壳聚糖基聚电解质复合物在生物医学领域的应用

近年来,国内外对壳聚糖在生物医学领域的应用研究十分活跃。壳聚糖在低pH时带正电荷,在溶液中可与带负电荷的聚离子形成聚电解质复合物。壳聚糖基聚电解质复合物除了具有壳聚糖的生物相容性,还表现出良好的物理化学性质,在药物控制释放体系、蛋白质分离、生物酶以及细胞固定化等领域具有广泛应用。本文重点介绍壳聚糖与几种天然的或合成的聚阴离子形成的聚电解质复合物及其在生物医学领域的应用。     

壳聚糖-纤维素硫酸钠聚电解质复合物膜对药物表观渗透系数的测试(英文)

药物渗透系数是考察复合物膜的药物释放性能的重要参数.本文以溶解性不同的两种药物扑热息痛和5-氨基水杨酸(5-ASA)为模型药物研究了其在壳聚糖-纤维素硫酸钠聚电解质复合物膜中的渗透性能.结果表明:壳聚糖-纤维素硫酸钠聚电解质复合物膜的渗透性能与其溶胀性能密切相关;复合物膜中壳聚糖和纤维素硫酸钠的配比、相对分子量和pH值对膜的渗透性能和溶胀性能影响显著,以扑热息痛作为模型药物研究了壳聚糖-纤维素硫酸钠聚电解质复合物膜在模拟胃肠液中对药物的渗透性能.通过调整该复合物膜的配方,可以使该膜分别实现胃、小肠和结肠定位释药的目的.     

壳聚糖-纤维素硫酸钠聚电解质复合物膜对药物表观渗透系数的测试

药物渗透系数是考察复合物膜的药物释放性能的重要参数. 本文以溶解性不同的两种药物扑热息痛和5-氨基水杨酸(5-ASA)为模型药物研究了其在壳聚糖-纤维素硫酸钠聚电解质复合物膜中的渗透性能. 结果表明：壳聚糖-纤维素硫酸钠聚电解质复合物膜的渗透性能与其溶胀性能密切相关;复合物膜中壳聚糖和纤维素硫酸钠的配比、相对分子量和pH值对膜的渗透性能和溶胀性能影响显著,以扑热息痛作为模型药物研究了壳聚糖-纤维素硫酸钠聚电解质复合物膜在模拟胃肠液中对药物的渗透性能. 通过调整该复合物膜的配方,可以使该膜分别实现胃、小肠和结肠定位释药的目的.     

pH响应壳聚糖衍生物的合成与自组装

以甲烷磺酸为反应溶剂,将己酰氯接枝到壳聚糖(CS)侧基上,得到可溶于常见有机溶剂的己酰化壳聚糖(HC);亲水性聚乙二醇单甲醚(mPEG)通过活泼酯法接枝到HC上,最终获得两亲性壳聚糖衍生物PEG-g-HC。用红外光谱(FT-IR)、核磁共振(1H-NMR)与紫外-可见光谱(UV-Vis)表征产物结构,用动态光散射、透射电镜与荧光光谱等方法研究了PEG-g-HC的自组装行为。结果表明:通过改变己酰氯与CS的投料比可调节HC的取代度;随着HC中己酰基取代度增大,HC在水介质中溶解的临界pH随之降低;PEG-g-HC可自组装为球形胶束,通过改变HC中己酰基的取代度可调控其pH响应行为。     

层状复合氢氧化物的药物控释动力学机制

以层状复合氢氧化物(LDH)为载体组装乙酰苯甲酸(ASP)的插层复合物LDH-ASP,以pH2.48~6.89的磷酸盐溶液为介质进行药物释放动力学实验,通过对不同时间药物释放度的测定及释放药物后载体结构变化分析研究了LDH对层间药物的控制释放机制。结果表明粉末状LDH-ASP能在较宽的pH范围表现明显缓控释作用,药物释放度积分方程与Higchi方程、Ritger-Peppas方程、Bhaskar方程及一级动力学方程等经验模型吻合。复合物与溶出介质的反应机制研究表明,药物释放速率及释放度大小取决于交换配比n(ASP)/n[HnPO4(3-n)-]所决定的LDH层间通道畅阻情况。     

