An improved interfacial coacervation technique to fabricate biodegradable nanocapsules of an aqueous peptide solution from polylactide and its block copolymers with poly(ethylene glycol)

ABA block copolymers of polylactide and poly(ethylene glycol) as amphiphilic bioabsorbable polymers were synthesized by the ring-opening polymerization of dl- lactide onto poly(ethylene glycol) (PEG 2000 or PEG 6000) and their structures were characterized on the basis of proton NMR. Biodegradable nanocapsules of an aqueous insulin solution were prepared from the block copolymers and polylactide by an improved interfacial coacervation technique. The results showed that the diameters of the nanocapsules were mainly dependent on the ratio of the two chains in the block polymers. The size of the nanocapsules decreased with an increase in the amount of surfactant used. More insulin solution resulted in an enlargement of the nanocapsules in diameter. In an optimum condition, biodegradable nanocapsules could be achieved with a size around 250 nm with a narrow distribution. The encapsulation percentages of insulin were larger in the nanocapsules from the PEG 2000 copolymers than in those from the PEG 6000 analogs and changed with the ratios of the blocks in the block copolymers. Received: 17 July 2000 Accepted: 24 November 2000     

两亲型聚L-亮氨酸-聚乙二醇单甲醚嵌段共聚物的合成与表征

开环聚合;生物降解共聚物;两亲型聚L-亮氨酸-聚乙二醇单甲醚嵌段共聚物的合成与表征     

聚对二氧环己酮/聚乙二醇多嵌段共聚物的合成与表征

首先合成双端羟基的聚对二氧环己酮预聚物(PPDO)和双端羧基的聚乙二醇预聚物(PEG),然后以丁二酸酐/二环己基碳二亚胺(DCC)将PPDO与PEG偶联共聚,得到PPDO/PEG多嵌段共聚物.通过1H-NMR和GPC表征了聚合物的结构和分子量.采用差示扫描量热法(DSC)和热重分析(TGA)研究了共聚物的结晶性能和热稳定性.用透析法制备了共聚物纳米粒子,并用动态光散射(DLS)表征了共聚物纳米粒子的粒径及分散度,结果表明,随着共聚物亲水链段PEG含量的增加,其纳米粒子更易形成,粒子粒径随共聚物分子量增大而增大.     

Preparation and characterization of biodegradable nanoparticles based on amphiphilic poly(3-hydroxybutyrate)-poly(ethylene glycol)-poly(3-hydroxybutyrate) triblock copolymer

Amphiphilic triblock copolymers of poly(3-hydroxybutyrate)-poly(ethylene glycol)-poly(3-hydroxybutyrate) (PHB-PEG-PHB) were directly synthesized by the ring-opening copolymerization of β-butyrolactone monomer using PEG as macroinitiator. Their structure, thermal properties and crystallization were investigated by ¹H NMR, differential scanning calorimetry (DSC) and X-ray diffraction. It was found that both PHB and PEG blocks were miscible. With the increase in the PHB block length, the triblock copolymers became amorphous because amorphous PHB block remarkably depressed the crystallization of the PEG block. Biodegradable nanoparticles with core-shell structure were prepared in aqueous solution from the amphiphilic triblock copolymers, and characterized by ¹H NMR, SEM and fluorescence. The hydrophobic PHB segments formed the central solid-like core, and stabilized by the hydrophilic PEG block. The nanoparticle size was close related to the initial concentrations of the nanoparticle dispersions and the compositions of the triblock copolymers. Moreover, the PHB-PEG-PHB nanoparticles also showed good drug loading properties, which suggested that they were very suitable as delivery vehicles for hydrophobic drugs.     

Micellization and gelation of aqueous solutions of star-shaped PEG-PCL block copolymers consisting of branched 4-arm poly(ethylene glycol) and polycaprolactone blocks

Star-shaped block copolymers consisting of non-toxic poly(ethylene glycol) and biodegradable polycaprolactone ((PEG5K-PCL)₄) were synthesized by ring-opening polymerization of the ε-caprolactone monomer with hydroxyl-terminated 4-armed PEG as initiator. These biodegradable, amphiphilic star block copolymers showed micellization and sol-gel transition behaviors in aqueous solution with varying concentration and temperature. In the dilute aqueous solutions of star block copolymers, micellization behavior occurred over specific concentration. The 1,6-diphenyl-1,3,5-hexatriene (DPH) solubilization method was used to determine the critical micellization concentration (CMC) of star block copolymers. The obtained micelle size increased with increasing hydrophobic PCL block length. In high-concentration solutions, the star block copolymers showed temperature-sensitive sol-gel transition behavior. The morphology of the micelle and gel was investigated by atomic force microscopy (AFM). As a result, the micelles showed a core-corona spherical structure at concentration near CMC, while the gel showed a mountain-chain-like morphology picture. It was proposed that with increasing the micelle concentration the worm-like micelle clusters formed firstly and the gel was constructed by the packing of micelle clusters.     

