单十二烷基磷酸酯辅助共轭亚油酸的囊泡化研究

以共轭亚油酸(CLA)为模型脂肪酸,与安全、温和的阴离子表面活性剂单十二烷基磷酸酯(MLP)进行复配,动态激光光散射和透射电镜表征结果表明,CLA在中性至弱酸性环境中仍然能够囊泡化.通过pH滴定曲线研究了CLA和MLP 2种分子的荷电物种随pH值的变化规律,据此分析各物种间的相互作用,并推断经MLP辅助CLA能够在中性至弱酸性环境中囊泡化的动因是CLA-MLP间的氢键或离子-偶极作用.     

高内相/自乳液聚合的共轭亚油酸低聚体的囊泡化及稳定性

采用自乳化法制备了高内相共轭亚油酸(CLA)的水包油(O/W)乳液, 并通过热引发乳液聚合反应得到共轭亚油酸低聚体(oligo-CLA); 将oligo-CLA用于自组装脂肪酸囊泡(FAV). 透射电子显微镜和动态激光光散射表征结果均表明, 在pH=8.6~13范围内得到了囊泡粒径为10~30 nm的FAV, 此结果对提高FAV的pH适应性具有理论意义. 自乳液聚合实验结果表明, 该高内相自乳化/热引发低聚反应策略可以使浓度高达75.3%(质量分数)的CLA完成无外加表面活性剂乳液聚合, 并使共轭双键总自交联率达到33%且控制oligo-CLA的平均聚合度约为6, 对规模化生产oligo-CLA及构筑FAV具有实用价值. 与CLA相比, oligo-CLA具有更好的低温溶解性, 由其自组装的FAV具有更好的环境适应性, 如耐酸性和抗钙皂能力, 而且显示出较好的钙响应囊泡体积膨胀率; 以极少量非离子表面活性剂Span 40或AEO₂辅助oligo-CLA形成的杂化囊泡具有更宽的pH适应性. 因此, 所制备的FAV在药物释放体系、 日用化学产品、 家用洗涤剂和个人护理产品中具有更广阔的应用前景.     

单糖/双糖对近中性pH下共轭亚油酸囊泡影响的比较

比较了乳糖等3种双糖或核糖等3种单糖及其复配物对近中性范围共轭亚油酸(CLA)形成脂肪酸囊泡(FAV)的影响. 用激光丁达尔效应确定FAV的pH窗口及各相区, 用透射电子显微镜及动态光散射表征其形貌和尺寸, 用浊度法研究了其稳定性, 用等温滴定量热证明各种糖及其复配物与FAV表面的弱非共价键合作用, 并经理论计算获得结合能. 实验和计算结果表明, 各种糖及其复配物均可以双向拓宽CLA形成FAV的pH窗口, 且拓宽其近中性pH窗口的能力按照双糖<单糖≈双糖/单糖≤单糖/单糖的顺序依次增强. 主要归结为单糖在FAV表面的强竞争吸附, 以及双糖可能因多结合位点吸附而减少其自由羟基与环境水分子的缔合作用, 从而影响多羟基小分子依靠自由羟基增强囊泡表面亲水性的效果.     

pH非敏感型自交联共轭亚油酸囊泡的构建和表征

以共轭亚油酸(Conjugated linoleic acid, CLA)为构造pH非敏感型脂肪酸囊泡(Fatty acid vesicle, FAV)的分子砌块, 通过碱异构化法从亚油酸半合成CLA, 然后采用pH刺激响应自组装法获得CLA的不饱和脂肪酸囊泡(Ufasome), 采用紫外辐照诱导方式对CLA-ufasome实施囊泡内化学绑定, 获得一种新的pH非敏感型FAV. 通过酸碱滴定和表面张力实验确定CLA-ufasome形成的适宜pH范围和浓度, 利用透射电子显微镜(TEM)表征了自交联CLA的FAV的形貌, 并通过动态光散射(DLS)法测定了自交联CLA的FAV的稳定性. 结果表明, 以CLA为分子砌块, 当浓度为3 mmol/L时在pH=8.6条件下构建CLA-ufasome, 紫外辐照2.5 h后得到粒径为10~20 nm, 壁厚为2.0 nm的自交联CLA的FAV, 并具有pH非敏感的特性. 以抗癌药物五氟尿嘧啶为目标包覆药物, 体外释放实验结果表明, 自交联CLA的FAV对五氟尿嘧啶具有良好的缓释效果.     

