Star-shaped Amphiphilic Block Copolymer Research Articles

Thermoresponsive properties of star-shaped amphiphilic block copolymers with a cholic acid core and functional amine groups

Block copolymers having stimuli-responsive properties are gaining impetus in the design of drug and gene delivery systems for therapeutic purposes. Thermoresponsive polymers are particularly interesting due to the ease of control over their solution behavior in aqueous media. The fine tuning of the lower critical solution temperature (LCST) of such polymers is necessary to achieve a successful drug delivery. In this work, the thermoresponsive properties of block copolymers based on a bile acid are studied in aqueous media to determine the factors affecting the LCST. Poly(allyl glycidyl ether) (PAGE) and poly(ethylene glycol) (PEG) blocks were grafted from a cholic acid (CA) core to yield star-shaped block copolymers with 4 arms. The PAGE block was further functionalized to bear pendant amine groups. The addition of amine groups may be expected to improve the hydrophilicty of the polymers, but the functionalized polymers showed pronounced thermoresponsive properties and aggregation under physiological conditions. It is thus necessary to understand the changes of their solution properties for a better design of such polymers for drug delivery applications. In this work, we studied the effects of PEG length and of the amine groups on the LCST behavior in water at various salt concentrations. A shorter PEG chain of 21 repeat units shows a LCST of 16 °C, whereas a longer PEG of 41 repeat units failed to show thermoresponsiveness up to 80 °C and at concentrations up to 50 mg/mL. Functionalizing the allyl groups increased the LCST of the polymers. A salting-out effect was observed by a decrease in LCST and the presence of salt also promoted precipitation of the nanoparticles.

Construction of a pH-responsive, ultralow-dose triptolide nanomedicine for safe rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronicautoimmune disease, marked by joint swelling and pain, articular synovial hyperplasia, as well as cartilage and bone destruction. Triptolide (TP) is an anti-inflammatory molecule but its use to treat RA is limited due to poor solubility and extremely high toxicity. In this study, by encapsulating TP into a star-shaped amphiphilic block copolymer, POSS-PCL-b-PDMAEMA, we engineered a pH-sensitive TP-loaded nanomedicine (TP@NPs) to simultaneously reduce the toxicity of TP and improve its therapeutic efficacy. TP@NPs shows a uniform spherical structure with a hydrodynamic diameter of ~92 nm and notable pH-responsiveness. In vitro TP@NPs showed reduced cytotoxicity and cell apoptosis of treated RAW264.7 cells compared to free TP. And in vivo intravenous injection of indocyanine green-labeled NPs into a collagen-induced arthritis model in mice showed that the engineered compound had potent pharmacokinetic and pharmacodynamic profiles, while exhibiting significant cartilage-protective and anti-inflammatory effects with a better efficacy and neglible systemic toxicity even at an ultralow dose compared to free TP. These results suggest that TP@NPs may be a safe and effective therapy for RA and other autoimmune diseases.

Accelerated wound healing by injectable star poly(ethylene glycol)-b-poly(propylene sulfide) scaffolds loaded with poorly water-soluble drugs

Injectable hydrogel matrices take the shape of a wound cavity and serve as scaffold for tissue repair and regeneration. Yet these materials are generally hydrophilic, limiting the incorporation of poorly water soluble, hydrophobic drugs. Here we show this shortcoming is circumvented through a star-shaped amphiphilic block copolymer comprising poly(ethylene glycol) and poly (propylene sulfide). This star-shaped amphiphilic polymer self-assembles in an aqueous medium into a physically stable hydrogel and effectively dissolves hydrophobic molecules delivering them at therapeutic doses. The self assembled hydrogel is a robust three-dimensional scaffold in vivo effectively promoting cellular infiltration, reducing inflammation, and wound clsoure. When combined with a hydrophobic BRAF inhibitor that promotes paradoxical mitogen-activated protein kinase (MAPK) activation in keratinocytes and wound closure, our self assembled scaffold supported dermal wound closure at a reduced drug dosage compared to administering the drug in dimethyl sulfoxide (DMSO) without a polymeric matrix. This family of star-shaped amphiphilic polymers delivers poorly water soluble active agents at a fraction of generally required dosage for efficacy and supports three-dimensional cell growth at tissue wounds, showing great promise for novel uses of hydrophobic drugs in tissue repair applications.

