SigmaPlot在拟合纳米载体蛋白药物的体外释放中的应用

采用SigmaPlot软件探讨水溶性壳聚糖(WSC)纳米蛋白药物载体的体外释放规律。以牛血清蛋白(BSA)为模型药物,分别采用动力学模型、Weibull模型、Gompertz模型、Logistic模型、Higuchi模型对纳米粒子的蛋白释放,进行拟合试验。供试7个模型中,除Higuchi和Logistic模型外,其余模型均能较好地拟合BSA的释放情况。因此SigmaPlot作出的Gompertz二级模型能很好地拟合WSC纳米载体体系BSA的释放规律。     

一种新型的负载蛋白质药物微球的制备和释药性能

为了制备具有蛋白药物结肠靶向释放性能的新型药物载体,采用了水相溶液滴定反应法,分别以牛血清白蛋白(BSA)和乳铁蛋白(LF)为模型蛋白质药物,制得壳聚糖/纤维素磷酸钠(NaCS)/三聚磷酸钠(TPP)载药微球。利用电镜SEM和显微镜观测拍照,对微球的表面和截面形貌进行了表征,发现微球球形规则且颗粒大小均一。同时进行了体外药物模拟释放试验,考察了载药微球先后经过模拟胃液、模拟小肠液和模拟结肠液时的释药性能,及不同的释放条件和制造条件对于微球释药性能的影响,尤其考察了不同蛋白药物和不同干燥方式的影响。结果表明由临界点干燥法制得的负载乳铁蛋白(LF)微球在模拟胃液和小肠液释放量中5 h内只释放出不到20%的蛋白药物,而后在结肠模拟液中4 h内释放出蛋白药物80%以上。这些结果表明,壳聚糖/NaCS/TPP体系具有一定的作为结肠靶向药物释放载体的应用潜力。     

可生物降解药物载体——纳米/亚微米壳聚糖微球的制备及性能

利用聚电解质的离子凝胶反应,在溶液中壳聚糖为聚阳离子电解质与带反相电荷的聚阴离子三聚磷酸钠(TPP)发生离子凝胶反应,在合适的浓度和适当的搅拌速度下,得到亚微米级的壳聚糖微球。利用环己烷作为油相,以壳聚糖溶液为水相,配制澄清透明的W/O反相微乳清液,滴加质量浓度为5mg/mL的TPP溶液于已配制好的微乳清液中,制得纳米级壳聚糖微球。采用上述两种方法制得的纳米/亚微米壳聚糖微球用作生物降解药物载体,载药实验结果表明,释放初期无明显暴释现象,具有良好的药物缓释作用。     

两亲性氟乐灵/羧甲基壳聚糖载药纳米粒子的制备及缓释性能

[目的]改善氟乐灵制剂的水溶性、延缓氟乐灵的降解速率,研究羧甲基壳聚糖纳米粒子作为氟乐灵载体缓释性能。[方法]采用化学接枝法、简单透析法制备了一种新型两亲性氟乐灵/八氢视磺酸-羧甲基壳聚糖(Tf-OR-CC)聚合物,通过FT-IR、动态激光散射和透射电镜分析确定聚合物的化学结构、Tf-OR-CC的粒径分布和形貌。采用HPLC和紫外分光光度计测定Tf-OR-CC的载药率和缓释性能。[结果]OR-CC和Tf-OR-CC纳米粒子近似球形,平均粒径介于255～361 nm之间,Zeta电位介于23.9～33.6 m V之间,说明载药纳米粒子不易发生团聚。3种投料比的Tf-OR-CC纳米粒子的载药率分别为43.6%、49.1%、42.4%,Tf-OR-CC(质量分数20%)为最佳配比。Tf-OR-CC(质量分数20%)在PBS缓冲溶液(p H值7.0)7 d的累计释放率为59.1%,表现出良好的控释缓释性能。[结论]该方法可为研制环境友好型水溶性氟乐灵除草剂提供科学依据。     

