巯基聚乙二醇5000修饰的金溶胶的稳定性: 从DLVO稳定到空间稳定

研究了α-甲氧基-ω-巯基聚乙二醇(mPEG-SH, 5000 MW)修饰的金溶胶的稳定性, 初步探讨了其稳定机制. 将线性mPEG-SH通过巯基化学吸附于金溶胶表面, 可形成高分子层包被的金溶胶. 研究结果表明, PEG修饰的金溶胶可以在pH＝1～13.5或盐浓度高达1.20 mol/L的较苛性条件下保持稳定. 这是由于金溶胶表面吸附的高分子保护层为溶胶提供了新的空间稳定, 取代了溶胶原来的DLVO稳定(实质是电荷稳定). 因而, PEG保护的金溶胶在很大程度上克服了DLVO稳定的溶胶对环境敏感、易聚沉的缺点, 能在复杂的条件(如生理条件)下应用. 鉴于PEG的水溶性、无毒性和生物亲和性, 这种具有较高稳定能力的金纳米粒子/PEG复合体结合了金纳米粒子和PEG的优异性能, 可作为生物纳米探针用于复杂条件下的生物分析.     

聚乙二醇-异黄酮复合物的合成

用聚乙二醇(PEG)修饰异黄酮类化合物(1)的侧链,并采用不同氨基酸做连接臂,合成了聚乙二醇-异黄酮复合物--聚乙二醇-异黄酮酯前药(6),其结构经1H NMR和IR表征.在磷酸缓冲溶液中,1能在10 h内释放完全;6的载药量有待进一步提高.     

(羟基喜树碱@胆酸钠)-层状双金属氢氧化物纳米杂化物的组装及表征

采用“药物修饰-共组装”法制备了(羟基喜树碱@胆酸钠)-层状双金属氢氧化物纳米杂化物. 先用胆酸钠(SCL)包裹羟基喜树碱(HCPT)形成胶束, 再与微反应器制备的层状双氢氧化物(LDH)纳米片共组装形成纳米杂化物, 其载药量可达12.9%, 杂化物中HCPT以高生物活性的内酯形式存在. 采用聚乙二醇(PEG)和羧甲基纤维素(CMC)分别对所制备的(HCPT@SCL)-LDH纳米杂化物进行了表面修饰, 结果表明, 纳米杂化物的分散性得到明显改善; PEG的修饰效果优于CMC, 所获得的PEG-(HCPT@SCL)-LDH杂化物的平均粒径可小至约70 nm, 具有良好的分散性和药物缓释效果. 其药物释放过程可用准二级动力学方程描述, 颗粒内部扩散是药物释放过程的控制步骤.     

具有可见光响应聚合物纳米粒子的制备及性能研究

利用可见光响应供体-受体Stenhouse加合物(DASAs)设计并制备了2种表面含有可见光响应单元的聚合物纳米粒子,并对纳米粒子的光响应性进行了研究.首先合成了修饰DASA分子的聚合物PGMD,研究结果表明PGMD可溶于与水互溶的有机溶剂(如DMSO)中并具有良好的光响应性,PGMD链段可在可见光刺激下响应为亲水状态.因此,含有PGMD链段的嵌段共聚物PCL-b-PGMD可在水中自组装形成胶束,并能与PCL-b-PEG在水中共组装形成复合壳层胶束,但PGMD链段在水中无法可逆响应为疏水状态.为获得具有可逆响应性的聚合物纳米粒子,利用硅烷偶联剂水解修饰的方法得到表面含有疏水三烯状态DASA分子与亲水PEG短链的复合壳层二氧化硅纳米粒子,实验结果表明复合壳层二氧化硅纳米粒子在水环境中有良好的分散稳定性,并且表面修饰的DASA分子仍具有良好的响应性.本研究为设计表面性质可调的响应性聚合物纳米粒子提供了新的设计思路.     