Synthesis and characterization of 4-arm star-shaped amphiphilic block copolymers consisting of poly(ethylene oxide) and poly(ε-caprolactone).

Star-shaped polymers exhibit lower hydrodynamic volume, glass transition temperature, critical micelles concentration (CMC), and higher viscosity and drug-loading capacity compared to their linear counterparts. In the present study, amphiphilic biodegradable 4-arm star-shaped block copolymers, based on poly(ethylene oxide) (PEO) as a hydrophilic part and poly(ε-caprolactone) (PCL) as a hydrophobic segment, are synthesized by ring-opening polymerization of ε-caprolactone employing pentaerythritol as an initiator and stannous octoate as a catalyst, followed by the coupling reaction with carboxyl-functionalized monomethoxy poly(ethylene oxide) (MeO-PEO-COOH). The structures of intermediates were deduced through 1H-NMR and FT-IR spectroscopy. Average chemical composition of the star block copolymer is determined by proton NMR. Information related to molar mass distribution of targeted products and their precursors is obtained by size exclusion chromatography (SEC). However, due to its inherent poor resolution SEC could not reveal whether all the parent homopolymers are coupled to each other or remained unattached to the other segment. In order to comprehensively characterize the synthesized star-block copolymers, liquid chromatography at critical conditions of both blocks is employed. The study allowed for separation of homopolymer precursors from targeted star-block copolymers. The study exposed heterogeneity of star block copolymers that was not possible by conventional techniques.

Fabrication of supramolecular star-shaped amphiphilic copolymers for ROS-triggered drug release

Star-shaped copolymers with branched structures can form unimolecular micelles with better stability than the micelles self-assembled from conventional linear copolymers. However, the synthesis of star-shaped copolymers with precisely controlled degree of branching (DB) suffers from complicated sequential polymerizations and multi-step purification procedures, as well as repeated optimizations of polymer compositions. The use of a supramolecular host-guest pair as the block junction would significantly simplify the preparation. Moreover, the star-shaped copolymer-based unimolecular micelle provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy if the association/dissociation of the supramolecular host-guest joint can be triggered by the biologically relevant stimuli. For this purpose, in this study, a panel of supramolecular star-shaped amphiphilic block copolymers with 9, 12, and 18 arms were designed and fabricated by host-guest complexations between the ring-opening polymerization (ROP)-synthesized star-shaped poly(ε-caprolactone) (PCL) with 3, 4, and 6 arms end-capped with ferrocene (Fc) (PCL-Fc) and the atom transfer radical polymerization (ATRP)-produced 3-arm poly(oligo ethylene glycol) methacrylates (POEGMA) with different degrees of polymerization (DPs) of 24, 30, 47 initiated by β-cyclodextrin (β-CD) (3Br-β-CD-POEGMA). The effect of DB and polymer composition on the self-assembled properties of the five star-shaped copolymers was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence spectrometery. Interestingly, the micelles self-assembled from 12-arm star-shaped copolymers exhibited greater stability than the 9- and 18-arm formulations. The potential of the resulting supramolecular star-shaped amphiphilic copolymers as drug carriers was evaluated by an in vitro drug release study, which confirmed the ROS-triggered accelerated drug release from the doxorubicin (DOX)-loaded supramolecular star-shaped micelles due to the oxidation-induced dissociation of β-CD/Fc pair and the consequent loss of the colloidal stability of the star-shaped micelles. Studies of the delivery efficacy by an in vitro cytotoxicity study further indicated that higher DBs and longer hydrophilic arm compromised the therapeutic efficacy of the DOX-loaded supramolecular star-shaped micelles, resulting in significantly reduced cytotoxicity, as measured by increased IC50 value. Overall, our results revealed that the screening of hydrophilic block by DB and MW for an optimized star-shaped copolymer should balance the stability versus therapeutic efficacy tradeoff for a comprehensive consideration. Therefore, the 12-arm star-shaped copolymer with POEGMA30 is the best formulation tested.

