高分子囊泡和空心球的制备和几个研究亮点

聚合物囊泡和空心球是具有重要理论研究价值和在很多领域特别是在生物医药方面具有潜在应用的大分子组装体本文综述了高分子囊泡及空心球的制备方法及某些新发展其传统的制备方法主要包括嵌段共聚物自组装法和聚合物胶束去核法以及模板上合成着重讨论了近年来新发展起来的非共价键合自组装法(NCCM)以及通过化学反应一步从单体获得聚合物空心...     

pH和还原双重敏感性超支化纳米胶束的制备及其释药性能

将聚乙二醇二缩水甘油醚(PEGDGE)与胱胺(Cys)置于水溶液中,通过亲核开环反应制备出超支化聚合物,并自组装形成多核-壳结构的纳米胶束,再通过甲氨蝶呤(MTX)与纳米胶束间的疏水作用制备出载药胶束。用FT-IR、~1H-NMR、DLS、SEM等方法对聚合物结构和胶束粒径与形貌进行表征,采用噻唑蓝(MTT)法测试纳米胶束和载药胶束的细胞毒性。结果表明:聚合物经过透析纯化后自组装形成纳米胶束,其粒径约为100nm,呈均一球形;载药胶束对MTX的载药率为10.32%;当载药胶束处于模拟肿瘤环境中时,酸性和还原性条件可刺激药物释放。细胞毒性实验表明,纳米胶束具有优良的生物相容性;载药胶束具有较强的抗肿瘤活性。     

聚肽胶束的超分子反应:聚合、环化及活性生长

聚合物自组装是制备纳米材料的有效途径.自组装纳米材料在药物载体、高性能材料、生物结构模型等领域具有重要的应用价值.近年来,在聚合物分子自组装研究的基础上,研究者们发展了聚合物纳米粒子的自组装研究,并取得了很大进步.聚合物纳米粒子的组装一般可称为超分子反应.以聚肽胶束为组装基元的超分子反应研究得到了很多关注,取得了一系列进展.本文以本课题组的工作为主,总结归纳了近年来在聚肽胶束自组装(超分子反应)研究方面的进展,主要包括超分子聚合、环化和活性生长.文中着重强调了理论模拟在探究胶束超分子反应中的作用.最后,本文展望了该研究领域的发展方向,并指出所面临的机遇和挑战.     

两亲性嵌段共聚物的合成及其在离子液体中的自组装行为

采用阴离子开环聚合法合成了两亲性嵌段共聚物PLA-PEG-PLA.用FT-IR,1H NMR和GPC等手段对嵌段共聚物的结构组成进行了表征.两亲性嵌段共聚物在离子液体1-丁基-3-甲基咪唑六氟磷酸盐中能自组装成胶束,用透射电子显微镜观察了聚合物在离子液体中形成胶束的纳米结构.当疏水链长固定时,胶束的自组装形状主要依赖于亲水链的长度.两亲性共聚物在离子液体中可自组装成可控制结构的纳米胶束,这种纳米结构胶束在很多领域具有广泛的应用前景.     

超支化聚合物胶束自组装

超支化聚合物因其独特的拓扑结构和物理化学性质,引起了科学界和工业界的广泛关注,成为高分子学科一个新的研究热点之一。近年来,超支化聚合物在分子自组装研究领域展示出了独特的潜力,实现了多维多尺度自组装,制备了各种超分子结构。而胶束是超支化聚合物最容易自组装得到的超分子结构。本文我们将系统总结超支化聚合物包括聚醚、聚酯、聚磷酸酯、聚多糖等胶束自组装行为、组装机理及其在生物医药、纳米载体、金属纳米粒子制备等方面的最新应用。     

无规共聚物自组装球形胶束表面亲水性的耗散粒子动力学模拟

建立了含不同亲疏水粒子比的双亲性无规共聚物粗粒化模型. 采用耗散粒子动力学方法模拟了两亲性无规共聚物选择性溶剂自组装球形胶束表面的亲水性能. 模拟结果表明, 无规共聚物在选择性溶剂中自组装得到实心球形胶束, 球形胶束表面的亲水性与聚合物链亲水粒子含量、溶剂的选择性有关. 随着聚合物链所含亲水粒子增加, 球形胶束表面的亲水性增强. 球形胶束表面的亲水性随着疏水粒子与溶剂粒子间的排斥参数增大而增强, 模拟结果与实验结论一致. 该模拟方法给出的胶束微结构信息可以为双亲无规共聚物分子设计及自组装双亲胶束制备提供一定的理论指导.     

