双重敏感mPEG-PDPA-P(AAm-co-AN)聚合物自组装体的药物递送

设计合成了一种新型两亲性三嵌段ABC聚合物聚乙二醇单甲醚-聚甲基丙烯酸二异丙胺基乙酯-聚(丙烯酰胺-co-丙烯腈)(mPEG-PDPA-P(AAm-co-AN))。该聚合物具有pH敏感嵌段PDPA和温度敏感嵌段P(AAm-co-AN)，临界溶解温度(UCST)较高，且可以通过改变单体比例来调节UCST。在室温、中性环境下，该聚合物通过自组装形成刺激响应型胶束，可用于抗肿瘤药物的控释研究。温度升高诱导聚合物胶束向不对称囊泡结构转变，pH降低促使聚合物形成更加松散的胶束。在体外释药探究中，聚合物胶束对亲水药物阿霉素(DOX)和疏水药物槲皮素都具有良好的载药效果，在37℃、pH=7.4的条件下泄漏量低，随着温度升高和pH降低，胶束释放药物的速率和释放量明显增加。     

无规共聚物P(MEO2MA-co-OEGMA)的合成及其在水溶液中温度诱导相转变行为

利用原子转移自由基聚合(ATRP)方法,由单体2-(2-甲氧基乙氧基)甲基丙烯酸乙酯(MEO₂MA)和寡聚(乙二醇)甲基醚甲基丙烯酸酯(OEGMA, M_n = 500 g·mol^-1)合成了无规共聚物P(MEO₂MA-co-OEGMA).并采用动态光散射(DLS)、紫外光谱及透射电子显微镜(TEM)等技术考察聚合物在水溶液中的温度响应性聚集行为,获得其在水溶液中的最低临界溶解温度(LCST)及其随组成的变化规律.结果表明,该聚合物具有良好且可逆的温度响应行为,这主要归因于聚合物与水分子之间氢键作用,及其分子本身疏水作用之间为了保持一种微妙的动态平衡而自发对聚集形态进行的“自我调整”,从而达到新的热力学平衡状态的结果.该聚合物的LCST与聚合物中单体OEGMA所占的摩尔比例呈线性关系,可以通过改变单体的摩尔配比实现对聚合物LCST的调控.     

双温度响应性新型糖聚合物的合成与表征

本文采用原子转移自由基聚合法(ATRP), 设计合成了具有双温度响应性质的新型糖聚合物, 并对其在水溶液中的胶束化行为进行了动态光散射研究. 结果表明, 该系列糖聚合物具有双温度响应区间, 并且在水中形成表面呈正电性的胶束, 因此可望将其作为带负电的生物大分子(如单链DNA等)的新型载体.     

ARGET ATRP 与ROP 结合制备pH 响应两亲性聚合物分子刷及其自组装研究

结合电子转移活化剂再生-原子转移自由基聚合(ARGET ATRP)和开环聚合(ROP)法合成了一种具有无规疏水/ pH 响应结构的两亲性聚合物分子刷聚(甲基丙烯酸聚丙交酯酯-co-甲基丙烯酸)-b-聚甲基丙烯酸单甲氧基聚乙二醇酯 [P(PLAMA-co-MAA)-b-PPEGMA]. 通过核磁共振氢谱(¹H NMR)和凝胶渗透色谱(GPC)表征了聚合物的结构、分子量及分子量分布. 优化了反应条件并合成出分子量可控、分子量分布窄的聚合产物. 采用动态光散射法(DLS)、扫描电子显微镜(SEM)研究了聚合物分子刷在水溶液中自组装胶束的粒径、形貌及pH 响应行为. P(PLAMA-co-MAA)-b-PPEGMA 自组装形成粒径分布均匀的球形胶束. 且随着溶液pH 值从7 降低至3, 胶束中的PMAA 逐渐去离子化, 溶胀的胶束逐渐收缩, 粒径由200～300 nm 减小至150 nm 左右; 但当pH 值减小到2 以下, 胶束表面电荷量非常小, 胶束聚集, 使得粒径增大.     

