【作者】 牟斌；

【导师】 刘鹏；

【作者基本信息】 兰州大学 ， 高分子化学与物理， 2011， 博士

【摘要】 近年来,由于智能型聚合物微/纳米囊在药物传递及其生物医学领域的重大潜在应用价值而成为聚合物科学领域研究的热点之一。在一定的特殊条件下,基于一定的刺激机理可以有效调节聚合物微/纳米囊囊壁的渗透性来进行客体分子的控制释放,其释放速率可以通过客体分子穿过聚合物微/纳米囊囊壁的扩散速率进行调节。因此,聚合微/纳米囊囊壁对外界环境的发生快速响应是必不可少的。目前已经报道的环境刺激响应的微/纳米囊的刺激因素主要有：pH、温度、糖、离子强度等等。本论文主要基于模板聚合法及其多种模板表面的聚电解质的层层自组装来制备功能性聚合物微/纳米囊,其主要包括以下几个部分。1.以纳米氧化硅为模板,通过表面引发原子转移自由基聚合在其表面接枝聚丙烯酸甲酯,通过酯交换反应将其链末端的酯基转变为胺基后与六甲撑二异氰酸酯发生交联反应,刻蚀模板后制得了粒径为20～50 nm的交联聚合物纳米囊。为了进一步优化上述制备聚合物纳米囊的过程,直接以乙二胺为交联剂,通过酯交换反应实现聚合物壳层的交联,刻蚀氧化硅之后得到了壳层含有交联聚N-烷基丙烯酰胺结构内径为10 nm的温度敏感的交联聚合物纳米囊。通过动态光散射研究发现其低临界溶液温度(LCST)大约为35℃,这比其他N-烷基取代的聚丙烯酰胺的LCST高。2.通过表面引发原子转移自由基聚合及其紫外光照交联接枝的聚苯乙烯壳层,刻蚀模板后制得了壳层结构可控的交联聚苯乙烯纳米囊。聚合物壳层的交联度可以通过紫外光照射的时间来进行控制,同时也考察了紫外光照交联过程中接枝聚合物的光降解情况。此外,通过表面引发原子转移自由基聚合技术,在纳米氧化硅表面接枝了丙烯酸叔丁酯和苯乙烯的共聚物后,紫外光照交联外围的聚苯乙烯壳层,刻蚀模板后将交联聚合物纳米囊内壁的酯基转变为羧基,得到内径为30-40nm羧基功能化的交联聚苯乙烯纳米囊。同时,我们以亚甲基蓝为模型分子研究了交联聚合物纳米囊的控制释放行为,发现由于羧基与亚甲基蓝染料之间的静电作用使得羧基化聚合物纳米囊的吸附量高于酯基水解前的交联聚合物纳米囊,而释放结果显示,由于羧基与染料之间静电作用被H+破坏使得交联聚合物纳米囊的释放速率在酸性条件下快于中性条件。3.利用模板聚合法制备了内壁接枝聚丙烯酸链、具有温度敏感交联聚合物壳层的新型pH/温度双重敏感的交联聚合物纳米囊。先是通过连续表面引发原子转移自由基聚合在氧化硅表面接枝聚丙烯酸叔丁酯及其温度敏感的交联聚合物壳层,刻蚀模板后得到内壁接枝聚丙烯酸叔丁酯的温度敏感交联聚合物纳米囊,再水解聚丙烯酸叔丁酯得到pH/温度双重敏感的交联聚合物纳米囊。其中空结构和多重环境响应行为分别通过透射电镜和动态光散射证实。通过改变聚合条件可以有效控制交联聚合物纳米囊的内径、内壁接枝功能聚合物刷的链长以及交联聚合物壳层的交联度。4.利用壳聚糖的胺基与柠檬酸改性的磁性纳米粒子羧基之间的静电作用,通过层层自组装技术在磺化聚苯乙烯表面交替沉积壳聚糖及其磁性纳米粒子,透析去除聚合物模板后制得了具有pH敏感杂化壳层、靶向控制释放的超顺磁性杂化聚电解质微囊。同时以亚甲基蓝为模型分子,研究了磁性杂化聚电解质壳层的对客体分子的负载及其靶向控制释放行为。发现碱性条件下磁性杂化聚电解质微囊对染料分子的吸附容量高于酸性介质的情况,与此相反,负载亚甲基蓝的磁性聚电解质微囊在酸性条件下的释放率经过48 h后达78%,但在碱性条件下基本没有释放。5.通过层层自组装及其Ce(IV)引发接枝聚合技术在磺化聚苯乙烯表面包覆聚合物之后,透析去除模板得到具有可控温敏壳层的pH/温度／离子强度多重响应聚电解质微囊,经透射电镜观察其内径约为200nm。根据动态光散射的结果得知,在pH敏感的聚电解质壳层中引入PNIPAm,不但可以实现通过pH和温度双重调控客体分子双嘧达莫的控制释放,还可以通过外围的PNIPAm链避免制得的多重环境敏感聚电解质微囊之间在较高盐浓度的水溶液发生团聚而絮凝的现象,从而或许可以实现在药物传递及其智能释放方面的实际临床应用。6.在磺化聚苯乙烯模板表面通过壳聚糖的胺基与氧化海藻酸钠醛基之间的共价层层自组装实现逐层吸附,刻蚀模板后制得可控崩解的刺激响应性多层聚电解质微囊。与非共价交联的聚电解质微囊相比,聚合物微囊壳层间席夫碱结构的引入,增加了微囊在溶液中的稳定性。经动态光散射研究发现,共价交联聚电解质微囊的粒径随着溶液pH或离子强度的增加而减小。这种pH和离子强度双重敏感的多层聚电解质微囊在酸性和中性条件下稳定,但是在强碱性介质中因壳层之间席夫碱结构的破坏而崩解。7.以含有药物分子双嘧达莫、油酸改性的Fe3O4磁性纳米粒子的油酸自乳化形成的水包油型磁性杂化微乳液滴为模板,通过层层自组装技术实现其杂化微乳液滴表面低聚壳聚糖及其海藻酸钠的交替逐层吸附,制备得到新型磁靶向、pH敏感的的药物释放体。在此过程中,由于药物分子直接被包埋进磁性的杂化微乳液滴,无需刻蚀去核进行目标客体分子的再填充过程,所得磁性药物释放体具有较高的药物包覆率及其负载率。这种低聚壳聚糖／海藻酸钠包覆的磁性微乳液滴在pH=1.8的条件下经过31 h,其药物的累计释放量接近100%,但是,在pH=7.4的条件下历经48 h才释放了约3.3%。此外我们以粒径300 nm左右的双嘧达莫颗粒作为模板,通过层层自组装技术实现其表面磁性纳米粒子和聚电解质的逐层沉积,制备了可用于靶向控制释放的磁性药物释放体。通过紫外-可见分光光度计研究其在不同pH条件下的药物控制释放行为,发现这种磁性多层杂化聚电解质包覆的药物释放体的控制释放行为主要由杂化聚电解质壳层的渗透性及其药物分子在本体溶液中的溶解性共同决定,结果显示其可以被靶向到病灶部位实现药物的快速、持续释放。更多还原

【Abstract】 In recent years, the "smart" polymeric micro/nanocapsules have received increasing attentions due to their potential applications in drug delivery and biomedical fields. The stimuli-responsive polymeric micro/nanocapsules permit the adjustable permeability of the guest molecules with the controllable release based on a designed mechanism under a given environmental stimulus. The release rate of the guest molecules was usually controlled by the diffusion rate of the guest molecules across the wall of the