紫杉醇两亲性共聚物纳米胶束体外释药动力学

采用低分子量PEG-PCL-PEG、mPEG-PLLA、mPEG-PDLLA等两亲性嵌段共聚物作载体包载紫杉醇形成纳米胶束.研究了不同载药率胶束在磷酸缓冲液中释放的动力学,发现紫杉醇PEG-PCL-PEG胶束和mPEG-PLLA胶束的体外释药遵从一级释放动力学;紫杉醇mPEG-PDLLA纳米胶束的体外释放多呈现出两段零级释放动力学;低载药率胶束表现出高释药率;体外释药过程中磷酸缓冲液的更新量越大,紫杉醇的释放率越高.     

水溶性紫杉醇两亲性共聚物纳米胶束研究

聚乙二醇聚己内酯聚乙二醇采用三嵌段共聚物为载体包载紫杉醇形成纳米胶束,胶束具有明显的核壳结构,有效地改善了紫杉醇的水溶性。研究表明,采用蒸发溶剂法、透析法和熔融法制备的胶束对紫杉醇都呈现良好的包封效果,其中,以熔融法制得的胶束粒径最小,分布最窄。文中还考察了蒸发溶剂法实验条件对胶束的影响,发现低沸点有机溶剂有利于获得小粒径胶束,胶束平均粒径随着载药量的提高相应增大。体外释药的结果表明,载药量高的胶束释药率却相对较小。     

靶向性紫杉醇纳米胶束的制备及体外评价

为了增加紫杉醇溶解度和稳定性,采用薄膜分散法制备紫杉醇纳米胶束;采用粒径测定仪测定粒径和PDI;采用UV法测定药物的含量,计算载药量和包封率;采用膜透析法对载药聚合物胶束的体外释药进行考察。本研究制备的纳米胶束粒径分布均匀,平均粒径为(64.34±1.83)nm,包封率大于85%;紫杉醇纳米胶束体外释放显示了良好的缓释特性。本研究制备的紫杉醇纳米胶束制备工艺操作简单,制备得到载药胶束的粒径较小且分布均匀,包封率、载药量较高。     

温度-pH双重敏感性嵌段共聚物胶束的制备及释药性能研究

RAFT法合成兼具温度-pH双重敏感性嵌段共聚物。以嵌段共聚物为载体,吲哚美辛为模型药物,透析法制备载药胶束并模拟在人体环境中的药物释放,考察载体的释药性能;FT-IR表征嵌段共聚物及载药胶束;UV法测定聚合物LCST及相变pH,并进行载药胶束的体外释药研究。一系列测试表明载药胶束在人体生理温度(37℃)下,酸性环境的药物释放速率和累积释放量要比碱性环境下小很多。嵌段共聚物兼具温度-pH双重敏感性,可作为药物载体,在药物缓释控释方面有潜在的应用。     

三嵌段氧化还原/pH双重响应型载药胶束的制备及性能研究

以含有缩醛键的端羟基聚己内酯(HO-PCL-Acetal-OH)和含有二硫键的端羧基聚乙二醇(PEG-SS-COOH)反应形成两亲性三嵌段共聚物PEG-SS-PCL-Acetal-SS-PEG。该嵌段共聚物在水溶液中自组装,形成了具有核壳结构的胶束纳米粒子。采用核磁共振谱(1H NMR)来表征嵌段共聚物的结构,用动态光散射(DLS)和透射电子显微镜(TEM)表征纳米粒子的尺寸和形貌。此外,通过DLS分别检测胶束在二硫苏糖醇(DTT)/p H=5.0和p H=7.4溶液中粒径的变化,结果证明在含有DTT和弱酸性的条件下,由于三嵌段共聚物胶束的二硫键/缩醛键断裂,使其负载有抗癌药物阿霉素(DOX)的胶束溶胀,粒径变大,药物快速释放。药物体外释放模拟结果表明,在p H 5.0、DTT/p H 7.4和DTT/p H 5.0的情况下,DOX 24小时的累积释放率分别为:40.07%、92.05%和95.36%,但是在p H=7.4时释放率仅为25.17%。在37℃条件下,这些载药纳米粒子表现出具有氧化还原/p H双重响应性的药物释放行为。     

聚乳酸—聚乙二醇嵌段共聚物胶束的制备及性能研究

分别以聚乙二醇(PEG)及聚乙二醇单甲醚(m PEG)引发L-丙交酯开环聚合得到PLLA(聚乳酸)-PEG-PLLA三嵌段与PLLA-m PEG两嵌段共聚物,通过1H-NMR分析确定共聚物的结构及分子量。采用直接溶解法和有机溶剂挥发法制备PLLA-PEG-PLLA及PLLA-m PEG胶束,并用TEM对其形态进行表征。利用激光粒度分析和染料探针的方法证实了共聚物自组装形成了胶束,且具有较小的临界胶束浓度(CMC),粒径约为100 nm。三嵌段PLLA-PEG-PLLA胶束的粒径小于两嵌段PLLA-m PEG胶束的粒径;有机溶剂挥发法制备的胶束粒径小于直接溶解法制备的胶束粒径。盐酸乌拉地尔胶束的体外释放结果表明,共聚物组成以及载药方式等对胶束载药、释药行为有一定影响,胶束对所包载的盐酸乌拉地尔具有明显的缓释作用。     