三维宏观网络状囊泡薄膜的分级自组装研究

分别合成以疏水性超支化聚醚(HBPO)为核,以亲水性聚环氧乙烷(EO)和聚甲基丙烯酸N,N-二甲氨基乙酯(DMAEMA)为臂的两亲性超支化多臂共聚物HBPO-star-PEO和HBPO-star-PDMAEMA.通过两者在水溶液中的复合自组装制备得到具有pH响应性的巨型聚合物囊泡(1~10μm),并用zeta电位仪,激光共聚焦显微镜及光学显微镜对囊泡的自组装行为进行了研究.结果表明,在等电点以前,复合囊泡始终以单个囊泡形式存在;随着溶液pH的升高,囊泡逐步线型缔合成串珠结构;在更高的pH下,囊泡进一步二次聚集形成具有宏观尺度的三维蜘蛛网状超分子结构,这是一类新的自组装体.     

自交联共轭亚油酸囊泡的温敏膨胀行为

采用紫外辐照引发共轭亚油酸(CLA)囊泡内聚合反应,获得自交联CLA囊泡.用动态激光光散射(DLS)和冷冻透射电子显微镜(cryo-TEM)等观察自交联CLA囊泡的粒径和形貌变化,结果表明,自交联CLA囊泡的囊泡结构不仅不随温度变化解体,而且表现出明显的温敏膨胀性.自交联CLA囊泡体外释放5-氟尿嘧啶的实验表明其具有温度响应的缓释和控释特性.     

贵金属纳米颗粒杂化囊泡的制备及拉曼增强效果研究

以超支化聚合物囊泡为模板制备了贵金属纳米颗粒表面功能化的杂化囊泡.模板囊泡通过多巴胺修饰的超支化聚醚HSP-DA在水中自组装形成.在碱性条件下,囊泡表面的多巴胺自聚合生成聚多巴胺,实现囊泡的交联.由于聚多巴胺具有强黏附特性,因此可以将HSP-PDA交联囊泡分别与Au纳米溶胶、Ag纳米溶胶直接混合,得到Au纳米颗粒或Ag纳米颗粒功能化的杂化囊泡.分别测定了2种杂化囊泡的拉曼光谱,发现杂化囊泡产生了明显的表面增强的拉曼光谱(SERS)信号,清晰显示了对应于囊泡模板分子的拉曼信号,表明可以通过SERS来原位检测囊泡的组成.Ag纳米颗粒杂化囊泡展示出更高的SERS灵敏度,可进一步作为探针检测水中浓度为10-7mol/L罗丹明6G分子,得到了显著增强的拉曼光谱,证明所制备的Ag纳米颗粒杂化囊泡可用于目标分子的痕量检测.     

利用超分子接枝聚合物体系制备具有pH响应能力的高分子囊泡及其在药物控制释放方面的应用

利用自由基聚合的链转移反应,制备了以羧基为端基的聚(N-异丙基丙烯酰胺)(PNIPAM-COOH),然后以该聚合物作为亲水的侧链,利用其羧端基和聚(4-乙烯基吡啶)(PVPy)疏水主链上的吡啶基团间的相互作用,在共溶剂DMF中形成超分子两亲接枝聚合物体系,在上述体系中逐滴加入水可以使其通过自组装形成高分子囊泡.通过控制PVPy与PNIPAM-COOH的质量比在1～3之间,可以控制囊泡尺寸在130～330nm之间.由于囊泡中含有吡啶基团,因而该囊泡具有pH敏感性.以日落黄为药物模型,以这些pH敏感性囊泡作为药物载体,通过调节环境的pH值可以实现对药物的控制释放.     

部分水解聚丙烯酰胺-羟乙基纤维素的水相pH响应性自组装

为考察无规共聚物在全水相环境中的自组装行为, 合成了结构类似于无规共聚物的低相对分子质量的部分水解聚丙烯酰胺(HPAM). 尝试改变水溶液pH值来诱导HPAM与羟乙基纤维素(HEC)发生自组装, 采用透射电子显微镜(TEM)观察到不同pH值时分别获得了100 nm的似正方体胶束, 200 nm×100 nm的类椭球胶束, 100 nm的串珠状胶束以及500 nm×300 nm×50 nm的半月形胶束等pH响应性核壳型聚合物胶束. 建立了金在胶束表面原位还原耦合TEM表征方法, 用于检测低衬度聚合物胶束的纳米细节; 配合电子探针X射线微区分析(EPMA)和扫描电子显微镜(SEM), 证实了半月形聚合物胶束的精致分级构造为亲水性内囊@疏水性连续囊壁@亲水性外壳的多泡囊泡, 并证实pH=0.9时多泡囊泡崩解为疏水性内核@亲水性外壳的10 nm类球体小胶束. 通过分析链节质子化状态的pH响应性, 结合zeta电位和吸光度测定结果, 阐释了不同pH值时组成聚合物胶束的核和壳的链段归属, 获得了全水相中HPAM自组装驱动力和形貌方面的全新知识.     