超支化聚合物的合成和自组装研究

超支化聚合物作为树形聚合物的一种,具有独特的结构和性能,受到了科学界和工业界的广泛关注.本文简要总结了研究者们在超支化聚合物的合成、组装及应用方面的部分工作成果.主要包括以下3方面的内容:第一部分介绍了超支化聚合物的合成方法;第二部分介绍了超支化聚合物多维多尺度的自组装结构和组装机理,包括纳米球形胶束,纳米、微米级囊泡,大的复合囊泡,纳米纤维,纳米、微米及宏观管和多孔膜等;第三部分介绍了超支化聚合物在生物医药、细胞模拟及纳米粒子模拟制备等方面的应用.     

聚苯乙烯-丙烯酸嵌段共聚物在Ca~(2 )或乙二胺存在下的自组装行为

近 1 0年来 ,人们对于具有纳米尺度聚合物自组装结构的研究日益增多 .其中 ,嵌段共聚物在选择性溶剂中的胶束行为的研究非常引人瞩目 [1～ 3] .其表现出诸多常规尺寸所不具备的特殊性能 ,使得纳米胶束不仅在理论上有研究价值 ,而且在材料化学、生物医学和环境科学等领域都具有广阔的应用前景 .Ma等[4 ] 对聚丙烯酸和聚苯乙烯接枝共聚物的研究发现聚合物接枝率和聚合物浓度以及溶液离子强度对胶束结构有影响 ;Zhang等 [1,5] 对不同嵌段比例的苯乙烯 -丙烯酸嵌段共聚物的自组装行为的研究 ,发现不同嵌段比例所对应的纳米结构不同 ;而胶束表面…     

聚苯乙烯-丙烯酸嵌段共聚物在不同pH值和Ca2+浓度下的胶束行为

近年来, 对具有纳米尺寸的聚合物自组装结构的研究日益增多. 其中, 嵌段共聚物在选择性溶剂中的胶束行为研究得最为广泛和深入[1~5]. 纳米胶束表现出诸多常规尺寸材料所不具备的特殊性能, 在材料化学、生物医学以及环境科学等领域有广阔的应用前景. Webber等[6]对聚丙烯酸和聚苯乙烯接枝共聚物的研究发现, 聚合物的接枝率和聚合物浓度以及溶液离子强度对胶束结构有影响; Eisenberg等[1,7]对不同嵌段比例的苯乙烯-丙烯酸嵌段共聚物的自组装行为进行研究发现, 不同嵌段比例所对应的胶束结构不同. 胶束形成的环境对胶束的形成与稳定性的影响是人们研究的重点. 本文报道了聚苯乙烯-丙烯酸嵌段共聚物在水中的胶束行为, 着重讨论了溶液pH值和钙离子浓度对聚丙烯酸链段相互作用的影响.     

聚合物胶束作为药物载体的研究进展

聚合物胶束是具有疏水核心和亲水壳的自组装纳米颗粒.作为一种新型的药物载体,聚合物胶束具有载药范围广、结构稳定、体内滞留时间长、毒副作用小等特点.可以通过肿瘤组织的高通透性和滞留效应被动地富集在癌组织中,也可以通过修饰聚合物胶束的表面基团来实现药物靶向给药.本文总结并分析了聚合物胶束作为药物载体的研究进展,包括聚合物胶束的功能特点、制备、应用和药物的包载.     