双硒交联智能纳米胶束的制备及其药物释放研究

以含有羟基的葡聚糖(Dex)和含有羧基的硒辛酸(SA)通过酯化反应得到两亲性聚合物Dex-SA,然后在水中自组装形成具有还原响应性的交联Dex-SA纳米胶束。该纳米胶束呈圆球形,平均粒径为(161±10)nm,多分散指数为0.13,Zeta电位为(-20.3±1.4)mV,负载阿霉素(DOX)后的载药率和包封率分别为10.4%和58.9%。药物释放实验表明,交联Dex-SA载药纳米胶束在pH值7.4的10mmol·L~(-1) PBS溶液中的12h累计释放率为20.4%,添加10mmol·L~(-1)还原型谷胱甘肽(GSH)后的12h累计释放率可达85.2%。细胞毒性实验表明,交联Dex-SA载药纳米胶束不仅保留了DOX原药本身的高细胞毒性,而且减少了对正常细胞的损伤。交联Dex-SA纳米胶束作为药物载体具有潜在的应用价值。     

二硫键链接的两亲性嵌段合物的合成及胶束化研究

通过二硫吡啶基活化的聚乙二醇与巯基聚己内酯之间的偶联反应,在聚乙二醇单元与聚己内酯单元间引入二硫键,合成二嵌段共聚物mPEG-SS-PCL,通过核磁氢谱和红外光谱等手段对聚合物的结构进行表征。以阿霉素(DOX)为药物模型,通过紫外分光光度法分析了聚合物对脂溶性药物的包载能力,用激光粒度仪测定胶束粒径、粒径分布。结果表明,空白胶束及载药胶束的平均粒径分别为117.7nm和146.1nm,该聚合物对阿霉素具有良好的药物包载能力,最高载药量为16.28%,包封率为54.26%。     

聚合物胶束载药体系研究进展

两亲性嵌段共聚物能够在水溶液中通过自组装形成聚合物胶束,其疏水嵌段构成胶束内核,可以有效包载疏水性药物;而亲水嵌段构成胶束外壳,有利于胶束的稳定和体内长循环。聚合物胶束作为药物载体得到了广泛研究,有些已经进入了临床试验和应用阶段。概述了聚合物胶束的特点,介绍了聚合物胶束的组成、载药胶束的制备方法以及聚合物胶束作为药物传递系统的一些实例,并对聚合物胶束载药体系的研究方向进行了展望。     

pH响应性聚氨酯胶束载体的设计合成

采用一锅缩聚反应法,合成出以N-甲基二乙醇胺与异佛尔酮二异氰酸酯预聚物作为疏水PU段、以聚乙二醇单甲醚作为亲水性链段的pH响应性嵌段聚氨酯MPEG-PUM-MPEG。然后采用"沉淀/溶剂蒸发法"制备两亲性聚合物纳米载药胶束,通过激光粒度仪和透射电镜研究了该纳米胶束在不同pH条件下的粒径分布和微观形貌变化,进而探究了该纳米胶束载体的体外药物释放行为。     

氟碳化合物FC-77——脂质体囊泡的制备及性能研究

通过19F NMR、紫外可见光谱、激光粒度仪、Zeta电势和透射电子显微镜等方法研究了生理条件下(pH7.4)FC-77与脂质体囊泡的相互作用。结果表明,脂质体囊泡使得FC-77分子的紫外吸收光谱发生明显位移;FC-77使得脂质体囊泡的粒径和电势均增加。进一步的研究表明,FC-77能够引起囊泡双层膜通透性的降低。为开发FC-77的脂质体药物、增加FC-77的临床利用率提供了基础。     

氟碳化合物与环糊精包合物的制备及其对牛血清白蛋白的影响

以氟碳化合物FC-77作为模型药物,制备FC-77与β-环糊精（卢一cD）包合物。考察包合物与牛血清白蛋白（BSA）的相互作用。通过紫外-可见光谱、红外光谱、热重分析等方法研究包合物的物理化学性能。通过荧光光谱法研究包合物对BSA的荧光猝灭作用。结果为Fc-77与β-cD之间存在强烈的相互作用,从而增加了FC-77的稳定性和水中的溶解性。荧光猝灭结果显示FC-77分子能进入BSA的疏水区域。结论是以β-CD为介质,能显著改善FC-77的理化性能,使FC-77粉末化,便于制成多种剂型,扩大给药方式。     