疏水修饰磁性壳聚糖载药纳米粒子的制备与表征

利用O-羧甲基壳聚糖(O-CMC)的表面多种官能团(如-NH_2,-OH,-COOH等)与胆酸(CA)进行化学修饰得到两亲性共聚物,再以反溶剂法将Fe_3O_4和阿霉素(DOX)包埋在两亲性共聚物疏水的核中,制备两亲性的磁性壳聚糖载药纳米粒子,并对磁性载药纳米粒子的形貌、粒径大小、磁性、药物控释等进行了研究。结果表明:磁性壳聚糖纳米粒子有较高的药物包埋效率(92.3%),与自由阿霉素相比,磁性复合物具有明显的缓释作用和pH响应性;同时,有较好的超顺磁性。这些说明制备的疏水修饰磁性壳聚糖载药纳米粒子具有双重响应性,有望作为药物输送载体对肿瘤进行实时跟踪、诊断和治疗。     

壳聚糖烷基化改性及其纳米微球负载扑热息痛的研究

将低分子量壳聚糖经长链烷基在碱性条件下改性制得烷基化壳聚糖衍生物 ,红外光谱研究表明取代反应主要发生在壳聚糖的氨基上 ,透射电镜研究表明该衍生物在水中可自动形成粒径分布在 1 0 0nm左右的纳米微粒。以扑热息痛为模型药物 ,对烷基壳聚糖纳米微球在磷酸缓冲液 (pH =7 4)中体外释放的研究表明 ,在取代度接近的情况下 ,随着烷基链的增长 ,扑热息痛在磷酸缓冲液中的缓释作用得到改善 ,累积达到平衡时的浓度降低。     

离子交联法制备聚唾液酸/壳聚糖纳米粒

以聚唾液酸和壳聚糖为原料,多聚磷酸钠为交联剂,采用离子交联法制备聚唾液酸/壳聚糖纳米粒。结果表明:当聚唾液酸质量浓度为1.25 mg/mL,壳聚糖质量浓度为1.00 mg/mL,壳聚糖与聚唾液酸质量比为2∶1,多聚磷酸钠质量浓度为0.15 mg/mL,滴加速度为1滴/s时,所制备的聚唾液酸/壳聚糖纳米粒粒径最小,平均粒径为217.2 nm,纳米粒粒径分散指数为0.236。以牛血清白蛋白(BSA)为模型药物,包封率为(44.95±1.22)%,载BSA率为(28.90±0.78)%。离子交联法制备聚唾液酸/壳聚糖纳米粒操作简单快捷,不使用有机溶剂,所得纳米粒粒径较小,有望成为蛋白类药物的载体。     

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.     

pH敏感性叶酸修饰羧甲基壳聚糖/CaCO_3混合纳米球作为药物载体的研究

以叶酸为靶向基团,将其连接到羧甲基壳聚糖(CMCS)上,制得偶联叶酸的羧甲基壳聚糖(FCMC),在FCMC溶液中碳酸钙自组装形成一种具有靶向性的FCMC/CaCO_3混合纳米球。同时对纳米球结构进行表征,并对比了修饰叶酸前后混合纳米粒理化性能。在此基础上,将亲水性药物二甲双胍作为模型药物,对2种载体的包封率、载药量及释放行为进行了对比研究。结果表明,FCMC/CaCO_3混合纳米球大小均一,分散性良好,碳酸钙的引入使得纳米球对亲水性药物包封率较高,该纳米球对药物的释放具有较好的pH敏感性和缓控释放能力,是潜在的智能药物给药系统基质材料。     

水杨酸壳聚糖/卵磷脂纳米粒的制备

采用溶剂注入法制备水杨酸壳聚糖/卵磷脂纳米粒。考察了粒子结构、形貌特征及表面电位等性能,并探讨了制备工艺对药物包封率的影响。确定最佳制备工艺为:卵磷脂质量浓度20 g/L、卵磷脂与壳聚糖及水杨酸与载体的质量比分别为3∶1和1∶6、水相pH=4。所制备的水杨酸壳聚糖/卵磷脂固体纳米粒子为球形粒子、表面电位+18.7 mV、包封率及载药量可分别达到55%和8.07%。     