New approaches to stimuli-responsive polymeric micelles and hollow spheres

This article briefly describes some new approaches to stimuli-sensitive polymeric micelles and hollow spheres, which were developed in the authors’ laboratory in recent years. (1) Self-assembly of component polymers to non-covalently connected micelles (NCCM) driven by specific interactions. For example, in water, PCL and PAA formed core-shell nanospheres due to interpolymer hydrogen bonding. After crosslinking the PAA shell and removing the PCL core, “nanocages” made of PAA network were obtained. This hollow structure shows perfect reversible size-pH dependence. (2) Simultaneous in-situ polymerization of monomers and self-assembly of the polymers. In this approach, PNIPAM network was formed by radical polymerization covering PCL particles. Hollow spheres of PNIPAM network were then obtained by biodegradation of the PCL core. Both the core-shell spheres and hollow spheres show reversible size dependence on temperature change because of the phase transition of PNIPAM around 32°C. (3) Complexation-induced micellization and transition between the micelles and hollow spheres. Graft copolymers of hydroxylethyl cellulose (HEC) and PAA were prepared by free radical polymerization. The copolymers showed pH dependent micellization, i.e., micelles formed when pH of the graft copolymer solution decreased to around 3. The micellar structure could be locked by crosslinking the PAA grafts. The resultant cross-linked micelles undergo pH-dependent transition between the micelles and hollow spheres, which accompanies a remarkable particle size change. Both the micellization and the structure transition were found to be reversible and associated with H-bonding complexation between the main chain and grafts. __________ Translated from Acta Polymerica Sinica, 2005, 650(5) (in Chinese)     

Synthesis and "schizophrenic" micellization of double hydrophilic AB4 miktoarm star and AB diblock copolymers: structure and kinetics of micellization

Poly(N-isopropylacrylamide) (PNIPAM)-based tetrafunctional atom transfer radical polymerization (ATRP) macroinitiator (1b) was synthesized via addition reaction of mono-amino-terminated PNIPAM (1a) with glycidol, followed by esterification with excess 2-bromoisobutyryl bromide. Well-defined double hydrophilic miktoarm AB4 star copolymer, PNIPAM-b-(PDEA)4, was then synthesized by polymerizing 2-(diethylamino)ethyl methacrylate (DEA) via ATRP in 2-propanol at 45 degrees C using 1b, where PDEA was poly(2-(diethylamino)ethyl methacrylate). For comparison, PNIPAM-b-PDEA linear diblock copolymer with comparable molecular weight and composition to that of PNIPAM-b-(PDEA)4 was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization. The pH- and thermoresponsive "schizophrenic" micellization behavior of the obtained PNIPAM65-b-(PDEA63)4 miktoarm star and PNIPAM70-b-PDEA260 linear diblock copolymers were investigated by 1H NMR and laser light scattering (LLS). In acidic solution and elevated temperatures, PNIPAM-core micelles were formed; whereas at slightly alkaline conditions and room temperature, structurally inverted PDEA-core micelles were formed. The size of the PDEA-core micelles of PNIPAM65-b-(PDEA63)4 is much smaller than that of PNIPAM70-b-PDEA260. Furthermore, the pH-induced micellization kinetics of the AB4 miktoarm star and AB block copolymers were investigated by the stopped-flow light scattering technique upon a pH jump from 4 to 10. Typical kinetic traces for the micellization of both types of copolymers can be well fitted with double-exponential functions, yielding a fast (tau1) and a slow (tau2) relaxation processes. tau1 for both copolymers decreased with increasing polymer concentration. tau2 was independent of polymer concentration for PNIPAM65-b-(PDEA63)4, whereas it decreased with increasing polymer concentration for PNIPAM70-b-PDEA260. The chain architectural effects on the micellization properties and the underlying mechanisms were discussed in detail.     

pH-responsive core-shell particles and hollow spheres attained by macromolecular self-assembly