micro/nanocapsules. Therefore, the fast response of the wall structure of the micro/nanocapsules to the external factors was indispensable. At present, the stimuli-responsive micro/nanocapsules have been reported in response to specific stimuli, such as pH, temperature, glucose, ionic strength and so on. In this paper, the functionalizated micro/nanocapsules have been prepared by polymerization from template technique and layer-by-layer assembly based on the various templates, respectively. Furthermore, the controlled release of the obtained micro/nanocapsules was also investigated. It mainly included several senctions as follows.1. The crosslinked polymeric nanocapsules with inner diameter of about 20-50 nm were prepared by surface-initiated atom transfer radical polymerization (SI-ATRP) technique based on the silica templates. Then SiO2 were removed by being etched with HF to produce the crosslinked polymeric nanocapsules after the ester groups of the grafted poly(methyl acrylate) (PMA) were transformed into amides by interesterification with diethylamine to complete crosslinking with hexamethylene diisocyanate (HDI). To optimize above the process of preparation crosslinked polymeric nanocapsules, we designed and prepared a crosslinked temperature-sensitive polymeric nanocapsules with inner diameter of about 10 nm based on the above grafted PMA silica nanoparticle with diethylamine as crosslinker after removing the silica templates. The obtained crosslinked nanocapsules had a higher lower critical solution temperature (LCST) about 35℃compared with other poly-(N-alkyl acrylamides).2. The crosslinked polystyrene nanocapsules with controllable shell were prepared by UV treatment the polystyrene grafted silica nanoparticles (SN-PS) to achieve polystyrene crosslinking after HF etching of the silica templates. The degree of crosslinking of polystyrene shell was well controlled by adjusting the time of UV irradiation. Furthermore, the degradation of grafted polymer was also investigated during the process of UV-induce crosslinking.And then the carboxyl groups functionalized crosslinked polystyrene nanocapsules with the inner diameter about 30～40 nm were prepared via combination of surface-initiated atom transfer radical polymerization and ultraviolet irradiated crosslinking techniques, while the ester groups of poly(tert-butyl acrylate) in the nanocapsules were transformed chemically into carboxyl ones after etching the silica templates by HF. Furthermore, we also investigated the controlled release of the carboxyl groups functionalized crosslinked polystyrene nanocapsules. The results of UV-vis spectra showed that the dye adsorbed amounts of the carboxyl group functional crosslinked polymeric nanocapsules (PAA-CPS nanocapsules) were superior to the PtBA-CPS nanocapsules due to the electrostatic interaction between the carboxyl group of PAA-CPS nanocapsules and the alkaline dye (MB). Furthermore, the release behavior