智能聚合物包覆的金纳米粒子*

本文综述了智能聚合物包覆的金纳米粒子的研究进展,重点介绍了智能聚合物包覆金纳米粒子的制备方法,包括原位合成法、配体置换法、表面引发聚合法和表面接枝聚合法等,以及智能聚合物包覆的金纳米粒子的智能响应类型,如温度敏感型、pH敏感型、pH/电解质双重敏感型、pH/温度双重敏感型、溶剂敏感型等。     

pH敏感型聚合物PEG-b-PHEMA(His)的合成及胶束性能研究

通过点击化学(Click chemistry)与原子转移自由基聚合(ATRP)一锅法合成AB型嵌段聚合物聚乙二醇嵌段聚甲基丙烯酸羟乙酯(PEG-b-PHEMA), 之后对所得聚合物进行组氨酸(His)修饰得到pH敏感型聚合物PEG-b-PHEMA(His), 运用核磁共振(¹H NMR)及凝胶渗透色谱(GPC)表征了该嵌段聚合物及组氨酸修饰后的产物的结构和分子量分布(M_n= 8.2×10³～13.0×10³ g/mol, PDI=1.27～1.51), 说明聚合物被成功地合成且具有较小的多分散系数. 之后对嵌段聚合物PEG-b-PHEMA(His)进行了动态光散射(DLS)、透射电镜(TEM)和临界胶束浓度(CMC)的测试, 结果表明, 聚合物胶束呈球形且粒径分布均匀, 并且粒径随组氨酸接枝率增大而减小. 最后我们做不同接枝比的PEG-b-PHEMA(His)的酸碱滴定曲线, 结果表明, 组氨酸的接入使聚合物具备明显的pH响应能力, 进一步的释药试验也证明了这一结果.     

新型温度敏感性自组装胶束P(NiPAAm-co-DMAA)-co-P(L-Ala)的合成和性能

通过原子转移自由基聚合(ATRP)合成了一种带有活性—NH2基团的温度敏感性亲水型共聚物P(NiPAAm-co-DMAA), 并将其作为引发剂, 合成了P(NiPAAm-co-DMAA)-co-P(L-Ala), 其分子量分布(PDI)在1.3左右. 聚合物通过自组装形成纳米胶束. 透射电镜(TEM)结果表明, 胶束大小200~300 nm, 具有明显的核壳结构. 共聚物的最低临界溶解温度(LCST)为45.5 ℃. 温度低于LCST时, 聚合物溶解形成胶束; 高于LCST时, 胶束解离, 聚合物不溶. 聚合物对温度的响应是快速而可逆的.     

pH敏感型mPEG-Hz-PLA聚合物纳米载药胶束的制备

以合成的含有腙键的聚乙二醇大分子(mPEG-Hz-OH)为引发剂,以丙交酯为单体引发开环聚合反应,并通过调整投料比,制备出3种不同分子量的含腙键的生物可降解嵌段聚合物(mPEG-Hz-PLA).将腙键引入到聚合物的骨架中,以此构建聚合物胶束并作为pH敏感型纳米药物载体.制备的pH敏感型胶束的CMC值等于或低于5.46×10-4 mg/m L,DLS和TEM显示粒径均小于100 nm,且粒径分布均匀.非pH敏感型胶束在不同pH下的粒径变化不明显,而pH敏感型胶束在酸性环境下(pH=4.0和pH=5.0)胶束粒径出现了明显变化.以阿霉素为模型药物制备了pH敏感型载药胶束,其粒径比空白胶束大(100~200 nm),且粒径分布均匀.药物释放实验表明pH敏感型载药胶束随着释放介质pH降低累积释药量增高.MTT实验表明空白胶束对HeLa细胞和RAW264.7细胞几乎没有抑制作用,而载阿霉素的胶束对2种细胞的抑制作用都随着剂量的增大和时间的延长而增强.     

温度/pH敏感性嵌段共聚物P(HEMA-co-DEAEMA)-b-PDEAM-b-P(DEAEMA-co-HEMA)的合成与性质研究

利用原子转移自由基聚合方法(ATRP)合成了组成递变的嵌段共聚物P(HEMA-co-DEAEMA)-b-PDEAM-b- P(DEAEMA-co-HEMA). 用FTIR, ¹H NMR和GPC技术表征了聚合物的组成、结构、分子量及其分布. 通过透光率测定、粘度、激光粒度分析和透射电镜研究了共聚物组成、温度及溶液pH对其溶液相行为和胶束化作用的影响. 结果表明: 所合成的嵌段共聚物具有温度和pH敏感性, 共聚物水溶液的低临界溶解温度(LCST)随HEMA量的增加而降低, 临界相变pH随HEMA量的增加而降低, 温度和pH诱导均可实现嵌段共聚物的胶束化. 控制HEMA量可以调控嵌段共聚物的LCST和pK_a.     