According to our "block-copolymer-free" strategy for self-assembly of polymers, noncovalently connected micelles (NCCM) with poly(epsilon-caprolactone) (PCL) as the core and poly(acrylic acid) (PAA) as the shell in aqueous solutions were attained due to specific interactions between the component polymers. The micellar structure was then locked in by the reaction of PAA with diamine. Afterward, hollow spheres based on PAA network were obtained by either core degradation with lipase or core dissolution with dimethylformamide of the cross-linked micelles. The cavitation process was monitored by dynamic light scattering, which indicated a mass decrease and size expansion. The hollow structure is confirmed by transmission electron microscopy observations. The resultant hollow spheres are pH- and salt-responsive: there is a substantial volume increase when pH changes from acid to base, and vice versa. The volume change takes place dramatically over the pH-range from 5.8 to 7.5. Furthermore, this volume-pH-dependence is found to be completely reversible provided the effect of ionic strength is excluded. The volume change can be adjusted by changing the shell thickness and the cross-linking degree of the hollow spheres. The salt effect on the hollow sphere size depends on pH: with increasing salt concentration the size shows an increase, a decrease, and a little change in acidic, basic, and neutral media, respectively.     

原位聚合法制备具有温敏PNIPAM壳的核-壳结构聚合物纳米微球的研究

结合大分子自组装和原位自由基聚合方法,采用油溶性引发剂偶氮二异丁腈(AIBN),在聚(ε-已内酯)(PCL)纳米粒子表面引发聚合单体N-异丙基丙烯酰胺(NIPAM)和交联剂亚甲基双(丙烯酰胺)(MBA),制备得到了核-壳结构的PCL/PNIPAM聚合物纳米微球.系统研究了单体和交联剂用量、壳层目标交联度、初始PCL/DMF溶液的浓度及引发剂AIBN含量4个反应参数对核-壳结构PCL/PNIPAM纳米微球的PNIPAM壳层得率、微球尺寸、温敏性能及电镜形貌的影响.结果表明,在制备核-壳结构PCL/PNIPAM纳米微球的反应过程中,PCL粒子表面的聚合和水中的聚合二者之间相互竞争.适当增加引发剂AIBN的添加量,有利于制备得到核/壳比例可控的PCL/PNIPAM纳米微球;交联剂MBA较高的反应活性导致形成了非均匀交联的PNIPAM壳层.     

Cononsolvency-induced micellization of pyrene end-labeled diblock copolymers of N-isopropylacrylamide and oligo(ethylene glycol) methyl ether methacrylate

Pyrene end-labeled double hydrophilic diblock copolymers, poly(N-isopropylacrylamide)-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (Py-PNIPAM-b-POEGMA), were synthesized via consecutive reversible addition-fragmentation chain transfer polymerization using a pyrene-containing dithioester as the chain transfer agent. These diblock copolymers molecularly dissolve in pure methanol and water, but form well-defined and nearly monodisperse PNIPAM-core micelles in an appropriate mixture of them due to the cononsolvency of PNIPAM block. 1H NMR, laser light scattering, fluorescence spectroscopy, and transmission electron microscopy were employed to characterize the cononsolvency-induced PNIPAM-core micelles. When the volume fraction of water, phi water, in the methanol/water mixture is in the range of 0.5-0.8, the sizes of micelles are in the range of 20-30 nm in radius for Py-PNIPAM50-b- POEGMA18. At phi water = 0.5, the formed micelles possess the highest overall micelle density and the largest molar mass. The effects of varying the block lengths of Py-PNIPAM-b-POEGMA diblock copolymers on the structural parameters of PNIPAM-core micelles have also been explored. Although we can observe the immediate appearance of bluish tinge upon mixing the diblock copolymer solution in methanol with equal volume of water (phi water = 0.5), which is characteristic of the formation of micellar aggregates, the whole micellization process apparently takes a relatively long time to complete, as revealed by monitoring the time dependence of fluorescence emission spectra. The excimer/monomer fluorescence intensity ratios, IE/IM, continuously decrease with time and then reach a plateau value after approximately 20 min. The decrease of IE/IM after the initial formation of pseudo-equilibrium micelles should be ascribed to the structural rearrangement and further packing of PNIPAM segments within the micelle core, restricting the mobility of pyrene end groups and decreasing the probability of contact between them. Compared to the conventional cosolvent approach employed for the micellization of block copolymers in selective solvents, the reported cononsolvency-induced unimer-micelle-unimer transition of Py-PNIPAM-b-POEGMA in methanol/water mixtures has been unprecedented.     

