聚电解质微胶囊的药物缓释及其血液相容性研究
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摘要
聚电解质微胶囊具有独特的结构与多变的性能。它的优点在于微胶囊的尺寸、壁厚及通透性精细可控,囊壁材料可选范围广。许多天然高分子都已被成功地用来制备微胶囊。由于微胶囊在医药领域的潜在应用前景,本文针对微胶囊的药物传递释放性能以及微胶囊进入体内后所面临的血液相容性问题,开展了如下研究:
     聚电解质微胶囊和聚电解质多层膜具有相同的物理和化学结构,在多层膜上得到的结果也可类推到聚电解质微胶囊上。可用于研究聚电解质多层膜的手段更丰富,从而将更便于定量研究蛋白质的吸附、优化多层膜的表面性能。因此,本文以硅片为基底,制备了(PAH/PSS)4PAH多层膜并利用肝素(heparin)、牛血清白蛋白(BSA)、聚乙二醇(PEG)等对其最外层进行修饰。采用椭圆偏振光谱(ellipsometry)、原子力显微镜(atomicforce microscope,AFM)、石英晶体微天平(QCM-D)等表征了各多层膜的表面形貌和结构。以BSA为血浆蛋白的模型蛋白,采用QCM-D跟踪了BSA在各多层膜上的动力学吸附过程。ellipsometry结果显示heparin、BSA、PEG等大分子被成功地固定到多层膜表面。吸附BSA或纤维蛋白原(fibrinogen)后,未修饰多层膜粗糙度增大,而heparin、BSA、PEG修饰的多层膜粗糙度则明显减小。修饰后的多层膜吸附BSA、fibrinogen等单组分蛋白质时的吸附模式是“谷底(surface valley)吸附”:BSA及fibrinogen更倾向于吸附在修饰后的多层膜的“谷底”使得膜粗糙度降低。最外层经修饰后的多层膜吸附的BSA、纤维蛋白原及血浆蛋白的量都较未修饰膜吸附的量要少。血小板在修饰heparin的多层膜表面黏附量最多,其它修饰后的多层膜血小板黏附量则比未修饰膜减少。修饰后的多层膜的凝血酶原时间(PT)较未修饰膜均有所延长。
     本文进一步研究了聚电解质微胶囊的血液相容性。在(PAH/PSS)_4/PAH微胶囊最外层通过戊二醛(GA)交联共价接枝PEG或BSA,或仅通过静电作用吸附一层BSA。以荧光标记的FITC-BSA为血浆模型蛋白,采用荧光显微镜、扫描电子显微镜(SEM)、Zeta-电位仪表征各类微胶囊吸附BSA前后的表面形貌及表面电荷的改变。结果表明:未修饰微胶囊与最外层静电吸附上BSA的微胶囊吸附FITC-BSA的量较多,其它各类微胶囊则吸附量较少。最外层接枝PEG和BSA后的微胶囊血浆复钙化时间(PRT)和全血凝固时间(CT)较未修饰的微胶囊均有所延长,且修饰PEG的微胶囊抗凝血性能更好,血液相容性得到改善。
     利用沉淀法合成羧甲基纤维素钠(CMC)掺杂的碳酸钙胶体微粒(CaCO_3(CMC)),在其表面层层组装壳聚糖(chitosan)和海藻酸钠(alginate),成功制备了多层膜包覆的CaCO_3(CMC)-(chitosan/alginate)_5核壳型结构微粒,研究了微粒装载抗癌药阿霉素(doxorubicin,DOX)的药物传递释放性能。CaCO_3(CMC)球形微粒主要是由球霰石构成,且表面有大量纳米孔洞。考察CaCO_3(CMC)微粒装载DOX的动力学,发现DOX的自发沉积在最初的6h内已基本完成,DOX最终包埋率大于95%。CLSM证明了DOX能高浓度地沉积进碳酸钙微粒内部,且分布较均匀。DOX的包埋量可高达I'=475 mg DOX/g CaCO_3(CMC)。BET方法分析了CaCO_3(CMC)微粒装载DOX前后的比表面积及孔径分布的变化。装载DOX之后,CaCO_3(CMC)微粒的比表面积及孔体积都明显下降,小于9nm的微孔体积急剧减小,而稍大孔径的微孔体积却有所增加。这种孔径分布的改变的机理可通过电荷屏蔽效应来解释。装载DOX的CaCO_3(CMC)微粒在pH7.4的PBS缓冲液中基本不释放,对于正常组织具有低毒性的安全优势。在pH=5及pH=2的缓冲液中,DOX的释放过程能持续150小时以上,对于将来体内的药物传递将具有良好的应用前景。(chitosan/alginate)_5多层膜在微粒上的组装能够明显减轻DOX的初期暴释现象,并在整个过程中有效控制DOX的释放速率。
     为提高微胶囊装载药物的利用率并减轻药物的毒副作用,进一步地研究了微胶囊的靶向传递性能。在掺杂硫酸葡聚糖的CaCO_3微粒表面通过戊二醛交联PAH的共价作用组装(PAH/GA)_3微胶囊,然后通过醛基化、PEG接枝、NaBH_4还原和水溶性碳化二亚胺(EDAC)/N-羟基琥珀酰亚胺(NHS)偶联接枝的方法将叶酸(FA)修饰到微胶囊上。SEM和AFM表明,在(PAH/GA)_3微胶囊的表面接枝PEG及FA等反应过程不会对微胶囊的表面形貌产生明显影响,上述微胶囊的表面形貌不是影响其被细胞所摄取的关键因素。Zeta-电位分析表明所制微胶囊的表面均带负电。红外及紫外光谱分析证明聚乙二醇和叶酸均被接枝在了微胶囊上。在一定时间内,随着微胶囊上接枝FA的反应时间的延长,FA的接枝量也会相应增加。表面接枝PEG后的微胶囊对细胞的非特异性黏附明显降低。修饰叶酸后的微胶囊在含有叶酸受体的HepG2细胞表面呈现明显的特异性黏附,其胞吞率较未修饰叶酸的(PAH/GA)_3/PEG/NaBH_4微胶囊明显提高;微胶囊表面的叶酸含量增加,被HepG2细胞所特异识别的效率也随之提高。