Polyelectrolyte complex beads composed of water‐soluble chitosan/alginate: Characterization and their protein release behavior

Polyelectrolyte complex (PEC) beads were prepared from water‐soluble chitosan (WSC) and alginate complex solution with different ratios by dropping method, and all procedures used were performed in aqueous medium at neutral environment. The structure and morphology of the beads were characterized by IR spectroscopy and scanning electron microscopy (SEM). IR spectroscopy confirmed the electrostatic interactions between amino groups of WSC and carboxyl groups of alginate. SEM showed internal section of the PEC bead, which had porous structure compared with compact structure of alginate beads. The swelling behavior, encapsulation efficiency, and release behavior of bovine serum albumin (BSA) from the beads at different pHs were investigated. PEC beads demonstrated different responses to pH from alginate beads. The ratio of WSC to alginate influenced the encapsulation and release of BSA. At pH 1.2, small amount (< 15%) of BSA was released from the PEC beads except AC12. However, at pH 7.4, a large amount (> 80%) of BSA was released from AL in the first 3 h due to the rapid disintegration of the beads, whereas BSA release was retarded from complex beads due to the forming of PEC. The results suggested that the WSC/alginate beads could be a suitable polymeric carrier for site‐specific protein drug delivery in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 4614–4622, 2006     

Preparation of nanoparticles composed of chitosan and its derivatives as delivery systems for macromolecules

Three different kinds of nanoparticles for paracellular transport were prepared using a simple and mild ionic‐gelation method. Sodium tripolyphosphate (TPP) as crosslinking agent was added into three kinds of solutions, which were chitosan solution, physical blending solution of chitosan, and glycidyl trimethylammonium chloride (GTMAC), and O‐(2‐hydroxyl) propyl‐3‐trimethyl ammonium chitosan chloride (O‐HTCC) solution respectively. O‐HTCC was synthesized by coupling of GTMAC to chitosan whose functional groups of the NH₂ groups were protected. The nanoparticles were characterized by transmission electron microscopy, atomic force microscopy, photon correlation spectroscopy, and zeta potential measurement. The results showed that increasing TPP concentration promoted the size of chitosan nanoparticles, a decrease in the size of O‐HTCC nanoparticles incurred on the contrary. The size of O‐HTCC nanoparticles is slightly bigger than that of pure chitosan nanoparticles, and smaller than that of physical blending nanoparticles (PBN). Bovine serum albumin (BSA), as a model protein drug, was incorporated into the nanoparticles. Compared with chitosan nanoparticles and PBN, high BSA loading efficiency (87.5%) and loading capacity (99.5%) are achieved by quaternized chitosan (O‐HTCC) nanoparticles, and the release profile of BSA from nanoparticles has an obvious burst effect and a slowly continuous release phase followed. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Ethylenediamino bridged bis(β‐cyclodextrin)/ poly(DL‐lactic‐co‐glycolic acid) nanoparticles prepared by modified double emulsion method: Effect of polyvinyl alcohol on nanoparticle properties

This study continues long‐standing efforts to develop protein delivery systems based on cyclodextrin‐conjugated polyester in our laboratory. The crude products of ethylenediamino bridged bis(β‐cyclodextrin)‐conjugated poly(DL ‐lactic‐co‐glycolic acid) were used in this study to make full use of unreacted reactant. With bovine serum albumin (BSA) as a model protein, the encapsulation effects (the encapsulation efficiency and particle size) of nanoparticles were similar to those of using pure conjugated products. Besides, a water‐in‐oil‐in‐water emulsification technique was conveniently modified. By adding polyvinyl alcohol (PVA) in the internal aqueous phase, a more stabilized emulsion was formed. Consequently, less PVA (～ 0.05%) was needed in the outer aqueous phase and less PVA (0.14 g/g nanoparticles) remained in the nanoparticles. This modification resulted in improved encapsulation efficiency (～ 89–94%) of BSA and an enlarged particle size (340–390 nm). Furthermore, the burst release of BSA at the 1st day was less pronounced (7–12% of the encapsulated amount) than that of nanoparticles with no PVA added in the internal aqueous phase. Degradation studies using transmission electron microscope and gel permeation chromatography suggested that the mechanism for protein release was mainly through nanoparticles erosion. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Preparation,characterization, and protein loading properties of N‐acyl chitosan nanoparticles