Non-ionic amphiphilic block copolymers by RAFT-polymerization and their self-organization

Water-soluble, amphiphilic diblock copolymers were synthesized by reversible addition fragmentation chain transfer polymerization. They consist of poly(butyl acrylate) as hydrophobic block with a low glass transition temperature and three different nonionic water-soluble blocks, namely, the classical hydrophilic block poly(dimethylacrylamide), the strongly hydrophilic poly(acryloyloxyethyl methylsulfoxide), and the thermally sensitive poly(N-acryloylpyrrolidine). Aqueous micellar solutions of the block copolymers were prepared and characterized by static and dynamic light scattering analysis (DLS and SLS). No critical micelle concentration could be detected. The micellization was thermodynamically favored, although kinetically slow, exhibiting a marked dependence on the preparation conditions. The polymers formed micelles with a hydrodynamic diameter from 20 to 100 nm, which were stable upon dilution. The micellar size was correlated with the composition of the block copolymers and their overall molar mass. The micelles formed with the two most hydrophilic blocks were particularly stable upon temperature cycles, whereas the thermally sensitive poly(N-acryloylpyrrolidine) block showed a temperature-induced precipitation. According to combined SLS and DLS analysis, the micelles exhibited an elongated shape such as rods or worms. It should be noted that the block copolymers with the most hydrophilic poly(sulfoxide) block formed inverse micelles in certain organic solvents.     

温度敏感性PNIPAM-b-PZLL-b-mPEG三嵌段共聚物的合成与自组装研究

通过大分子引发剂引发ε-苄氧羰基-L-赖氨酸-N-羧酸酐(Lys-NCA)开环聚合和大分子缩合的方法合成了聚(N-异丙基丙烯酰胺)-b-聚(ε-苄氧羰基-L-赖氨酸)-b-聚乙二醇单甲醚三嵌段共聚物(PNIPAM-b-PZLL-b-mPEG).用GPC和1H-NMR对其结构进行了表征.用芘荧光探针法证明了该三嵌段聚合物形成胶束的性质并测定了临界胶束浓度(CMC).动态光散射(DLS)研究表明,在固定PNIPAM-b-PZLL链段长度的情况下,mPEG分子量为2000时,胶束在温度高于临界溶解温度(LCST)时发生聚集,mPEG分子量为5000时,胶束在LCST以上没有发生聚集.     

窄分布两亲性嵌段共聚物的合成及其胶束化行为研究

利用原子转移自由基聚合合成了具有两亲性的嵌段聚合物聚苯乙烯-b-聚丙烯酸(PS-b-PAA),用FTIR,¹H NMR,SEC对其进行了表征,并利用荧光探针技术研究了其在水溶液中的胶束化行为.进一步的研究表明,PS-b-PAA胶束可对水中存在的多环芳香化合物芘有效地吸收并进而分离和回收.     

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.     

Synthesis and Self-Assembly Behaviors of Four-Arm Star Block Copolymers Poly(ϵ-caprolactone)-b-poly(2- (diethylamino) ethyl methacrylate)) in Aqueous Solution

Four-arm star block polymers consisting of hydrophobic poly(?-caprolactone) (PCL) block and hydrophilic poly(2-(diethylamino) ethyl methacrylate)) (PDEAEMA) block were successfully synthesized by ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP). Chain lengths of PDEAEMA segments were varied to obtain a series of star copolymers with different hydrophilic/hydrophobic ratio, which were desired for self-assembly study. Dynamic light scattering (DLS) and transmission electron microscopic (TEM) were used to study their self-assembly behavior. In the PBS solution with different pH value, the star polymers formed micelles or nanoparticles. Furthermore, the morphologies of the micelles were also pH-dependent. Critical micelle concentrations of star copolymers changed from 5.0 to 17.5 mg/L with the increase of hydrophilic block length or the pH decrease. Moreover, a steady increase was found on the micelles diameters when the pH decreased from 7.0 to 3.0. The low CMC value and slight changes on micelle diameter indicated that the micelle remained stable under the changing external stimulus.