A star-shaped amphiphilic block copolymer with dual responses: synthesis, crystallization, self-assembly, redox and LCST–UCST thermoresponsive transition

The micelles/aggregates that were self-assembled from a star-shaped copolymer presented redox-responsive behaviour and LCST–UCST thermoresponsive transition.

Hydrogels from amphiphilic star block copolypeptides

Star-shaped amphiphilic block copolymers form hydrogels as opposed to their linear counterparts.

Synthesis and Drug Release of Star‐Shaped Poly(benzyl L‐aspartate)‐block‐poly(ethylene glycol) Copolymers with POSS Cores

Star-shaped amphiphilic block copolymers with polyhedral oligomeric silsesquioxanes (POSS) as cores are synthesized using the "arm-first" strategy. First, the block copolymer poly(benzyl L-aspartate)-block-poly(ethylene glycol) (PBLA-b-PEG) is synthesized via ring-opening polymerization of β-benzyl L-aspartate-N-carboxyanhydride (BLA-NCA) with α-methoxy-ω-aminopoly(ethylene glycol) (mPEG-NH2 ) as a macroinitiator. The copolymers are then immobilized on the eight groups of the polyhedral oligomeric silsesquioxanes (POSS-COOH). The star-shaped copolymers (POSS-g-(PBLA-b-PEG)) are characterized by (1) H NMR and FT-IR spectroscopy and gel permeation chromatography. The star-shaped block copolymers self-assemble into micelles in aqueous medium. Quercetin is used as a model drug and the drug loading content and encapsulation efficiency increases with increasing chain length of the PBLA blocks. The drug release behaviors of drug loaded micelles are investigated and the cytotoxicity assay demonstrates that the POSS-g-(PBLA-b-PEG) copolymers are non-toxic. The star-shaped block copolymers are potential carriers for anticancer drug delivery.

两亲性六臂星型端氨基PEG-PLGA的合成、表征及胶束化行为

采用本体开环聚合法, 以乙交酯(GA)和 DL -丙交酯(DLA)为原料, 肌醇为引发剂, 合成了一系列不同分子量的六臂星型聚乳酸聚乙醇酸(PLGA)(6-s-PLGA 50 , 6-s-PLGA 100 , 6-s-PLGA 200 , 其中50, 100, 200为原料与引发剂的摩尔比), 采用羧基化反应对其端基进行羧化处理. 以聚乙二醇4000(PEG4000)为原料用对甲苯磺酰化法得到sTO-PEG-OTs, 再进行氨解得到双端氨基PEG(H 2 N-PEG-NH 2 ). 末端羧基6-s-PLGA x 通过 N -环己基碳二亚胺(DCC)缩合反应与双端氨基PEG连接得到两亲性星型六臂结构的聚合物(6-s-PLGA x -PEG-NH 2 ). 分别用核磁共振氢谱法( 1 H NMR)、 凝胶排阻色谱法(GPC)及差示热量热分析法(DSC)等手段对6-s-PLGA x 和6-s-PLGA x -PEG-NH 2 进行了表征. 以6-s-PLGA 100 -PEG-NH 2 聚合物为例, 自组装得到空白的纳米粒子, 并用透射电子显微镜法(TEM)和动态光散射法(DLS)考察了粒子的表面形态以及粒径分布特征, 用 1 H NMR分析了胶束的核-壳结构. 用噻唑蓝四氮唑溴化物(MTT)比色法探讨了该两亲性材料的体外细胞毒性. 研究结果表明, 合成了不同分子量的两亲性六臂星型端氨基PEG-PLGA, 该两亲性聚合物可自组装形成纳米胶束, 粒径范围在40~60 nm, 与PLGA 相比体外细胞毒性无显著性差异.