Characterization of amphiphilic hydrocarbon modified Poly(ethylene glycol) synthesized through ring-opening reaction of 2-(1-octadecenyl)succinic anhydride

Poly(ethylene glycol) (PEG) triblock and diblock amphiphilic block copolymers were synthesized from poly(ethylene glycol) and poly(ethylene glycol) monomethyl ether, respectively. The hydroxyl groups of PEG readily react with 2-(1-octadecenyl) succinic anhydride (OSA) at 140 °C through ring-opening reaction of the succinic anhydride. Both the PEG-OSA diblock and triblock copolymers are produced without use of any solvent or catalyst. The molecular structure of the copolymers was characterized by ¹H NMR and FTIR spectroscopy, and the thermal properties by DSC. The behavior of the copolymers in selective and nonselective solvents was studied by ¹H NMR spectroscopy in deuterium oxide and d-chloroform. The aggregation of the polymers in water was studied with a particle size analyzer and a transmission electron microscope (TEM) in bright field mode. The results show that the hydrophobic C₁₈ chain with intramolecular succinic anhydride linker can be attached to the hydrophilic PEG chain, an ester bond forming between the blocks. The copolymers exhibit flexible, liquid-like hydrophobic blocks even in water, which is a nonsolvent for OSA. PEG-OSA block copolymers self-organize in water, forming micellar polymer aggregates in nanoscale.     

Synthesis and characterization of novel biodegradable folate conjugated polyurethanes

In order to obtain targeting polyurethane micelle drug carriers, a series of biodegradable folate conjugated polyurethanes (FPUs) were synthesized using poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) as soft segments, L-lysine ethyl ester diisocyanate (LDI) and 1,3-propanediol (PDO) as hard segments, and folic acid-ethylenediamine conjugate (FA-EDA) as an end-capping reagent. The resultant FPUs were fully characterized by (1)H NMR, Fourier-transform infrared (FTIR) spectroscopy, ultraviolet spectrophotometry (UV), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). These polymers can self-assemble into micelles in aqueous solutions confirmed by dynamic light scattering (DLS), pyrene fluorescence probe techniques, and transmission electron microscopy (TEM). The results indicated that the bulk structures and micellar properties of the prepared polyurethanes could be controlled by varying the PEG content in the soft segments. The present work provides a facile approach to prepare amphiphilic multiblock copolymers with tumor targeting moiety, which is a good candidate as biodegradable carriers for active intracellular drug delivery.     

Application of New Modified Poly(ethylene Oxide)-Block-Poly(propylene oxide)-Block-Poly(ethylene oxide) Copolymers as Demulsifier for Petroleum Crude Oil Emulsion

Water soluble nonionic amphiphilic block copolymers based on hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(propylene glycol) (PPG) were prepared. Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymers, PEG-PPG-PEG, were prepared in the normal condition. The chemical composition and molecular weights of the prepared copolymers were determined from ¹H NMR and GPC techniques. The surface properties of the prepared surfactants were determined by measuring the surface tension at different temperatures. The prepared nonionic surfactants were evaluated as demulsifiers for water in crude-oil emulsions that were pronounced at different ratios of crude oil: water at 318 K and 333 K. The experimental results showed that the dehydration rate of the prepared demulsifiers reached 100% based on demulsifier chemical compositions and concentrations.     

Y‐shaped poly(ethylene glycol) and poly(trimethylene carbonate) amphiphilic copolymer: Synthesis and for drug delivery

New Y‐shaped (AB₂‐type) amphiphilic copolymers of poly(ethylene glycol) (PEG) with poly(trimethylene carbonate) (PTMC), PEG‐b‐(PTMC)₂, were successfully synthesized by the ring‐opening polymerization (ROP) of TMC with bishydroxy‐modified monomethoxy‐PEG (mPEG). First, a bishydroxy functional ROP initiator was synthesized by esterification of acryloyl bromide with mPEG, followed by Michael addition using excess diethanolamine. A series of Y‐shaped amphiphilic PEG‐(PTMC)₂ block copolymers were obtained via ROP of TMC using this PEG with bishydroxyl end groups as macroinitiator and ZnEt₂ as catalyst. The amphiphilic block copolymers with different compositions were characterized by gel permeation chromatography (GPC) and ¹H NMR, and their molecular weight was measured by GPC. The results showed that the molecular weight of Y‐shaped copolymers increased with the increase of the molar ratio of TMC to mPEG‐(OH)₂ initiator in feed while the PEG chain length was kept constant. The Y‐shaped copolymer mPEG‐(PTMC)₂ could self‐assemble into micelles in aqueous medium and the critical micelle concentration values of the micelles decrease with increase in hydrophobic PTMC block length of mPEG‐(PTMC)₂. The in vitro cytotoxicity and controlled drug release properties of the Y‐shaped amphiphilic block copolymers were also investigated. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 8131–8140, 2008     