不同功能化基团修饰的硅壳纳米颗粒分散性研究

采用反相微乳液体系中功能化基团同步修饰(油相修饰)以及反相微乳液制备纳米颗粒后再通过功能化基团后续修饰(水相修饰)的方法分别制备了纯硅壳纳米颗粒(SiNP)、氨基化硅壳纳米颗粒(NSiNP)、羧基化硅壳纳米颗粒(CSiNP)和聚乙二醇硅壳纳米颗粒(PSiNP). 通过沉降时间和离心速度观察了不同方法获得的不同功能化基团修饰的硅壳纳米颗粒在水中的分散及稳定性, 并采用激光粒度仪、透射电子显微镜对分散效果进行了分析. 结果表明, 采用同一修饰方法分别制备的纳米颗粒在水中的分散及稳定性顺序是CSiNP≥PSiNP>SiNP>NSiNP; 油相修饰法获得的CSiNP和PSiNP的分散性要优于水相修饰法获得的. PSiNP和CSiNP在Hela细胞表面的非特异性吸附非常小, 而NSiNP却显示了强烈的细胞非特异性吸附.     

表面电荷对聚乙二醇修饰金纳米粒子生物行为的影响

利用硫-金键将末端修饰甲氧基、氨基或羧基的巯基化聚乙二醇(Thiolated polyethylene glycol,HS-PEG)分子分别组装到金纳米粒子表面, 合成了3种带有不同表面电荷的聚乙二醇修饰金纳米粒子(PEGylated gold nanoparticles,PEG-Au NP).细胞共培养和小鼠尾静脉注射实验结果表明,表面电荷能够显著影响PEG-Au NP的生物行为.细胞对PEG-Au NP的吞噬量遵循正电荷＞电中性＞负电荷的规律.尾静脉注射的PEG-Au NP能够随小鼠的血液循环由全器官分布逐渐向肝脾转移.表面带负电荷的PEG-Au NP较难被小鼠肝脾清除,带但正电荷的PEG-Au NP能够引起小鼠免疫系统较强的响应.     

修饰剂链长变化对核壳结构CdS纳米晶尺寸和光学性质的影响

采用液液两相法,在甲苯和水的两相体系中制备了由不同烷基链长单硫醇修饰的具有无机-有机核壳结构的CdS半导体纳米晶.使用透射电子显微镜(TEM)、X射线粉末衍射(XRD)和紫外-可见吸收光谱(UV-Vis)对样品的结构和组成进行了表征.结果表明,样品CdS半导体纳米晶是由无机纳米核及其表面化学吸附的硫醇组成的,而且壳层有机修饰剂对无机纳米核的尺寸和光学性质影响很大.进一步分析发现,层修饰剂的烷基链长和CdS纳米核的尺寸之间存在着类似抛物线的关系.这主要是由于在两相体系中,Cd纳米核的形成和成长两个阶段受到修饰剂在有机相中的迁移率以及其在纳米核表面的组装有序度两种关键因素竞争结果的控制.     

齐墩果酸-聚乙二醇纳米载药粒子的制备及性能研究

将齐墩果酸(OA)与聚乙二醇(PEG)化学连接,并自组装包载10-羟基喜树碱(HCPT),获得了粒径均一的聚乙二醇-齐墩果酸/10-羟基喜树碱(PEG-OA/HCPT)纳米粒子。采用1H-NMR对聚乙二醇-齐墩果酸(PEG-OA)进行表征,透射电镜观察PEG-OA/HCPT纳米粒子的形貌;测定了OA和HCPT的载药量,并研究了其在不同p H值下PBS溶液中药物的体外释放试验。结果表明,1H-NMR证实了OA通过酯键与PEG成功连接,PEG-OA/HCPT纳米粒子呈球形;OA和HCPT的载药量分别为(5.1±0.2)%和(13.2±0.3)%;制备出的纳米粒子在缓冲溶液中可实现OA和HCPT的缓慢释放,在240h后,OA在p H值为7.4和5.5的PBS缓冲液中释放率分别为38.4%和55.9%,HCPT的释放率分别达到57.5%和73.5%。     

基于碳酸钙-金纳米粒子无机杂化复合物固定硫堇的新方法及其在过氧化氢传感器中的应用

通过静电作用,经碳酸钙-金纳米粒子(CaCO3-AuNPs)无机杂化复合物实现了电活性物质硫堇(Th)在金电极表面的有效固定.AuNPs静电吸附到CaCO3微球表面形成CaCO3-AuNPs无机杂化复合物,该杂化复合物具有微孔结构、大的表面积和好的生物相容性,使得Th的固定量和稳定性大大提高.探讨了Th修饰电极在过氧化...     