油酸囊泡尺度多分散性及二元醇对其pH窗口的影响

以油酸(OA)为模型脂肪酸, 依据目测激光丁达尔现象在pH滴定曲线上划分相区, 确定OA囊泡化pH窗口为8.2~10.1. 利用光学显微镜、 激光共聚焦显微镜和冷冻刻蚀-透射电子显微镜共同表征了OA囊泡的形貌及粒径, 发现体系中微米和亚微米级的多层囊泡以及纳米级的单层囊泡共存, 呈现尺度多分散性. 用不同链长的短链二元醇辅助OA形成囊泡, 结果表明, 短链二元醇有助于脂肪酸囊泡(FAV)的pH窗口拓宽, 拓宽的方向取决于表面氢键作用方式或疏水插入方式. 在酸性条件下二元醇与FAV相互作用后, 在囊泡表面残留的自由羟基越多, 越有助于拓宽其酸性pH窗口.     

利用烷基糖苷迁移和扩张共轭亚油酸囊泡pH窗口

脂肪酸囊泡(FAV)具有与脂质体类似的中空核壳结构, 且原料来源广泛, 绿色安全, 在包埋/缓释方面有重要意义. 但FAV对pH值依赖性强, pH窗口很窄并偏离生命体系适应pH范围, 限制了其作为包埋/缓释体在日用化学品及外用药等中的应用. 本文用绿色安全非离子表面活性剂烷基糖苷(APG)使共轭亚油酸(CLA)形成FAV的pH窗口从原先的8.0-9.0 迁移并扩张至6.0-8.0, 从而与生命体系适应pH值范围相匹配, 并探讨了改善FAV的pH值依赖性和敏感性的原理.     

Halloysite nanocontainers for controlled delivery of Gibberellic Acid

Inorganic halloysite nanocontainers were employed for controlled delivery of plant growth regulator (PGR)–Gibberellic Acid. The cylindrical geometry of nanocontainer was found to be found to indicate 600 ± 200 nm length and 50 ± 10 nm outer diameter with inner lumen to be in the range of 12–15 nm. Attempts were made to encapsulate GA and obtain controlled release in aqueous buffer through nanocontainers capped with a copper stopper. Halloysite nanocontainers were characterized using TEM, EDX and TGA. In vitro release studies of GA in water were studied wherein the pH of the solution was maintained using phosphate buffer. Increase in amount of copper was found to be successful in retarding the amount of GA release. Complex between GA and copper ions was found to be responsible for the stopper formation. For tube stopper opening, addition of excessive amounts of ammonia solution was added. Parameters such as effect of temperature, pH and UV light were studied in detail. Encapsulation and stopper formation onto the nanocontainer was found to effective in achieving overall release control. Kinetic release model proposed by Peppas was analyzed for best fit.     

用共轭亚油酸构筑层状液晶的药物传递系统

在水相中用共轭亚油酸(CLA)及其钠盐(SCL)构筑层状液晶相, 并考察了其药物缓释行为. 借助偏光显微镜并辅以目测确定CLA/SCL/H₂O三元相图中的层状液晶相区, 然后用偏光显微镜、 小角X射线散射仪和旋转流变仪获得层状液晶的偏光织构、 相参数和流变参数等, 证实其适用于药物传递系统(DDS). 采用透析法研究了负载亲水性药物5-氟尿嘧啶或亲油性药物姜黄素的层状液晶的释药曲线, 结果表明, 该类层状液晶对2种药物均有良好的缓释能力.     