壳聚糖-O-聚(聚乙二醇甲醚甲基丙烯酸酯)接枝共聚物的ATRP合成及其自组装研究

以十二烷基硫酸钠-壳聚糖复合物(SCC)为起始物,将溴代异丁酸偶联到SCC的羟基上,得到溴代SCC(Br-SCC).以Br-SCC作为大分子引发剂,溴化亚铜、二联吡啶为催化剂,引发聚乙二醇单甲醚甲基丙烯酸酯(MPEGMA)原子转移自由基聚合,得到SCC-O-PMPEGMA;SCC-O-PMPEGMA中十二烷基硫酸钠(SDS)用Tris-2-甲基-2-氨基-1,3-丙二醇(Tris)解复合脱除,最终制备得到壳聚糖-O-PMPEGMA(CS-O-PMPEGMA).用FTIR和1H-NMR对中间产物与CS-O-PMPEGMA进行了表征,结果表明SCC的溴化度可以通过改变溴代异丁酸/SCC的投料比调节,改变MPEGMA/Br-SCC的投料比则可调控PMPEGMA的聚合度.用动态光散射、zeta电位仪以及TEM等手段研究了CS-O-PMPEGMA与肝素钠的复合行为,结果表明随着肝素钠/壳聚糖结构单元摩尔比(X)增加,复合胶束的粒径增大、表面电位降低;当X超过2时,肝素钠与CS-O-PMPEGMA复合形成球形纳米颗粒,其水合半径约44nm,zeta电位为-8.9mV.合成得到的CS-O-PMPEGMA具有规整化学结构,能与聚阴离子复合形成球形胶束,很有希望在基因传递与肿瘤靶向等领域得到应用.     

新型羧甲基壳聚糖水凝胶的合成与表征

通过1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)/N-羟基琥珀酰亚胺(NHS)催化体系使羧甲基壳聚糖(CMCS)交联,制备了新型羧甲基壳聚糖水凝胶.探讨了EDC用量和EDC/NHS质量比对水凝胶特性的影响.CMCS水凝胶具有pH响应特性,在等电位点溶胀率最小.降解实验结果表明,水凝胶浸泡在磷酸盐缓冲溶液中,10 d失重率在15%~45%之间,主要是未交联部分溶解所致.而浸泡在含有0.2 mg/mL溶菌酶的磷酸盐缓冲溶液中,低交联度水凝胶80 h基本降解,高交联度水凝胶不易降解.初步研究了CMCS水凝胶包埋牛血清白蛋白(BSA)的释放行为.     

离子键交联聚两性电解质凝胶在电场作用下的溶蚀现象

以丙烯酸(AA)和甲基丙烯酸二乙氨基乙酯(DEAM)形成的离子复合物和丙烯酰胺(AAm)为单体,采用自由基聚合制备了一系列新型的离子键交联聚两性电解质凝胶(PADA凝胶).非接触直流电场的实验表明,该离子键交联的PADA凝胶在电场下发生溶蚀现象,该现象鲜见文献报道.PADA凝胶的溶蚀速率与电场强度、溶液浓度、pH值、酸碱基团摩尔比、溶液离子价态等诸多因素有关,如溶蚀随电压的升高而增大,随盐溶液浓度的加大而增大.其溶蚀动力学研究表明PADA凝胶的溶蚀度随时间线性的增加,即溶蚀速率在整个实验时间内基本保持恒定.     

温度敏感性壳聚糖基聚电解质载药纳米粒子的制备及表征

以天然高分子壳聚糖(CS)、羧甲基纤维素(CMC)和温度敏感性单体N-异丙基丙烯酰胺(NIPAM)为原料,通过自组装制备了温度敏感性聚电解质复合纳米粒子CS-g-PNIPAM/CMC-g-PNIPAM,并以5-氟尿嘧啶(5-FU)为模型药物研究了纳米粒子对药物的负载与可控释放性能。当CMC-g-PNIPAM与CS-g-PNIPAM的质量比为3:7时,形成的纳米粒子结构最稳定,动态光散射(DLS)测得其平均粒径为116nm,粒径分布较窄。载药纳米粒子对5-FU具有较高的载药量和包封率。在磷酸盐缓冲溶液中的释药行为表明,其累积药物释放量随pH和温度的增加而增大,表现出良好的pH与温度可控性能。     

P(MMA-MAA)/PEO氢键复合物的结构和性能

本文研究了P(MMA-MAA)/PEO氢键复合物的制备,结构和性能.实验结果表明,P(MMA-MAA)共聚物中MAA含量、共聚物与PEO的比值、在其水/乙醇溶液中的浓度、溶液pH值以及反应时间等对复合物的形成皆有影响.DSC,X射线衍射和显微镜观察表明,分子氢键复合限制了P(MMA-MAA)和PEO分子链的自由度,从而抑制了PEO的结晶.复合物不具备三维有序结构但仍有一定有序度.P(MMA-MAA)/PEO氢键复合物无色,透明,成膜性好,热稳定性明显优于其组分聚合物,对二氧化碳的渗透系数远小于对氧气的渗透系数.屈服应力和断裂应力远大于PEO.     