Amphiphilic PEG‐grafted poly(ester‐carbonate)s: Synthesis and diverse nanostructures in water

Novel biodegradable amphiphilic graft copolymers containing hydrophobic poly(ester‐carbonate) backbone and hydrophilic poly(ethylene glycol) (PEG) side chains were synthesized by a combination of ring‐opening polymerization and “click” chemistry. First, the ring‐opening copolymerization of 5,5‐dibromomethyl trimethylene carbonate (DBTC) and ε‐caprolactone (CL) was performed in the presence of stannous octanoate [Sn(Oct)₂] as catalyst, resulting in poly(DBTC‐co‐CL) with pendant bromo groups. Then the pendant bromo groups were completely converted into azide form, which permitted “click” reaction with alkyne‐terminated PEG by Huisgen 1,3‐dipolar cycloadditions to give amphiphilic biodegradable graft copolymers. The graft copolymers were characterized by proton nuclear magnetic resonance (¹H NMR), Fourier transform infrared spectra and gel permeation chromatography measurements, which confirmed the well‐defined graft architecture. These copolymers could self‐assemble into micelles in aqueous solution. The size and morphologies of the copolymer micelles were measured by transmission electron microscopy and dynamic light scattering, which are influenced by the length of PEG and grafting density. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011.     

Synthesis and characterization of controlled drug release carriers based on functionalized amphiphilic block copolymers and super‐paramagnetic iron oxide nanoparticles

In this study, synthesis and characterization of magnetic nanocarriers are reported for drug delivery based on the amphiphilic di‐block and tri‐block copolymers of poly(ethylene glycol) (PEG) and poly(ε‐caprolactone) (PCL) with surface modified super‐paramagnetite Fe₃O₄ nanoparticles (magnetic nanoparticles (MNPs)). The synthesized block copolymers (methoxy poly(ethylene glycol) (mPEG)–PCL and PCL–PEG–PCL) were characterized by Fourier transform infrared (FT‐IR), ¹H nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC), and their properties such as critical micelle concentration, hydrophilicity to lipophilicity balance, and hydrolytic degradation were investigated. The block copolymers were functionalized with terminal azide groups (mPEG–PCL(N₃) and (N₃)PCL–PEG–PCL(N₃)), and magnetic Fe₃O₄ nanoparticles were surface modified with poly(acrylic acid) (PAA) and propargyl alcohol (MNP–PAA–C≡CH). Magnetic nanocarriers were synthesized by click reaction between azide‐terminated block copolymers and MNP–PAA–C≡CH and characterized by FT‐IR, thermogravimetric analysis (TGA), dynamic light scattering (DLS), vibrating sample magnetometer (VSM), and transmission electron microscopy (TEM), and cytotoxicity was investigated by methyl thiazolyl tetrazolium assay. In vitro drug loading and release and release kinetics were investigated. Copyright © 2015 John Wiley & Sons, Ltd.     

Chitooligosaccharide Copolymers: Synthesis and Aqueous Self-assembly

Novel water-soluble amphiphilic graft copolymers (COS-g-PCL-b-MPEG) were synthesized by the coupling reaction between chitooligosaccharide (COS) and MPEG-b-PCL-COOH, which was synthesized via ring-opening polymerization of ε-caprolactone (CL) using MPEG as an initiator and subsequent carboxylation by succinic anhydride. The chemical composition of the graft copolymers was confirmed by ¹H-NMR spectra and FT-IR spectrometry. The thermal properties and crystallinity of the copolymers were observed by DSC and XRD measurements, which showed the existence of separate backbone and graft chain phases in the copolymer. The micellar behavior via self-assembly of the graft copolymers in aqueous solution was studied using pyrene fluorescence dye technique. AFM measurements showed that the micelles had a spherical morphology at the critical micelle concentration (CMC) and ranged in size from 20–45 nm. The amphiphilic ternary biodegradable graft copolymer endows the hydrophilic outer shell of micelles with structural and functional diversification, which might be desirable for drug delivery applications.     