两亲性杂臂星型嵌段共聚物胶束的制备、表征及载药性能研究

以溴代异丁酰溴与3,5-二羟基苯甲酸制备3,5-二(2-溴-2丙酰氧基)苯甲酸,再与聚乙二醇单甲醚酯化,合成含溴大分子引发剂PEG-Br2。以苯乙烯为单体,利用原子转移自由基聚合方法(ATRP)合成了两种不同亲疏水段比例的两亲性星型杂臂嵌段共聚物PEG-b-(PS)2。本实验利用FTIR、1H-NMR、GPC等技术对聚合物的分子结构及分子量进行表征,利用透析法制备聚合物胶束;采用AFM对聚合物胶束的纳米结构进行观察;采用荧光探针法测得其临界胶束浓度(CMC)分别为0.99 mg·L-1和0.59 mg·L-1;利用DLS测得聚合物胶束粒径为150 nm左右;以疏水型抗肿瘤药物氨甲喋呤(MTX)为模型药物,对载药胶束的体外释药行为进行了研究,测得聚合物胶束的载药量分别为为13.32%和10.00%,包封率分别为61.75%和46.82%。结果表明,随着疏水段的增大,星型杂臂嵌段共聚物胶束药物包载量及CMC随之降低,且在人体pH条件下药物释放较低;同时发现两种载药胶束在肿瘤细胞酸性条件下释药速率增加。综上,此类结构的聚合物胶束作为抗肿瘤药物MTX的载体分子具有很好的应用前景。     

纳微尺度层状MgAl固体碱催化解聚木质素磺酸钙制取含氧化合物的研究

在水热合成体系中引入羟基化合物制备纳微尺度层状镁铝水滑石前驱体(MgAl-LDHs), 通过正交实验优化合成工艺参数, 焙烧后得到固体碱氧化物(MgAlO_x); 采用X射线衍射(XRD)、 扫描电子显微镜(SEM)和二氧化碳程序升温脱附(CO₂-TPD)对水滑石前驱体及固体碱氧化物进行晶相、 形貌和碱度表征, 对MgAlO_x解聚木质素磺酸钙(CLS)的催化性能进行评价, 采用气相色谱(GC)、 气相色谱-质谱联用(GC-MS)和凝胶渗透色谱(GPC)对反应后气、 液和固三相产物组成规律进行分析. 结果表明, 在n(Mg)/n(Al)=3, pH=12, 180 ℃, 24 h条件下, 添加15%(体积分数)C₂H₅OH时, 可以制备晶粒尺寸140~230 nm的层状MgAl-LDHs, 在空气气氛下于600 ℃焙烧6 h得到MgAlO_x. 水热体系下固体碱氧化物对木质素磺酸钙解聚的优化条件为270 ℃, 4 h, 65% C₂H₅OH, m(MgAlO_x)/m(CLS)=1/2, 此时其气、 液和固三相产物的产率分别为4.50%, 58.30%和37.20%, 其中液相产物收率比纯木质素磺酸钙解聚提高了13.30%, 液相产物主要组成为酚类、 芳香类、 酯类和其它化合物, 含氧化合物总选择性为79.05%(酚类66.06%, 酯类12.99%), 反应后的MgAlO_x经焙烧氧化再生后, 循环使用4次仍具有较高的活性和稳定性.     

Self-assembled micellar nanoparticles of a novel star copolymer for thermo and pH dual-responsive drug release

An amphiphilic star block copolymer comprised of a hydrophobic PMMA block and a hydrophilic tri-arm poly(NIPAAm-co-DMAEMA) block was synthesized by copolymerization of NIPAAm and DMAEMA, with Ce(4+) ions and tris(hydroxymethyl)methylamine as a redox initiatory system. The star copolymer undergoes self-assembly to the micellar nanoparticles with a core-shell structure and the thermo/pH dual-response, originated from the thermo-sensitivity of PNIPAAm and the pH-sensitivity of PDMAEMA. A fluorescence probe study showed the pH-dependent low CMCs (7.5 to 11.2 mg/L) of the micelles, confirming the formation of stable micelles. Morphological investigations showed that the blank and drug-loaded micelles both had spherical and uniform shapes. The sizes of the blank and drug-loaded nanoparticles were between 80 and 120 nm, depending on the given pH. The LCSTs of the star copolymer were determined to be 32 degrees C, 36.6 degrees C and 39.5 degrees C, corresponding to pH 5, pH 7.4 and pH 9, respectively, demonstrating a pH-dependent thermo-response. As a drug delivery, the micellar nanoparticles showed the dual-responsive release profiles in vitro, which were confirmed by the drug release studies. The obtained results showed the thermo-triggered accelerated release at pH 7.4, and the pH-triggered accelerated release at 37 degrees C, indicating the micelles nanoparticles would be a promising site-specific drug delivery for enhancing the accumulation of drug in targeting pathological areas.     