Various N‐acyl chitosans with propionyl‐, hexanoyl‐, nonanoyl‐, lauroyl‐, pentadecanoyl‐, and stearoyl‐groups were synthesized and self‐aggregated N‐acyl chitosan nanoparticles (CSNPs) were prepared by sonication. By the modification with N‐acyl groups, CSNPs increased their hydrophobic character and changed its structural features to be more suitable as a delivery carrier. The mean diameters of bovine serum albumin (BSA)‐loaded N‐acyl CSNPs ranged from 138 to 551 nm. Uniform particle size distribution of BSA‐loaded N‐acyl CSNPs was observed. The protein loading efficiency of N‐acyl CSNPs was about 94–95% with lower BSA concentration (0.1 mg/mL) and not significantly different with acyl chain length. With higher BSA concentration (1.0 mg/mL), however, the highest protein loading efficiency was observed with lauroyl and pentadecanoyl CSNPs. The results suggest that lauroyl and pentadecanoyl CSs are interesting candidates for protein delivery system. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Synthesis and characterization of an amphiphilic hyperbranched poly(amine‐ester)‐co‐D,L‐lactide (HPAE‐co‐PLA) copolymers and their nanoparticles for protein drug delivery

A series of hyperbranched poly(amine‐ester)‐co‐D ,L ‐lactide (HPAE‐co‐PLA) copolymer were synthesized by ring‐opening polymerization of D ,L ‐lactide with Sn(Oct)₂ as catalyst to a fourth generation branched poly(amine‐ester) (HPAE‐OHs4). The chemical structures of copolymers were determined by FTIR, ¹H‐NMR, ¹³C‐NMR, and TGA. Double emulsion (DE) and nanoprecipitation (NP) method were used to fabricate the nanoparticles of these copolymers encapsulating bovine serum albumin (BSA) as a model. DSC thermo‐grams indicated that the nanoparticles with BSA kept stable below 40°C. Different factors which influence on particular size and encapsulation efficiency (EE) were investigated. Their EE to BSA could reach 97.8% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The stability maintenance of BSA in the nanoparticle release in vitro was also measured via circular dichroism and fluorescence spectrometry. The results showed that the copolymer nanoparticles have a promising potential in protein delivery system. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Encapsulation and release of cladribine from chitosan nanoparticles

This study shows the potential of chitosan (CH) nanoparticles as both an oral and IV drug delivery system using the anticancer drug cladribine as a model drug. Smooth, spherical nanoparticles were prepared by the ionotropic gelation of CH with sodium tripolyphosphate. Nanoparticle size depended on degree of hydration, drug loading, and crosslinking conditions, with the smallest nanoparticles in the size range of 212 ± 51 nm. Cladribine was entrapped in the CH matrix with an entrapment efficiency of up to 62%, depending on the initial loading. The release of cladribine followed a near‐Fickian diffusion rate over the first several hours and then reached a plateau. A second release phase began after 30–40 h of incubation in the release medium, and proceeded until ～100 h. Loaded CH nanoparticles that were crosslinked with genipin showed a delayed release profile, with only 40% of loaded drug being released after 100 h. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Novel polysaccharides-based nanoparticle carriers prepared by polyelectrolyte complexation for protein drug delivery