结肠酶特异响应性两亲高分子载体的合成和表征

合成了一种可在结肠部位被特异酶解的两亲性嵌段高分子,由聚丙交酯(PLA)疏水嵌段和聚乙二醇(PEG)亲水嵌段组成,两者通过5,5′-偶氮二水杨酸(OLZ)偶联,其中的偶氮键可被结肠部位的偶氮还原酶特异酶解.利用FTIR、NMR和GPC等方法表征了共聚物的结构,并通过透射电镜(TEM)和动态光散射(DLS)等方法研究了该高分子载体在水溶液中的组装行为.结果表明MPEG-OLZ-b-PLA可在水介质中形成尺寸在30nm左右的球形胶束,并在大鼠全盲肠提取液中被特异性酶解。     

Synthesis and characterization of poly(ɛ-caprolactone-co-ethylene glycol) star-type amphiphilic copolymers by “click” chemistry and ring-opening polymerization

Abstract

The synthesis of poly(?-caprolactone-co-ethylene glycol) AAB star-type amphiphilic copolymers were carried out by use of a “click” chemistry reaction to block propargyl polyethylene glycol (propargyl-PEG) to terminally azide poly(?-caprolactone) (PCL-N₃). For this purpose, propargyl-PEG was synthesized by the reaction of PEGs (3000?Da, 2000?Da, 1500?Da, and 1000?Da) and propargyl chloride. Terminally chloride poly(?-caprolactone) (PCL-Cl) was carried out by means of ring-opening polymerization (ROP) of ?-caprolactone (CL) and 3-chloro-1,2-propanediol. Synthesis of PCL-N₃ was obtained by the chemical interaction of PCL-Cl and sodium azide. By reacting propargyl-PEG and PCL-N₃, the star-type amphiphilic copolymers were obtained. The characterization of products was accomplished by using multiple instruments including ¹H-NMR, FT-IR, GPC, TGA, contact angles, and elemental analysis techniques.     

二维核磁共振法研究线型聚乙二醇与树枝状聚苄醚形成的三嵌段共聚物

嵌段共聚物是由几个不同的高分子链段通过化学键相连所构成的 .在合成方法上一般是通过几类不同的活性聚合 ,调控单体的加料次序或者通过不同的大分子链段末端的反应活性点偶联而成[1～ 3 ] .所形成的化学键将嵌段共聚物中不相溶的几段相连 ,于是在特定的条件下就产生了微相分离的现象 ,继而可以在 1 0～ 1 0 0nm尺度范围内形成各种各样的微区结构[4,5] .在过去的几十年里 ,研究的重点是认定嵌段共聚物的微区结构和研究微相分离的动力学 ,已发表了大量重要的结果 ,至今仍然是高分子科学中的热门课题 .非常重要的一点是 ,正是由于不同的高分…     

ABA-type amphiphilic triblock copolymers containing p-ethoxy azobenzene via atom transfer radical polymerization: Synthesis,characterization, and properties

ABA-type amphiphilic triblock copolymers composed of poly(ethylene glycol)s (PEGs) with different number-average molecular weights as the hydrophilic blocks (B) and poly{6-[4-(4-ethoxyphenylazo)phenoxy]hexyl methacrylate} (PA6C) as the hydrophobic blocks (A) were prepared via atom transfer radical polymerization. These copolymers were prepared from bromo-terminated macroinitiators based on PEG6000, PEG2000, and PEG600, with CuBr/N,N,N′,N″,N″-pentamethyldiethylenetriamine as the catalytic system, at 85 °C in anisole. The block copolymers were characterized with ¹H NMR spectroscopy and gel permeation chromatography. Differential scanning calorimetry measurements were performed to reveal the phase segregation. In contrast to those polymers with similar compositions and structures in previous reports, these amphiphilic copolymers exhibited unusual liquid-crystalline properties over a wide temperature range, being stable even at room temperature. These copolymers showed photoresponsive isomerization under the irradiation of UV–vis light both in THF solutions and in solid films. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2225–2234, 2007     

Poly(sodium styrene sulfonate)-b-poly(methyl methacrylate) diblock copolymers through direct atom transfer radical polymerization: Influence of hydrophilic–hydrophobic balance on self-organization in aqueous solution