Thermo and pH Dual-Responsive Micelles of N-phthaloylchitosan-g-Poly(N-isopropylacrylamide) and Poly(acrylic acid-co-tert-butyl acrylate) for Drug Delivery

A novel amphiphilic copolymer N-phthaloylchitosan graft poly(N-isopropylacrylamide) and poly(acrylic acid-co-tert-butyl acrylate) (PHCS-g-PNIPAAm&P(AA-co-tBA)) was synthesized. The graft copolymer could form micelles in aqueous medium, and the critical micelle concentration (CMC) of the copolymer was 7.5 × 10^{? 3}mg/mL. The lower critical solution temperature (LCST) of the micelles was measured to be 30°C. Transmission electron microscopy (TEM) image showed that the micelles exhibited a regular spherical shape, and the mean diameter of the micelles was 94.1 ± 0.8 nm as determined by dynamic light scattering (DLS). The potential usefulness of the micelles as drug delivery systems was investigated using anti-inflammation drug prednisone acetate as the model. The drug loading capacity of the micelles was measured to be 22.86 wt%, and the DLS results showed that the mean diameter of the drug-loaded micelles was 133.3 ± 2.4 nm. In vitro drug release studies indicated that the micelles exhibited thermo and pH dual-responsive release profiles.     

Dual-responsive controlled drug delivery based on ionically assembled nanoparticles

Ionically assembled nanoparticles (INPs) have been formed from poly(ionic liquid-co-N-isopropylacrylamide) with deoxycholic acid through electrostatic interaction. The structure and properties of the INPs were investigated by using (1)H NMR, Fourier transform infrared (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS), and so on. Due to pH-responsive deoxycholic acid (pK(a) = 6.2) and thermo responsive N-isopropylacrylamide included in the ionic complex, the INPs exhibit highly pH and thermal dual-responsive properties. The potential practical applications as drug delivery carriers were demonstrated using doxorubicin (DOX) as a model drug. With a lower pH (pH 5.2) and higher temperature (above 37 °C), structural collapse of the INPs occurred as well as release of DOX owing to protonated DA departure from the INPs and a lower LCST (lower critical solution temperature) at the pathological conditions. The result shows that 80% of DOX molecules were released from INPs within 48 h at pH 5.2, 43 °C, but only 30% of the drug was released within 48 h at 37 °C and pH 7.4. Moreover, drug-loaded INPs exhibit an inhibitory effect on cell growth.     

Temperature and pH dually-responsive poly(<Emphasis Type="Italic">β</Emphasis>-amino ester) nanoparticles for drug delivery

Stimuli-responsive polymers have undoubtedly been of great interest in the past decades due to a variety of their potential applications in biomedical territory. However, their non-degradability limits their in vivo applications. Herein, we report a novel pH and temperature dual-stimuli responsive-poly(β-amino ester). The pH/temperature sensitivities are interrelated and can be easily tuned by changing PEG-diacrylate chain length and the percentage of biamines in the feed ratio. These dual-responsive polymers are very useful in drug delivery. Reaction of methyl ether poly(ethylene glycol) (MPEG) and poly(β-amino ester) resulted in an amphiphilic MPEG-PBAE block copolymer which could form nanoparticles by self-assembly. A hydrophobic drug (DOX) was loaded in the self-assembled nanoparticles at low temperature without using organic solvents. The loaded drug was released very slowly and steadily at 37 °C under physiological conditions (pH 7.4), but rapidly released from the micelles in weakly acidic environments (pH 6.4 and 5.0) for intracellular drug release. Thus, these poly(β-amino ester) polymers constitute ideal drug carriers since their thermal sensitivity allows the drug loadings without using organic solvent and their pH sensitivity permits fast intracellular drug release.     

Rod-like liquid crystals of organic transition metal complexes. I. Reversible transformation between blue smectogen and red nematogen