The role of polymer/drug interactions on the sustained release from poly(dl-lactic acid) tablets

The release profiles of model drugs (propranolol HCl, diclofenac sodium, salicylic acid and sulfasalazine) from low molecular weight poly(d,l-lactic acid) [d,l-PLA] tablets immersed in buffer solutions were investigated in an attempt to explore the mechanism of the related phenomena. It was confirmed that drug release is controlled by diffusion through the polymer matrix and by the erosion of the polymer. The pH of the surrounding medium influences the drug solubility as well as swelling and degradation rate of the polymer and therefore the overall drug release process. Physicochemical interaction between d,l-PLA and drug is an additional factor which influences the degree of matrix swelling and therefore its porosity and diffusion release process. Propranolol HCl shows extended delivery time at both examined pH values (5.4 and 7.4) and especially at pH 7.4 where release was accomplished in 190 days, most probably due to its decreased solubility at higher pH values. The acidic drugs gave shorter delivery times especially at pH 7.4. A slower drug release rate and more extended delivery time at pH 7.4 in comparison with that at pH 5.4 was recorded for tablets loaded with diclofenac sodium and salicylic acid. The opposite effect was observed with samples loaded with propranolol HCl.     

pH- and temperature-dependent release from cationic vesicles coexisting with copolymer of N-isopropylacrylamide and methacrylic acid

Vesicles containing rhodamine B were prepared by evaporation and hydration method using N-[3-(dimethylamino)propyl]-octadecanamide (DMAPODA) and stearic acid (SA). The vesicles were multi-lamellar on optical and electron micrographs. The mean size of vesicle was 807.9 nm and the values markedly increased by the addition of copolymers of N-isopropylacrylamide (NIPAM) and methacrylic acid (MAA) (P(NIPAM-co-MAA)), possibly due to electrostatic interactions between the cationic vesicle and the anionic copolymer. The release of rhodamine B from the vesicles for 20 h was 50–60% at neutral pHs and the values increased up to 93.1% when pH decreased to 3. The increased release is possibly because the salt bridge formed between DMAPODA and SA was broken down at the acidic pH, leading to the disintegration of the vesicles. On the other hand, the release was not as sensitive to temperature as it was to pH. The salt bridge seemed to be stable at the temperatures of the release experiments (23 °C, 33 °C and 43 °C). P(NIPAM-co-MAA) was added to the suspension of the vesicle and the release was investigated with varying pHs and temperatures. The copolymer was pH- and temperature-sensitive in terms of the turbidity change of its solution. Nevertheless, the copolymer was found to have little effect on the pH- and temperature-dependent release of the vesicles.     

Self-assembling dipeptide-based nontoxic vesicles as carriers for drugs and other biologically important molecules

Self-assembling short peptides can offer an opportunity to make useful nano-/microstructures that find potential application in drug delivery. We report here the formation of multivesicular structures from self-assembling water-soluble synthetic amphiphilic dipeptides containing a glutamic acid residue at the C-terminus. These vesicular structures are stable over a wide range of pH (pH 2-12). However, they are sensitive towards calcium ions. This causes the rupturing of these vesicles. Interestingly, these vesicles can not only encapsulate an anticancer drug and a fluorescent dye, but also can release them in the presence of calcium ions. Moreover, these multivesicular structures have the potential to carry biologically important molecules like cyclic adenosine monophosphate (cAMP) within the cells keeping their biological functions intact. A MTT cell-survival assay suggests the almost nontoxic nature of these vesicles. Thus, these peptide vesicles can be used as biocompatible delivery vehicles for carrying drugs and other bioactive molecules.     

Reduced fluidity of dipalmitoyl phosphatidic acid membranes by salicylic acid

This paper presents DSC and NMR study of how the kerotolytic drug, salicylic acid (SA), affects the thermotropic and morphological behavior of a model membrane, dipalmitoyl phosphatidic acid (DPPA). The membrane-drug system has been studied in the multilamellar vesicular (MLV) and in the unilamellar vesicular (ULV) forms, for SA/DPPA molar ratios from 0 to 0.5. The mode of interaction of SA molecules with DPPA is similar in MLV and ULV. Chain-melting transition becomes sharper and shifts to higher temperatures in the presence of the drug, implying an enhanced co-operativity of the acyl chains. NMR and DSC data indicate that the drug molecules are located in the aqueous interfacial region neighboring the lipid headgroups. The membrane becomes more rigid in the presence of the drug molecules, due to a stronger interaction between the lipid headgroups leading to reduced permeability. ULVs are destroyed by even a short equilibration at room temperature, whereas prolonged equilibration of the MLV only leads to a slightly reduced interaction between the lipid headgroups due to sequestering of the drug molecules in the interfacial aqueous region.