聚乙二醇-金纳米棒介导的近红外光热抑菌作用

种子生长法合成纵向表面等离子体共振吸收峰为785 nm的金纳米棒,并对其表面进行聚乙二醇(PEG)修饰,研究了表面修饰PEG的金纳米棒(polyethylene glycol modified gold nanorods,PEG-GNR)的光热转化效应,并测试了其细胞毒性.以革兰氏阳性菌金黄色葡萄球菌、蜡状芽孢杆菌,革兰氏阴性菌大肠埃希氏菌及铜绿假单胞菌为细菌模型,详细研究了PEG-GNR在808 nm波长近红外激光照射下金纳米棒浓度和照射功率对抑菌效果的影响.结果表明,PEG-GNR对革兰氏阳性菌和革兰氏阴性菌在近红外照射下均有较好的抑菌效果,并且抑菌效果与金纳米棒的浓度和照射功率有着密切的关系;结合荧光显微镜和透射电子显微镜对细菌坏死状况的观察,初步证实细菌对PEG-GNR有效吸收是近红外光热杀菌的关键因素.     

PEGylated inorganic nanoparticles

Application of inorganic nanoparticles in diagnosis and therapy has become a critical component in the targeted treatment of diseases. The surface modification of inorganic oxides is important for providing diversity in size, shape, solubility, long-term stability, and attachment of selective functional groups. This Minireview describes the role of polyethylene glycol (PEG) in the surface modification of oxides and focuses on their biomedical applications. Such a PEGylation of surfaces provides "stealth" characteristics to nanomaterials otherwise identified as foreign materials by human body. The role of PEG as structure-directing agent in synthesis of oxides is also presented.     

Metabolic delivery of methacryloyl groups on living cells and cell surface modification via thiol-ene "click" reaction

Methacryloyl groups are delivered on a living cell surface via a glycosylation pathway. The mannosamine derivative ManMA is synthesized as a precursor of cell-surface sialic-acid residues. HeLa cells are cultivated in a culture medium containing ManMA, after which a sufficient amount of PEG(4)10K-SH is in contact with the cells in the presence of a photoinitiator. The cells are then exposed to UV-light for 10 min. The immobilization of PEG(4)10K-SH, termed PEGylation, on the cell surface is confirmed by fluorescence microscopy. The surface modification does not influence cell viability. Biotinylation of cell surface can also be achieved by the addition of a vinyl compound during PEGylation. By using this process, the functionalities of a cell surface can be freely controlled.     

Modification and stabilizing effects of PEG on resveratrol-loaded solid lipid nanoparticles

Resveratrol-loaded solid lipid nanoparticles (SLNs) modified by polyethylene glycol (PEG2000) (RES–PEG–SLNs) were prepared to study the stabilizing influences of PEG2000 on SLNs properties including loading capacity, particle size, photostability, and release. The micromorphology, particle size distribution, drug–lipid–modifier interaction and crystalline structure were characterized to elucidate stabilizing effects of PEG2000 on SLNs. Compared with ordinary SLNs, SLNs modified by PEG2000 at relatively low amounts of [m(PEG2000):m(lipids) = 1:10] exhibit high drug loading, steady nanoparticle size distributions, photostability and sustained release. According to characterizations, RES–PEG–SLNs formation is dependent on the physical interactions of drug–lipid–modifier. Since PEG2000 is doped into lipid matrix in a non-crystalline state, the lipids crystalline arrangement is disrupted. Additionally, RES–PEG–SLNs are crystallized in a PEG2000/lipid eutectic mixture rather than a simple mixture, inhibiting the lipid polymorphism transformation from α- to β-form, and therefore preventing drug exclusion from the lipid matrix. The PEG2000/lipid matrix contains lattice defects, which allow for the incorporation of more resveratrol and preventing it from photodegradation effectively. In contrast to the burst release of SLNs modified without PEG2000, resveratrol is released more slowly from the lattice defects in lipid matrix of RES–PEG–SLNs, resulting in a sustained release fitted by a two-stage exponential kinetic equation. PEG2000 is distributed on the RES–PEG–SLNs surface, increasing repulsion between nanoparticles and avoiding particles aggregation. These results confirm that both matrix doping effects and surface steric hindrance produced by the presence of PEG2000 play important roles in maintaining high loadings, nanoparticle size, photostability and sustained release.     