Synthesis and gas permeability of ABA‐type triblock copolymers derived from fluorine‐containing polyimide with polyhedral oligomeric silsesquioxane

ABA‐type triblock copolymers derived from 4,4'‐(hexafluoroisopropylidene)diphthalicanhydride‐2,3,5,6‐tetramethyl‐1,4‐phenylenediamine (6FDA‐TeMPD) and methacryl phenyl polyhedral oligomeric silsesquioxane (MPPOSS) were synthesized by atom transfer radical polymerization. The chemical structure of the synthesized ABA‐type triblock copolymer was confirmed by ¹H NMR, ¹³C NMR, ²⁹Si NMR and Fourier transform infrared analyses. The ratios of 6FDA‐TeMPD and MPPOSS determined by TGA were 94/6, 85/15, 77/23, 68/32, 57/43 and 31/69. The film density of the ABA‐type triblock copolymer films did not conform to the mixing rule because of polyimide (PI) chain aggregation. Based on contact angle and water uptake analyses, the hydrophobicity of the ABA‐type triblock copolymer film was determined to be higher than the theoretical value because of POSS cage effects and PI chain aggregation. The gas permeability coefficient of the ABA‐type triblock copolymer decreased compared with that of PI because of aggregation of PI chains and inhibition of solubility decreases by substitutes with high affinity. ABA‐type triblock copolymer CO₂/H₂ separation performance increased compared with that of PI. The ABA‐type triblock copolymer derived from PI and MPPOSS can be described as a polymer material with higher hydrophobicity and higher CO₂/H₂ selectivity than PI. © 2015 Society of Chemical Industry     

Non-invasive tumor detection in small animals using novel functional Pluronic nanomicelles conjugated with anti-mesothelin antibody

In this study QDs were encapsulated in carboxylated PluronicF127 (F127COOH) triblock polymeric micelles and conjugated with anti-mesothelin antibody for the purpose of alleviating potential toxicity, enhancing the stability and improving targeting efficiency of CdTe/ZnS quantum dots (QDs) in tumors. The amphiphilic triblock polymer of F127COOH contains hydrophilic carboxylated poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) units. After encapsulating QDs into carboxylated F127 (F127COOH-QD) micelles, the particles were conjugated with anti-mesothelin antibodies to allow targeting of cancerous areas. The size of the monodispersed spherical QD-containing micelles was determined to be ～120 nm by dynamic light scattering (DLS). The critical micelle concentration (CMC) was estimated to be 4.7 × 10(-7) M. In an in vitro study, the anti-methoselin antibody conjugated F127COOH (Me-F127COOH-QD) nanomicelles showed negligible cytotoxicity to pancreatic cancer cells (Panc-1). Confocal microscopy demonstrated that the Me-F127COOH-QD nanomicelles were taken up more efficiently by Panc-1 cells, due to antibody mediated targeting. An in vivo imaging study showed that Me-F127COOH-QD nanomicelles accumulated at the pancreatic tumor site 15 min after intravenous injection. In addition, the low in vivo toxicity of the nanomicellar formulation was evaluated by pathological assays. These results suggest that anti-mesothein antibody conjugated carboxylated F127 nanomicelles may serve as a promising nanoscale platform for early human pancreatic cancer detection and targeted drug delivery.     

Crystal Morphology of Mesoporous Silica Thin Films Synthesized by the Spin-Coating Method Using PEO–PPO–PEO Triblock Copolymer

Mesoporous thin films on Si substrates with thicknesses of about 460–610 nm have been synthesized by the spin-coating method using a Pluronic EO₇₇PO₂₉EO₇₇ (F68), EO₁₀₄PO₃₉EO₁₀₄ (F88), and EO₁₃₃PO₅₀EO₁₃₃ (F108) triblock copolymer system. The triblock copolymers were preserved within the synthesized mesoporous thin films. Transmission electron microscopy (TEM) characterization of these films clearly demonstrates that long-range mesostructural ordering strongly depends on the molecular weight of the poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) triblock copolymer, with lower molecular weight producing higher degrees of order. Plane and cross-sectional high-resolution TEM studies coupled with X-ray diffraction (XRD) analysis also show that highly ordered F68 mesoporous silica thin film forms a cubic structure with a lattice spacing a = 6.70 nm.     