Polyeletrolyte microcapsules possess unique structure and variable properties. Theyhave many merits, such as finely controlled wall thickness, dimension and permeability. Therange for choosing wall materials is considerably wide and many kinds of naturalmacromolecules have been successfully used in the preparation of microcapsules.Polyeletrolyte microcapsules have attractive future application prospects; however, they haveto face the problem of blood compatibility in terms of in vivo application. Therefore, thiswork mainly studies the blood compatibility, the controlled drug release, and the targeteddelivery of microcapsules.
     Polyeletrolyte microcapsules and the corresponding polyeletrolyte multilayer have thesame physical and chemical structure. The results obtained from multilayer can beanalogically applied to microcapsules. Compared to microcapsules, however, the methodsand instruments to analyze the multilayer are more abundant. Therefore, poly(styrenesulfonate) /poly(allylamine hydrochloride) multilayers were assembled on silicone wafers viathe technique of layer-by-layer assembly. Their surfaces were further modified eitherphysically or chemically with bovine serum albumin (BSA), heparin and polyethylene glycol(PEG). Protein adsorption on these surfaces was investigated by quartz crystalmicrobalance-dissipation (QCM-D), ellipsometry and atomic force microscopy (AFM). Thedynamic adsorption process of BSA on these multilayers was monitored by QCM-D,revealing that the adsorption equilibrium was rapidly achieved within 3min on the controland heparin adsorbed multilayer surfaces, and within 5-10 min on the chemically bondedBSA and PEG surfaces, but more than 80min on the BSA physically modified surface. Afteradsorption of BSA or fibrinogen, all the modified multilayers became smoother due to theeffect of "surface valley adsorption". Ellipsometry characterization found that the adsorbedmount of BSA, fibrinogen and plasma proteins on all the modified multilayers were smallerthan that of the unmodified control multilayers. The platelet adsorption on the multilayerswas analyzed by SEM, revealing that the number of the adsorbed platelets on all the modifiedsurfaces except of the heparin modified one was significantly reduced. The prothrombin time(PT) of all the modified multilayers was prolonged compared with that of the unmodifiedmultilayers, but there was no significant difference between all the samples.