Adsorption of poly(ethylene glycol)-modified lysozyme to silica

Covalent grafting of poly(ethylene glycol) (PEG) to pharmaceutical proteins, "PEGylation", is becoming more commonplace due to improved therapeutic efficacy. As these conjugates encounter interfaces in manufacture, purification, and end use and adsorption to these interfaces may alter achievable production yields and in vivo efficacies, it is important to understand how PEGylation affects protein adsorption mechanisms. To this end, we have studied the adsorption of unmodified and PEGylated chicken egg lysozyme to silica, using optical reflectometry, total internal reflection fluorescence (TIRF) spectroscopy, and atomic force microscopy (AFM) under varying conditions of ionic strength and extent of PEG modification. PEGylation of lysozyme changes the shape of the adsorption isotherm and alters the preferred orientation of lysozyme on the surface. There is an abrupt transition in the isotherm from low to high surface excess concentrations that correlates with a change in orientation of mono-PEGylated conjugates lying with the long axis parallel to the silica surface to an orientation with the long axis oriented perpendicular to the surface. No sharp transition is observed in the adsorption isotherm for di-PEGylated lysozyme within the range of concentrations examined. The net effect of PEGylation is to decrease the number of protein molecules per unit area relative to the adsorption of unmodified lysozyme, even under conditions where the surface is densely packed with conjugates. This is due to the area sterically excluded by the PEG grafts. The other major effect of PEGylation is to make conjugate adsorption significantly less irreversible than unmodified lysozyme adsorption.     

Cell Spheroid Formation on the Surface of Multi-Block Copolymers Composed of Poly(2-methoxyethyl acrylate) and Polyethylene Glycol

3D structured cells have great drug screening potential because they mimic in vivo tissues better than 2D cultured cells. In this study, multi-block copolymers composed of poly(2-methoxyethyl acrylate) (PMEA) and polyethylene glycol (PEG) are developed as a new kind of biocompatible polymers. PEG imparts non-cell adhesion while PMEA acts as an anchoring segment to prepare the polymer coating surface. The multi-block copolymers show higher stability in water than PMEA. A specific micro-sized swelling structure composed of a PEG chain is observed in the multi-block copolymer film in water. A single NIH3T3-3-4 spheroid is formed in 3 h on the surface of the multi-block copolymers with 8.4 wt% PEG. However, at a PEG content of 0.7 wt%, spheroid formed after 4 days. The adenosine triphosphate (ATP) activity of cells and the internal necrotic state of the spheroid change depending on PEG loading in the multi-block copolymers. As the formation rate of cell spheroid on low-PEG-ratio multi-block copolymers is slow, internal necrosis of cell spheroid is less likely to occur. Consequently, the cell spheroid formation rate by changing the PEG chain content in multi-block copolymers is successfully controlled. These unique surfaces are suggested to be useful for 3D cell culture.     

药物的聚乙二醇修饰研究进展

简要介绍了聚乙二醇(polyethylene glycol, PEG)的生理化学特性, 药物的聚乙二醇修饰的优势, 详细介绍了蛋白质药物和小分子药物的聚乙二醇修饰技术及其在药物研究中的应用进展, 认为药物的聚乙二醇修饰技术通过改变药物的分子结构, 可以有效地改善药物动力学和药效等性质, 增加注射药物的临床应用范围. 同时基于药物的聚乙二醇修饰技术的优势和研究现状, 评述了药物的聚乙二醇修饰技术的发展前景.     

Native PAGE eliminates the problem of PEG-SDS interaction in SDS-PAGE and provides an alternative to HPLC in characterization of protein PEGylation

PEGylation of proteins has become an increasingly important technology in recent years. However, determination and characterization of the PEGylation products are problematic especially for the reaction mixture containing various modified proteins, unreacted PEG, and unmodified protein. A comparative study was carried out with two HPLC methods and two electrophoresis methods for characterization of the reaction mixture in PEGylation of HSA with PEG 5000, 10000, and 20000. RP-HPLC fails to give the correct information about the reaction of PEG 20000. Size-exclusion HPLC (SE-HPLC) produced very poor resolution on the PEG 5000 reaction. SDS-PAGE can run multiple samples of all PEGylation but the bands were smeared or broadened probably due to the interaction between PEG and SDS. On the other hand, native PAGE eliminates the problem of PEG-SDS interaction and provides better resolutions for all samples. Various PEGylated products and unmodified protein migrate differentially in native PAGE under nondenatured conditions. The results demonstrated that native PAGE could be a good alternative to HPLC and SDS-PAGE for the analysis of PEG-protein conjugates especially for characterization of the PEGylation mixture.     

