Direct Synthesis and Stimulus-Responsive Micellization of Y-Shaped Hydrophilic Block Copolymers

Two bifunctional atom transfer radical polymerization (ATRP) macroinitiators were synthesized via Michael addition of 2 equivalents of 2-hydroxyethyl acrylate to two commercial monoamine-capped poly(alkylene oxides), Jeffamine XTJ-506 and Jeffamine XTJ-507, followed by esterification using excess 2-bromoisobutyryl bromide. 1H NMR and MALDI−TOF mass spectra (MALDI−TOF MS) were consistent with the expected structures for these two ATRP macroinitiators. A range of well-defined, Y-shaped, pH-responsive or thermoresponsive block copolymers was synthesized using these macroinitiators by polymerizing various hydrophilic methacrylic monomers via ATRP in methanol at 20 °C. The stimulus-responsive micellization of selected Y-shaped block copolymers in aqueous solution was investigated by 1H NMR, dynamic light scattering (DLS), and surface tensiometry. For comparative purposes, their linear diblock copolymer counterparts were also synthesized, and their micellization properties in aqueous solution were investigated. DLS studies indicated that the nonlinear architectures of selected Y-shaped block copolymers usually resulted in micelles with differing dimensions to those formed by the corresponding linear diblock copolymers. DLS studies also confirmed that one of these new Y-shaped block copolymers exhibited “schizophrenic” thermoresponsive behavior in aqueous solution. Near-monodisperse spherical micelles were obtained at higher temperatures (above 45 °C), whereas polydisperse nonspherical micelles appear to be formed at lower temperatures (below 12 °C).

Direct synthesis and aqueous solution properties of Y-shaped, stimulus-responsive block copolymer surfactantsElectronic Supplementary Information (ESI) available: synthesis and characterisation of diblock copolymers. See http://www.rsc.org/suppdata/cc/b4/b400161c/

We report the direct synthesis of a wide range of well-defined, Y-shaped stimulus-responsive block copolymers under mild conditions; the aqueous solution behaviour of these new polymeric surfactants has been investigated.