Two novel types of transition-metal-containing liquid crystals, bis(p-n-koxydithiobenzoato)nickel(II) (abbreviated as (C_nO-DTB)₂Ni), and (p-n-alkoxydithiobenzoato)(p-n-alkoxyperthiobenzoato)nickel(II) (abbreviated as (C_nO-DTB)(C_nO-PTB)Ni), were synthesized. It was found that the (C_nO-DTB)₂Ni complex for n = 8 has smectic H and C mesophases, and that the (C_nO-DTB)₂Ni complexes for n = 4 and 8 easily transform into the corresponding monoperthio complexes, _nO-PTB)Ni, by heating at temperatures between 230°C and 285°C. It was confirmed that the transformation originates from an intermolecular reaction between the (C_nO-DTB)₂Ni complexes at high temperatures, and that the origin of the extra sulphurs in the resulting (C_nO-DTB)(C_nO-PTB)Ni complexes is the neighbouring (C_nO-DTB)₂Ni complexes. Interestingly, each of the (C_nO-DTB)(C_nO-PTB)Ni complexes (n = 4 and 8), has nematic mesophase and exhibits a unique double melting behaviour via the nematic phase, which is the first example in liquid crystals. The reversible transformation between the blue smectic rod-like (C_nO-DTB)₂Ni complex and the red nematic Λ-like (C_nO-DTB)(C_nO-PTB)Ni complex is possible.     

温度敏感性P(MEO2MA-co-OEGMA)共聚物的合成与性质

利用原子转移自由基聚合(ATRP)方法合成了组成递变的2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯(MEO₂MA)与寡聚乙二醇甲醚甲基丙烯酸酯(OEGMA)共聚物P(MEO₂MA-co-OEGMA). 核磁共振氢谱(¹HNMR)和凝胶渗透色谱(GPC)表征了聚合物的结构、分子量及其分布. 通过测定透光率、粘度、激光粒度分析了共聚物组成对共聚物低临界溶解温度(LCST)的影响, 考察了共聚物组成、浓度、盐浓度、盐种类、温度对其溶液相行为的影响. 结果表明: 所合成的共聚物具有温度敏感性, 其LCST 可以通过合成时共聚单体MEO₂MA与OEGMA投料比的改变来调控, 随着OEGMA量的增加共聚物的LCST升高, 共聚物溶液浓度升高其LCST减小, 随盐溶液浓度的增大共聚物的LCST降低, 共聚物的LCST降低主要受盐溶液中阴离子价数的影响; HCl的引入使共聚物水溶液的LCST降低; NaOH的引入使共聚物水溶液的LCST升高.     

Self‐assembly of thermo‐ and pH‐responsive poly(acrylic acid)‐b‐poly(N‐isopropylacrylamide) micelles for drug delivery

Self‐assembled thermo‐ and pH‐responsive poly(acrylic acid)‐b‐poly(N‐isopropylacrylamide) (PAA‐b‐PNIPAM) micelles for entrapment and release of doxorubicin (DOX) was described. Block copolymer PAA‐b‐PNIPAM associated into core‐shell micelles in aqueous solution with collapsed PNIPAM block or protonated PAA block as the core on changing temperature or pH. Complexation of DOX with PAA‐b‐PNIPAM triggered by the electrostatic interaction and release of DOX from the complexes due to the changing of pH or temperature were studied. Complex micelles incorporated with DOX exhibited pH‐responsive and thermoresponsive drug release profile. The release of DOX from micelles was suppressed at pH 7.2 and accelerated at pH 4.0 due to the protonation of carboxyl groups. Furthermore, the cumulative release of DOX from complex micelles was enhanced around LCST ascribed to the structure deformation of the micelles. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5028–5035, 2008     

CO_2诱导的五嵌段非离子共聚物与阴离子氟碳表面活性剂的相互作用

聚合物-表面活性剂复合物在诸多工业领域都具有重要的应用潜力,但利用CO_2气体调节复合物的相互作用及微观聚集体形貌鲜见报道。本文基于三嵌段共聚物普兰尼克F127制备了五嵌段共聚物聚甲基丙烯酸二乙氨基乙酯-block-聚氧化乙烯-block-聚氧化丙烯-block-聚氧化乙烯-block-聚甲基丙烯酸二乙氨基乙酯(PDEAEAM-b-F127-b-PDEAEMA)。通过聚合物溶液pH和电导率的变化研究了PDEAEAM-b-F127-b-PDEAEMA的CO_2刺激响应性,应用动态光散射和透射电子显微镜考察了PDEAEAM-b-F127-b-PDEAEMA与阴离子氟碳表面活性剂在CO_2刺激作用下的相互作用。结果表明,CO_2/N_2的交替通入可以使PDEAEAM-b-F127-b-PDEAEMA产生相应的质子化/去质子化过程,从而可逆地改变PDEAEAM-b-F127-b-PDEAEMA溶液的pH值和电导率;质子化/去质子化过程可以"开关"共聚物与阴离子氟碳表面活性剂之间的静电吸引作用,使体系中的聚集体在球形胶束与蠕虫状胶束之间发生可逆转变。CO_2可控的聚合物-表面活性剂复合物的形貌转变为构建气体响应的软材料提供了一种新的思路。