     Furthermore, the blood compatibility of the polyeletrolyte microcapsules was studied.PAH/PSS microcapsules were fabricated and their surfaces were further modified eitherphysically or chemically with bovine serum albumin (BSA), heparin and polyethylene glycol(PEG). Protein adsorption on the surfaces was investigated by fluorescence microscopy,scanning force microscopy (SEM) and AFM. The amount of BSA adsorbed on theunmodified control microcapsules and the BSA physically modified microcapsules arecomparatively larger than that on other capsules. The plasma recalcifation time (PRT) and thewhole blood coagulation time (CT) of microcapsules with the chemically bonded BSA andPEG outmost surfaces were prolonged than than that of the unmodified controlmicrocapsules.
     Subsequently, carboxymethyl cellulose (CMC)-doped CaCO_3 microparticles with anaverage diameter of 5μm were prepared and coated by chitosan and alginate multilayers. Theprepared CaCO_3 microparticles had a dominant phase of vaterite and a spherical morphologywith nanopores on their surface. These particles could spontaneously load positively chargeddoxorubicin (DOX) molecules, whose amount was 475 mg DOX/g CaCO_3 for theCaCO_3(CMC) microparticles. The loading was almost completed within 5 h, with a finalencapsulation efficiency of>95%. Confocal laser scanning microscopy (CLSM) alsoconfirmed the deposition and even distribution of DOX into the inner core of microparticles.Bunauer-Emmett-Teller (BET) method was used to analyze the specific surface area and thepore size distribution of the CaCO_3(CMC) microparticles before and after DOX loading.After DOX loading, S_(BET) and pore volume were reduced obviously, and the volume ofsmaller pores less than 9 nm decreased significantly, whereas that of larger pores wereincreased. The increase of the volume of larger pores was explained by an electric chargescreening effect. DOX release from the CaCO_3 microparticles in pH 5 was relatively smallwithin the first 15 h, and could be sustained to more than 150 h The release amount at lowerpH was larger at the same time. In pH7.4 PBS buffer, DOX would not be released from themicroparticles. This would be a safe advantage to normal tissue for future in vivo applicationprospects. Coating of the CaCO_3(CMC) microparticles with the chitosan/alginate multilayerscould obviously assuage the initial burst release and reduce the release rate.
     To enhance the utilization efficiency of loaded drugs and reduce their side-effects, the targeted delivery of the folic acid (FA)-modified microcapsules was also studied. (PAH/GA)_3microcapsules were fabricated on the dextran sulfate (DS)-doped CaCO_3 microparticlesthrough the chemical bonding of PAH with glutaraldehyde (GA). Then FA was immobilizedon the microcapsules through the linkage of diamino terminated poly(ethylene glycol) (PEG)under the catalysis of l-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDAC)/N-hydroxysuccinimide (NHS). The chemical bonding reaction did not affect the surface morphology ofthe microcapsules as evidenced by SEM and AFM. The morphology of the microcapsuleswould not deter the cell uptake. The infrared spectroscopy (IR) and the ultravioletspectroscopy (UV) confirmed the chemical bonding of PEG and FA on the microcapsules.The amount of FA bonding on capsules was increased as the reaction time prolonged. Thenon-special adherence of capsules bonding with PEG on cells reduced obviously comparedwith that of unmodified capsules. The FA modified microcapsules could selectively adsorbonto HepG2 tumor cells with folate receptor mediated specific recognition. The amount of FAmodified microcapsules ingested by HepG2 cells were larger than that of capsulesunmodified with FA. Also the amount of FA modified capsules ingested by HepG2 cellsincreased with the increased amount of FA on the surface.
引文
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