Photophysical properties and self-assembly of triblock copolymer with complexes of positively charged PDMAEMA and oppositely charged chromophores

The self-assembly and photophysical properties of a triblock copolymer with complex mid-block in THF and aqueous solution were investigated in this research. Poly(poly(ethylene glycol) methyl ether methacrylate)-block-poly(2-(dimethylamino ethyl methacrylate)-block- poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA–b–PDMAEMA–b–PPEGMA) triblock copolymer was synthesized by subsequent atom transfer radical polymerizations (ATRP) of DMAEMA and PEGMA. The PDMAEMA blocks were quaternized by a reaction with iodomethane. The complex of the positively charged PDMAEMA chain unit and sodium salt of 1-pyrenebutyric acid was prepared by mixing equimolar amount of the two components in THF/water mixture. Transmission electron microscopy and fluorescence technique results show that the triblock copolymer chains self-assemble into micelles in THF at high concentration. The critical aggregation concentration (CAC) of the triblock copolymer in THF determined by fluorescence technique is 6.8 × 10^?5 M. The triblock copolymer was also able to self-assemble into micelles in water. The value of CAC of the triblock copolymer in water is 2.0 × 10^?5 M. The photophysical properties and self-assembly structures of the triblock copolymer in aqueous solutions were influenced by added sodium chloride. After salt addition, a transition of the assembled structures from micelles to hollow structures was observed.     

Synthesis and Characterization of PVAc-b-PDMS-b-PVAc Triblock Copolymers by Atom Transfer Radical Polymerization Initiated by PDMS Macroinitiator

Poly(dimethylsiloxane) based triblock copolymer was synthesized from bis(bromoalkyl)-terminated PDMS macroinitiator (Br-PDMS-Br) and vinyl acetat telomers. Vinyl acetate telomers prepared from radical and controlled radical telomerization with Co(acac)₂/DMF catalyst and ligand, were used in atom transfer radical polymerization to synthesize Poly(vinylacetate-b-dimethylsiloxane-b-vinylcetate) triblock copolymer. The PDMS based triblock copolymers revealed a significant effect of Co(acac)₂/DMF on PVAc telomere which was used in the synthesis of highly ordered triblock copolymer on a well-defined microstructure. The results were confirmed by ¹H NMR and DSC indicating that a low T_g of PDMS in the microstructure of triblock copolymer has made the block copolymer flexible for new applications.     

Nano-phase structures and mechanical properties of epoxy/acryl triblock copolymer alloys

Phase structures and mechanical properties of epoxy/acryl triblock copolymer alloys using several curing agents were studied. PMMA-b-PnBA-b-PMMA triblock copolymers synthesized by living anionic polymerization were applied as the toughening modifiers for the epoxy resins. An aromatic amine, an acid anhydride and an anionic polymerization catalyst as curing agents resulted in macro-phase separation in the epoxy/triblock copolymer blends during the cure process. However, a phenol novolac as the curing agent created nano-phase structures in the epoxy blends. The size of the spherical phases or cylindrical phases was about 40 nm in diameter, and the main component in the nano-phases was the PnBA of the triblock copolymer. The fracture toughness of the epoxy/triblock copolymer alloys with the nano-cylindrical phases reached 2530 J/m². The fracture toughness was more than twenty fold relative to the unmodified epoxy resin, and was equivalent to the toughness of polycarbonates.     

以三嵌段共聚物为模板介孔氧化铝的形貌控制合成

以三嵌段共聚物作为结构导向剂,采用水热法合成了片状和棒状介孔氧化铝,采用X射线衍射仪、场发射透射电子显微镜、低温氮气吸脱附实验对合成的介孔氧化铝的晶相、形貌和介孔结构进行表征。研究结果表明,三嵌段共聚物的引入能够有效调控氧化铝的形貌、介孔结构以及孔参数。三嵌段共聚物在氧化铝前驱体表面的吸附诱导了晶体的取向生长,并最终形成了棒状氧化铝。     

Novel zwitterionic ABA-type triblock copolymer for pH- and salt-controlled release of risperidone

An ABA-type triblock copolymer was synthesized through group-transfer polymerization by using poly[2-(diethylamino) ethyl methacrylate] (PDEA) as A block and poly[2-(dimethylamino) ethyl methacrylate] (PDMA) as B block. By utilizing the 1,3-propane sultone to obtain polyzwitterionic triblock copolymer under moderate conditions, PDMA block of the triblock copolymer has been selectively betainized. The selectively betainized block copolymer and its precursor were molecularly dissolved in acidic aqueous media without any use of cosolvent at room temperature. In both cases, an increase in solution pH caused near monodisperse cationic or neutral flower-like micellization with hydrophobic PDEA-core at basic aqueous solution. However, at higher polymer concentrations where precursor triblock copolymer does not exhibit any gelling behavior (10% and higher), polyzwitterionic copolymer derivative can be gelated as a result of inter-chain integration of polyzwitterionic groups. Furthermore, the load of risperidone (RISP) into gel matrix and release studies have been successively realized. The results indicated that the betainized novel gel is appropriate for using as a pH- and salt-controlled risperidone-releasing system.