Folate-decorated thermoresponsive micelles based on star-shaped amphiphilic block copolymers for efficient intracellular release of anticancer drugs

In this study, a new type of folate-decorated thermoresponsive micelles based on the star-shaped amphiphilic block copolymer 4s[poly(ε-caprolactone)-b-2s(poly(N-isopropylacrylamide-co-acrylamide)-b'-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate)] (i.e., 4s[PCL-b-2s(P(NIPAAm-co-AAm)-b'-MPEG/PEG-FA)] (PCIAE-FA)), were developed for the tumor-targeted delivery and temperature-induced controlled release of hydrophobic anticancer drugs. These amphiphilic star copolymers are capable of self-assembling into spherical micelles in aqueous solution with an average diameter of 91 nm. The lower critical solution temperature (LCST) of micelles was around 39.7 °C. The anticancer drug, paclitaxel (PTX), was encapsulated into the micelles. In vitro release studies demonstrated that the drug-loaded delivery system (PTX-PCIAE-FA) is relatively stable at physiologic conditions but susceptible to temperatures above LCST which would trigger the release of encapsulated drugs. The cytotoxicity studies showed that the PTX transported by these micelles was higher than that by the commercial PTX formulation Tarvexol(®). The efficacy of this thermoresponsive drug delivery system was also evaluated at temperatures above the LCST; the results demonstrated that the cellular uptake and the cytotoxicity of PTX-loaded micelles increase prominently. These results indicate that these thermoresponsive micelles may offer a very promising carrier to improve the delivery efficiency and cancer specificity of hydrophobic chemotherapeutic drugs.

Temperature sensitivity and drug encapsulation of star‐shaped amphiphilic block copolymer based on dendritic poly(ether‐amide)

The star-shaped amphiphilic block copolymer (DPEA-PCL-PNIPAAms) with different PCL block lengths was prepared through ring opening polymerization of epsilon-caprolactone (CL) initiated by hydroxyl end-capped dendritic poly(ether-amide) (DPEA-OH), and then coupling with carboxyl end-capped linear poly(N-isopropylacrylamide) (PNIPAAm-COOH) via an esterification process. The molecular structure was characterized by FT-IR, (1)H NMR, and GPC analysis. As the copolymer dissolved in water, the core-shell structural nanoparticle was formed as a micelle. The fluorescence, (1)H NMR, and dynamic light scattering (DLS) techniques were utilized to confirm the formation of micelles. The optical transmittance and US-DSC measurements demonstrated that the micelles performed the reversible dispersion/aggregation behavior in response to temperature through the outer PNIPAAm polymer shell. The micelles loaded with daidzein showed a very rapid drug release speed at temperatures above the lower critical solution temperature (LCST) due to the temperature-induced structural change of the polymeric micelles.

Synthesis and Properties of Amphiphilic Star Polysulfides

We here present the synthesis and characterisation of linear and star-shaped amphiphilic block copolymers based on hydrophobic polysulfides (poly(propylene sulfide), PPS) and hydrophilic polyethers (poly(ethylene glycol), PEG). We also discuss the proof of the principle of their responsiveness to oxidising conditions. In a water environment, these polymers aggregate in the form of sub-micron carriers that, due to the sensitivity to oxidation reactions typical of PPS, can be used for responsive drug delivery. In this first study we have focused on the study of large aggregates, which do not apparently show dramatic differences in behaviour when polymer chains with different degrees of branching are studied.

Crystallization behavior and micelle formation of star-shaped amphiphilic block copolymer based on dendritic poly(ether-amide)

The star-shaped amphiphilic block copolymer (DPEA-PCL-PEG) was prepared through ring opening polymerization of ε-caprolactone (CL) initiated by hydroxyl end-capped dendritic poly(ether-amide) (DPEA-OH), then coupling with monomethoxy-terminated poly(ethylene-glycol) (PEG) via an esterification process. The molecular structure was verified by FT-IR, 1H NMR and gel permeation chromatography (GPC). The number average molecular weight of the PCL arm was calculated to be about 1910 g mol −1 by 1H NMR analysis. The number average molecular weight of the copolymer was determined to be 74,020 with the molecular weight distribution of 1.15 by GPC. The DSC and X-ray diffraction analysis indicated that the copolymer possesses double melting and crystallization peaks, attributed to PCL and PEG segments in DPEA-PCL-PEG. The corresponding melting and crystallization temperature, and value of crystallinity are much lower than that of their individual homopolymers. The copolymer easily formed the core–shell structural nanoparticles as micelles in water with a lower critical micelle concentration of 5.524 mg l −1.