A series of poly(sodium styrene sulfonate)-b-poly(methyl methacrylate), PSSNa-b-PMMA, amphiphilic diblock copolymers have been synthesized through atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA) in N,N-dimethylformamide/water mixtures, starting from a PSSNa macroinitiator. The kinetics of the polymerization was followed by ¹H NMR, while the chemical composition of the copolymers was verified by a variety of techniques, such as ¹H NMR, FTIR and TGA. The MMA content of the copolymers ranges from 0 up to 60 mol%, while the number–average molecular weight of the PSSNa macroinitiator was 9000 g/mol. The self-association of the diblock copolymers in aqueous solution was compared to the respective behavior of similar random P(SSNa-co-MMA) copolymers through optical density measurements, pyrene fluorescence probing, dynamic light scattering and surface tension measurements. It is shown that the diblock copolymers form micellar structures in water, characterized by an increasing hydrophobic character and a decreasing size as the length of the PMMA block increases. These micelle-like structures turn from surface inactive to surface active as the length of the PMMA block increases. Moreover, contrary to the MMA-rich random copolymers, the respective diblock copolymers form water insoluble polymer/surfactant complexes with cationic surfactants such as hexadecyltrimethyl ammonium bromide (HTAB), leading to materials with antimicrobial activity.     

Synthesis and characterization of amphiphilic block copolymers with allyl side‐groups

The synthesis of a new cyclic carbonate monomer containing an allyl group was reported and its biodegradable amphiphilic block copolymer, poly(ethylene glycol)‐block‐poly(L ‐lactide‐co‐5‐methyl‐5‐allyloxycarbonyl‐propylene carbonate) [PEG‐b‐P(LA‐co‐MAC)] was synthesized by ring‐opening polymerization (ROP) of L ‐lactide (LA) and 5‐methyl‐5‐allyloxycarbonyl‐1,3‐dioxan‐2‐one (MAC) in the presence of poly (ethylene glycol) as a macroinitiator, with diethyl zinc as a catalyst. ¹³C NMR and ¹H NMR were used for microstructure identification of the copolymers. The copolymer could form micelles in aqueous solution. The core of the micelles is built of the hydrophobic P(LA‐co‐MAC) chains, whereas the shell is set up by the hydrophilic PEG blocks. The micelles exhibited a homogeneous spherical morphology and unimodal size distribution. By using the cyclic carbonate monomer containing allyl side‐groups, crosslinking of the PEG‐b‐P(LA‐co‐MAC) inner core was possible. The adhesion and spreading of ECV‐304 cells on the copolymer were better than that on PLA films. Therefore, this biodegradable amphiphilic block copolymer is expected to be used as a biomaterial for drug delivery and tissue engineering. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5518–5528, 2007     

Self-assembly of amphiphilic liquid crystal polymers obtained from a cyclopropane-1,1-dicarboxylate bearing a cholesteryl mesogen

We study the self-assembly of a new family of amphiphilic liquid crystal (LC) copolymers synthesized by the anionic ring-opening polymerization of a new cholesterol-based LC monomer, 4-(cholesteryl)butyl ethyl cyclopropane-1,1-dicarboxylate. Using the t-BuP(4) phosphazene base and thiophenol or a poly(ethylene glycol) (PEG) functionalized with thiol group to generate in situ the initiator during the polymerization, LC homopolymer and amphiphilic copolymers with narrow molecular weight distributions were obtained. The self-assemblies of the LC monomer, homopolymer, and block copolymers in bulk and in solution were studied by small-angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), polarizing optical microscopy (POM), and transmission electron microscopy (TEM). All polymers exhibit in bulk an interdigitated smectic A (SmA(d)) phase with a lamellar period of 4.6 nm. The amphiphilic copolymers self-organize in solution into vesicles with wavy membrane and nanoribbons with twisted and folded structures, depending on concentration and size of LC hydrophobic block. These new morphologies will help the comprehension of the fascinating organization of thermotropic mesophase in lyotropic structures.     

聚乙二醇嵌段树枝状聚赖氨酸共聚物的合成及其基因载体研究

采用液相多肽合成法制备得到窄分子量分布、结构可控的生物相容性聚乙二醇嵌段共聚树枝状聚赖氨酸阳离子功能大分子(PEG-b-Dendritic PLL). 运用¹H NMR核磁共振、凝胶电泳以及荧光淬灭滴定手段对所得阳离子两嵌段大分子的化学结构及其与质粒DNA (pDNA)结合作用与复合行为进行了研究. 结果表明聚乙二醇嵌段树枝状聚赖氨酸与pDNA分子可以在缓冲溶液中形成稳定的胶束, pDNA与阳离子树枝赖氨酸嵌段通过静电相互作用形成胶束核, 其水溶性聚乙二醇嵌段形成水溶性胶束壳, 提高了阳离子大分子/pDNA复合胶束的稳定性. 同时发现随着阳离子嵌段树枝状赖氨酸代数的增加, 阳离子两嵌段大分子与pDNA的结合作用增强, 有利于其作为基因转染生物功能载体的应用.