Polyelectrolyte complexation, as one simple and promising method for preparing nanoparticles, is employed to find the use in the delivery of protein drugs. Using this method, we fabricated one kind of novel nanoparticles based on two natural polysaccharides, which are the negatively charged carboxymethyl pachyman (CMP) and the positively charged chitosan (CS). The major effect factors on the average particle size, polydispersity, and zeta potential of the nanoparticles were studied. The research indicated that the physicochemical properties of the nanoparticles were deeply affected by the molecular weight, concentration, and the ionic content of two polysaccharides. The mean particle size of CMP/CS nanoparticles was almost in the range of 100–200 nm for various preparation conditions. The morphology of nanoparticles characterized by a transmission electron microscope was spherical in shape with smooth surface structure. In order to study the feasibility of these nanoparticles as oral protein delivery carriers, the encapsulation efficiency of CMP/CS nanoparticles for bovine serum albumin (BSA) was evaluated for optimized condition. It turned out that the encapsulation efficiency of BSA-loaded CMP/CS nanoparticles varied from 30.1 to 52.9% depending on the initial loading concentration of BSA as well as the concentration of CMP and CS employed in particle formation, which indicated that the concentration of polymers and drugs were all contributed to the encapsulation efficiency of nanoparticles. This report opened up another interesting perspective to develop these natural polysaccharides with emerging new applications, which have great potentials in application in the nanoparticulate delivery system.     

Characterization of novel quaternary chitosan derivative nanoparticles loaded with protein

The objective of this work was to characterize a novel quaternary chitosan derivative [O‐(2‐hydroxyl) propyl‐3‐trimethyl ammonium chitosan chloride (O‐HTCC)] nanoparticle system. O‐HTCC nanoparticles were prepared with a simple and mild ionic gelation method upon the addition of a sodium tripolyphosphate solution to a low‐molecular‐weight O‐HTCC solution. Highly cationic chitosan nanoparticles were prepared. Bovine serum albumin (BSA), a model protein drug, was incorporated into the nanoparticles. The physicochemical properties of the nanoparticles were determined with transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared analysis, differential scanning calorimetry, and X‐ray diffraction (XRD) patterns. The results showed that increasing the BSA concentration from 1.5 to 2.5 mg/mL promoted the BSA encapsulation efficiency from 57.3% to 87.5% and the loading capacity from 70.2% to 99.5%. Compared with the chitosan nanoparticles, the O‐HTCC nanoparticles had lower burst release. TEM revealed that the BSA‐loaded O‐HTCC nanoparticles were smaller than the O‐HTCC nanoparticles when the BSA concentration was 1.5 mg/mL; SEM showed that the size of the BSA‐loaded O‐HTCC nanoparticles was mostly affected by the BSA concentration, and the increase in size occurred with the concentration increasing. Thermograms and XRD of the BSA‐loaded nanoparticles suggested that polyelectrolyte–protein interactions increased with the BSA concentration increasing and greater chain realignment in the BSA‐loaded nanoparticles. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Synthesis and characterization of an amphiphilic pluronic‐poly(D,L‐lactide‐co‐glycolide) copolymer and their nanoparticles as protein delivery systems

A new amphiphilic Pluronic (F68)‐PLGA copolymer, which can be used to prepare the stealth or long‐circulating nanoparticles, was synthesized with Pluronic (F68), DL ‐Lactide, and glycolide. The structures of Pluronic (F68)‐PLGA copolymer as the products were characterized with infrared spectrometry, nuclear magnetic resonance and their molecular weights were determined by gel permeation chromatography. Two methods, double emulsion (DE) and nanoprecipitation (NP), were employed to fabricate the polymeric nanoparticles. Bovine serum albumin (BSA) was loaded into nanoparticles as a model protein. Influence of the preparation conditions on the nanoparticles size, encapsulation efficiency, and release profile in vitro was investigated. They showed the entrapment efficiency of 42.9–63.4% and the average diameter of 119.1–342.8 nm depending on the fabrication technique of nanoparticles and the type of copolymer. The stability maintenance of BSA in the nanoparticle release in vitro was also measured via sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), circular dichroism (CD), and fluorescence spectrometry. The results showed that the new copolymer could load BSA effectively and BSA kept stable after it was released from the nanoparticles. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008