of dye molecules of MB-load nanocapsules is quicker under acid medium compared to the neutral medium becaus of the electrostatic interaction between the carboxyl group of PAA-CPS nanocapsules and the dye was destroyed.3. The novel intelligent nanocapsules with the temperature-responsive crosslinked polymer shells and the pH- responsive polymer brushes on their inner walls have been designed and fabricated by using the "polymerization from template" strategy via the surface-initiated atom transfer radical polymerization (SI-ATRP) technique from the silica nanoparticles as sacrificial templates. The two steps sequential SI-ATRP procedures could provide the poly(tert-butyl acrylate) (PtBA) brushes on the inner walls of the temperature responsive crosslinked poly(N-isopropyacrylamide) (PNIPAm) shells. Then the tert-butyl ester groups in the nanocapsules were transformed chemically into acrylic acid groups after etching the silica templates with hydrofluoric acid (HF). The hollow structures and the multiple environmental stimuli responsive properties were validated with TEM and DLS techniques, respectively. In the strategy developed, the inner diameter, the crosslinking degree and the thickness of the shells, the length of the functional brushes could be controlled by adjusting the preparation conditions.4. The magnetic hybrid polyelectrolyte microcapsules with pH-sensitive shell and targeted controlled release have been prepared via the layer-by-layer self-assembly technique by electrostatic interaction between amino groups of chitosan (CS) and carboxyl groups of citrate onto the sacrificial templates (PSS) after etching above templates by dialysis. The behavior of loading and targeted controlled release of the magnetic hybrid polyelectrolyte microcapsules was researched by UV-vis spectrometer in methylene blue as a model molecule. It is found that the dye adsorbed capacity of the magnetic hybrid polyelectrolyte microcapsules was higher under basic medium compared with the acid medium. In contrast, the releasing raio of methylene blue from the MB-loaded magnetic hybrid hollow spheres was up to 76% after 48 h at pH= 4 without releasing under basic medium.5. The pH/temperature/ionic strength multi-sensitive polyelectrolyte microcapsules with controllable thermoresponsive layer were successfully prepared via combination of layer-by-layer assembly and Ce (Ⅳ) initiated grafting polymerization techniques after etching the templates by dialysis. The hollow structure of the obtained multi-sensitive polyelectrolyte microcapsules was characterized by transmission electron microscopy (TEM), which indicated the inner diameter of hollow microspheres is about 200 nm. The introduction of PNIPAm in pH-sensitive polyelectrolyte shell achieved the controlled release of drug molecules (a model hydrophobic drug, dipyridamole) could be dually controlled by the solution pH and temperature. Furthermore, the PNIPAm layer also could