Biodegradable hyaluronic acid/n-carboxyethyl chitosan/protein ternary complexes as implantable carriers for controlled protein release

An ampholytic N-carboxyethyl chitosan (CEC), with various isoelectric points (IPs), was synthesized by grafting acrylic acid on chitosan utilizing Michael's reaction. Compared to native chitosan, CEC has enhanced water solubility and dramatically accelerated enzymatic degradation; the rate of degradation is proportional to the degree of substitution (DS). The results from turbidimetric titration and fluorescence studies revealed that CEC formed complexes with either hyaluronic acid (HA) or bovine serum albumin (BSA) within a certain pH range. The HA/CEC/BSA ternary complexes could be prepared by colloid titration with quantitative yield and BSA entrapment. The rate of BSA release from the complexes was affected by pH, ionic strength, DS of CEC, and the molecular weight (MW) of HA. The endurance of BSA release from the complexes could be extended up to 20 d by formulating them with high-MW HA and CEC with low DS.BSA release profiles from HA/CEC-2/BSA complexes.     

脱乙酰壳多糖─羧甲基纤维素聚电解质复合物的合成和药物控制释放研究

本文研究合成条件对脱乙酰壳多糖─羧甲基纤维素聚电解质复合物的组成、结构及药物控制释放性能的影响。结果表明,反应介质的ｐＨ值对生成的脱乙酰壳多糖─羧甲基纤维素聚电解质复合物的组成和结构的影响最大,在ｐＨ值５．５合成的脱乙酰壳多糖─羧甲基纤维素聚电解质复合物具有较好的药物控释性能。     

脱乙酰壳多糖-羧甲基纤维素聚电解质复合物的合成和药物控制释放研究

本文研究合成条件对脱乙酰壳多糖－羧甲基纤维素聚电解质复合物的组成、结构及药物控制释放性能的影响。结果表明，反应介质的ｐＨ值对生成的脱乙酰壳多糖－羧甲基纤维素聚电解质复合物的组成和结构的影响最大，在ｐＨ值５．５合成的脱乙酰壳多糖－羧甲基纤维素聚电解质复合物具有较好的药物控释性能。     

Polyelectrolyte complexes of chitosan/heparin and <Emphasis Type="Italic">N,N,N-</Emphasis>trimethyl chitosan/heparin obtained at different pH: I. Preparation,characterization, and controlled release of heparin

Chitosan and N,N,N-trimethyl chitosan (TMC) were treated with heparin (HP) to produce polyelectrolyte complexes (PECs). The structures of PECs were characterized by Fourier transform infrared and CP-MAS ¹³C NMR spectroscopies. A thermal stability of TMC/HP complex was evaluated by thermogravimetric analyses, and morphology was investigated by SEM images. The ratio between the carbons bonded to noncharged nitrogen atoms (CΦ) and the carbons bonded to positively charged nitrogen atoms (Cω) in TMC was calculated through of the degree quaternization (DQ), being the DQ obtained through ¹H NMR data. Experiments of controlled release of HP were performed in distilled water at pH ∼7, using methylene blue/heparin system as solute. The release profiles of HP from TMC/HP complex are quite different each other. The value of CΦ/Cω ratio was used for explaining such an effect. The CΦ/Cω ratio tends to be constantly (∼0.69) as high as the pH of medium in which the PEC of TMC/HP was obtained. The change of CΦ/Cω ratio on the pH was also considered to explain the improvement of thermal stability of PEC2 with increase of pH. Data show that PEC of TMC/HP formed at pH 8 is a promising material for uses in oral site-specific HP release systems.     

Complexation of bovine serum albumin and sugar beet pectin: Stabilising oil-in-water emulsions

In a previous study (Langmuir 28 (2012) 10164-10176.), we investigated the complexation of bovine serum albumin (BSA) with sugar beet pectin (SBP). A pH-composition phase diagram was established and structural transitions in relation to the phase diagram during complexation were identified. The present study examines the implications of these interactions on the emulsifying performance of BSA/SBP mixtures. Middle-chain triglycerides (MCTs) in water emulsions were prepared using conditions corresponding to different regions of the phase diagram. At high pHs and in the stable region of mixed individual soluble polymers where complexation is absent, there is no improved emulsifying performance, compared with the individual protein and polysaccharide. For these mixtures, the emulsion characteristics are controlled by the major component in the solutions, as determined by the competitive adsorption of the two components at the oil-water interface. At low pHs and low BSA/SBP ratios, and so mainly within the stable region of intramolecular soluble complexes, BSA/SBP mixtures greatly improve the stability of emulsions. Here, stabilisation is controlled by the cooperative adsorption of the two components at the oil-water interface. Through electrostatic complexation BSA promotes the adsorption of SBP on to interfaces to form a thick steric layer around emulsion droplets and thus providing better stability. At low pHs and high BSA/SBP ratios, that is, mainly within the unstable region of intermolecular insoluble complexes, emulsions prepared are extremely unstable due to bridging flocculation between emulsion droplets.     