Colloidal stability and drug incorporation aspects of micellar-like PLA–PEG nanoparticles

The drug delivery properties of a series of poly(lactic acid)–poly(ethylene glycol) (PLA–PEG) micellar-like nanoparticles have been assessed in terms of their colloidal stability and their ability to incorporate a water soluble drug. These studies have focused on a range of PLA–PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3–110 kDa). In aqueous media, these copolymers formed micellar-like assemblies following precipitation from water miscible solvents. There was a controlled increase in the particle size as the molecular weight of the PLA block was increased. The characteristics of the PEG corona were also highly dependent on the PLA moiety. Copolymers with a low molecular weight PLA block (3–15 kDa) formed highly colloidally stable dispersions, with a complete PEG surface coverage. However, increasing the molecular weight of the PLA block resulted in significantly less colloidally stable nanoparticle dispersions, which flocculated in solvents that were significantly better than θ-solvents for the stabilising PEG chains. This can be attributed to a reduced PEG surface coverage and the probable presence of naked PLA ‘patches’ on the particle surface. These larger PLA–PEG nanoparticles (30:5–110:5) were found to be stabilised in the presence of serum components, which are thought to adsorb into the gaps on the particle surface and prevent flocculation. All of the dispersions were found to be stable under physiological conditions and therefore suitable for in vivo administration. A reasonable loading (3.1% w/w) of the micellar-like PLA–PEG 30:5 nanoparticles with the water soluble drug procaine hydrochloride was achieved. The incorporated drug was found to have no effect on the nanoparticle structure or recovery, which can be attributed to the micellar character of these assemblies and the presence of the stabilising PEG chains.     

Effect of different molecular weights of polyethylene glycol as a plasticizer on the formulation of dry powder inhaler capsules: Investigation of puncturing size,morphologies, and surface properties

Today, the principle of research and development is pulmonary drug delivery due to the potential for maximizing therapeutic effects for patients by direct drug targeting the pathology site in the lungs. Amongst the convenient delivery alternatives, the Dry Powder Inhaler (DPI) is the preferred device to remedy a variety of diseases. In this regard, the fabrication and development of a novel formulation for DPI capsules have been studied. We investigated the effects of various parameters, such as percentages of polyethylene glycol (PEG), propylene glycol (PG), glycerol (Gly), brittleness, test conditions, and particle release of manufactured DPI capsules. The efficacy of each parameter was evaluated in detail to understand and address the consequences of the mentioned factors. The results illustrated that the lower molecular weight of PEGs presented the better plasticizing capability of gelatin. Owing to the hygroscopicity of the utilized plasticizer, polyethylene glycol 400 (PEG 400) increased the capsule flexibility for a longer time and its stability under environmental conditions in the gelatin capsule formulation. Likewise, no particle release was observed in the gelatin/PEG capsule. The prepared gelatin/PEG400 capsules were compared with pure gelatin and HPMC capsules. The capsules were evaluated in terms of loss on drying (LOD), surface morphology, roughness, and puncture type. The results show that using PEG-400 can lead to the production of capsules that have low moisture content and minimal interaction with APIs. In addition, gelatin/PEG capsules have no particles due to the smooth surface after the punching process. The as-produced capsules are not blocked again after punching, allowing the patient to take the drug completely. In fact, the present research provided substantial insight regarding the development of DPI formulation in capsule investigations on an industrial scale.     

Thermodynamic Studies of Insulin Loading into a Glucose Responsive Hydrogel Based on Chitosan‐polyacrylamide‐polyethylene Glycol

The insulin therapy constitutes the preferred treatment for Diabetes Mellitus (DM). The traditional insulin therapy, which consists of daily subcutaneous insulin injections to control blood glucose level, is not able to regulate the blood glucose level precisely. In this research, to facilitate the diabetic patient life, an intelligent drug delivery system based on a biodegrable biopolymer to control the insulin release, was designed. In this system, chitosan‐polyethylene glycol hydrogel and glucose oxidize play the role of drug carrier and glucose biosensor, respectively. To increase the hydrogel drug loading capacity, hydrogels with different PEG content were synthesized and insulin was loaded by swelling‐diffusion method into them. The loaded hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), High performance liquid chromatography (HPLC), and Thermogravimetric analysis (TGA). Finally, the thermodynamic study for insulin loading process was performed to investigate the stability of the drug in the system.