prevent from flocculation among the obtained multi-responsive polyelectrolyte microcapsules in the solution of higher salt concentration according to the results of DLS. This represents the first reported of pH/temperature/ionic strength multi-sensitive hollow microspheres prepared by layer-by-layer assembly, which might find practical application such as drug delivery and smart release in clinical application.6. The disintegration-controllable stimuli-responsive polyelectrolyte multilayer microcapsules have been fabricated via the covalent layer-by-layer assembly between the amino groups of chitosan (CS) and the aldehyde groups of the oxidized sodium alginate (OSA) onto the sacrificial templates (PSS), which was removed by dialysis subsequently. The introduction of Schiff base between the polyelectrolyte shells could increase the stability of microcapsules in the solution compared with noncovalent polyelectrolyte microcapsules. The diameter of the multilayer microcapsules decreased with the increasing of the pH values or the ionic strength. The pH and ionic strength dual-responsive multilayer microcapsules were stable in acidic and neutral media while they could disintegrate only at strong basic media.7. Novel magnetic-targeted pH-responsive drug-delivery system have been designed and prepared via layer-by-layer self-assembly of polyelectrolytes (oligochitosan as polycation and sodium alginate as polyanion) via electrostatic interaction with the oil-in-water type hybrid emulsion droplets containing superparamagnetic ferroferric oxide nanoparticles and drug molecules (Dipyridamole (DIP)) as cores. And the drug molecules were directly encapsulated into the interior of droplets without etching the templates and refilling with the desired guest molecules. The drug-delivery system showed high encapsulation efficiency of drugs and drug-loading capacity. The cumulative release ratio of dipyridamole from the oligochitosan/sodium alginate multilayer encapsulated magnetic hybrid emulsion droplets (DIP/Fe3O4-OA/OA)@(OCS/SAL)4 was up to almost 100% after 31 h at pH= 1.8. However, the cumulative release ratio was only 3.3% at pH= 7.4 even after 48 h.Furthermore, the dipyridamole microparticles with a size about 300 nm have been encapsulated by magnetic nanoparticles and polyelectrolyte hybrid multilayers via layer-by-layer assembly technique for the purpose of targeted controlled release. UV-vis spectroscopy was employed to monitor the drug release processes in both pH 1.8 and pH 7.4 buffer solutions. It was found that the release of drug molecules from magnetic hybrid multilayers coated drug-delivery was mainly dependent on the following factors such as the permeability of the hybrid polyelectrolyte shell and the solubility of the drug molecules in the bulk solutions. The results revealed that it could achieve the quick and continuous controlled release by magnetically-guide to the target tissue of the organism.更多还原