Tripolyphosphate-responsive release property of monoolein cubic phase containing sodium dodecyl sulfate and oligo chitosan

Tripolyphosphate (TPP)-responsive MO cubic phase was prepared by immobilizing oligo chitosan in the water channel through its electrostatic attraction with sodium dodecyl sulfate (SDS). The phase transition temperature (PTT) increased with increasing the content of SDS. The PTT of cubic phase whose SDS content was 0%, 0.21%, 0.42%, 0.84%, and 1.68%, determined by polarized microscopy, was about 69.5°C, 72°C, 75°C, 80.5°C, and 95°C, respectively. The PTT did not markedly deviate from that determined by differential scanning calorimetry. The release degree for 72 h of dye (i.e., amaranth and methylene blue) was dependent on the pH value of release medium (pH 3.0 and pH 7.0). Moreover, the release degree significantly increased when the TPP concentration in the release medium increased to 0.4% (w/v). Oligo chitosan was electrostatically complexed with TPP and the complexation took place extensively at the oligo chitosan/TTP mass ratio of 1:0.125 and 1:0.25 and at the oligo chitosan concentration of 1.6% (w/v), evidenced by optical spectroscopy and scanning electron microscopy. It was thought that the complexation was responsible for the TPP concentration-dependent release.     

Complexation of bovine serum albumin and sugar beet pectin: structural transitions and phase diagram

The complexation between bovine serum albumin (BSA) and sugar beet pectin (SBP) was studied in situ by coupling glucono-δ-lactone (GDL) induced acidification with dynamic light scattering and turbidity measurements. Individual measurements at specific pHs and mixing ratios were also carried out using zeta potentiometry, gel permeation chromatography-multiangle laser light scattering (GPC-MALLS), and isothermal titration calorimetry (ITC). These investigations together enabled the establishment of a phase diagram of BSA/SBP and the identification of the molecular events during protein/polysaccharide complexation in relation to the phase diagram, which showed five regions: (I) a stable region of mixed individual soluble polymers, (II) a stable region of intramolecular soluble complexes, (III) a quasi-stable region of intermolecular soluble complexes, (IV) an unstable region of intermolecular insoluble complexes, and (V) a second stable region of mixed individual soluble polymers, on lowering pH. We found for the first time that the complexation could take place well above the critical pH(c), the value that most previous studies had regarded as the onset occurrence of complexation. A model of structural transitions between the regions was proposed. The borderline between region II and region III represents the BSA/SBP stoichiometry for intramolecular soluble complex at a specific pH, while that between region III and region IV identifies the composition of the intermolecular insoluble complex. Also studied was the effect of NaCl and CaCl(2) on the phase diagram and structural transitions.     

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH-sensitive drug release property

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH sensitivity were developed for oral delivery of protein drugs, using bovine serum albumin (BSA) as a model drug. The composite drug-loaded microparticles with a mean particle size less than 200 μm were prepared by a convenient shredding method. Since the microparticles were formed by tripolyphosphate cross-linking, electrostatic complexation by alginate and/or pectin, as well as ionotropic gelation with calcium ions, the microparticles exhibited an improved pH-sensitive drug release property. The in vitro drug release behaviors of the microparticles were studied in simulated gastric (pH 1.2 and pH 5.0), intestinal (pH 7.4) and colonic (pH 6.0 and pH 6.8 with enzyme) media. For the composite microparticles with suitable compositions, the releases of BSA at pH 1.2 and pH 5.0 could be effectively sustained, while the releases at pH 7.4, pH 6.8 and pH 6.0 increased significantly, especially in the presence of pectinase. These results clearly suggested that the microparticles had potential for site-specific protein drug delivery through oral administration.     

Molecular-weight distribution and structural transformation in water-soluble complexes of poly(acrylic acid) and bovine serum albumin

Interaction of polyacrylic acid (PAA) with bovine serum albumin (BSA) at different pH values and in a wide range of mixing molar ratios, γ = n_BSA/n_PAA, of components was investigated by size-exclusion high performance liquid chromatography with on-line refractive index, UV, light scattering and viscometer detectors. The results revealed the formation of stable water-soluble polymer-protein complexes at pH 5.0. For the soluble complexes thus formed, the number of the bound BSA molecules with one PAA molecule was expressed by a Langmuir-type equation as a function of the amount of excess BSA existing free in the solution. At saturation, one BSA molecule is bound to about 48 acrylic acid residues.The γ-dependencies of molecular properties and structural parameters (molecular weights, molecular-weight distribution, radius of gyration, and the Mark-Houwink equation constants) of aqueous solutions of polycomplex particles have been studied. It has been concluded from these results that the complex molecule is formed by the molecular association-dissociation processes between particles depending on protein molecules in mixtures. We assume that side-by-side association of BSA-PAA complex particles took place at γ ? 5. At γ > 5, dissociation of the aggregates occurred by the including certain protein molecules into composition and by the compactization of polycomplex particles.