【作者】 张世平；

【导师】 史真； 宫永宽；

【作者基本信息】 西北大学 ， 有机化学， 2009， 博士

【摘要】 脂肪族聚酯类高分子良好的生物相容性和生物可降解性,使它成为目前最重要的生物医用材料和绿色高分子材料之一。但是,现有的生物降解性脂肪族聚酯的大分子骨架的高度疏水性,分子间作用力弱,亲水性差、难以调解亲水/疏水平衡并且缺乏反应活性位点等问题的存在,很大程度上制约了它们在生物医用材料尤其是作为药物控释材料的广泛应用。聚磷酸酯是近十几年来发展较快的另一类新型生物可降解材料。它的主链骨架类似于核酸和磷壁质酸,主链上的磷酸酯键具有在生理条件下易降解的特点,且其结构可变性高,有利于对其进行结构修饰及功能化。然而,聚磷酸酯较易水解,单独用作药物控释材料时释药速度过快,限制了其在药物控释领域的应用。为了使脂肪族聚酯和聚磷酸酯作为生物医用材料更好的服务于人类,本论文试图通过脂肪族酯和磷酸酯的共聚以及在脂肪族聚酯的末端引入亲水的磷酰胆碱基团的方法来实现对脂肪族聚酯进行亲水性和药物控释性能调控的目的。本论文的主要工作及结论如下:(1)采用溶液聚合的方法合成了一系列脂肪族酯和磷酸酯的共聚物。~1H NMR和FT-IR证实了聚合物的化学组成。动态接触角(DCA)的研究结果显示,随着共聚单元中磷酸酯单元含量的增加,聚合物的亲水性增加。以中性红为模型药物研究了系列聚合物的的药物控释性能。结果显示,亲水性较强的均聚磷酸酯(聚乙基磷酸二缩三乙二醇酯)释药速度最快,十天之内释药率达到90%;而疏水性较强的均聚脂肪族聚酯(聚己二酸二缩三乙二醇酯)的释药速度最慢,十天内释药率仅为50%。共聚物的释药速度介于两类共聚物之间,且随着共聚单元中脂肪族聚酯的含量增加释药速率减慢。综合动态接触角和药物控释的研究结果,可以认为通过磷酸酯与脂肪族聚酯的共聚,确实能够实现对聚合物亲/疏水性和释药速率的调节。(2)通过四步反应合成得到了末端为磷酰胆碱基团的聚丁二酸丁二醇酯PBS-PC。首先通过调节丁二酸二甲酯和1,4-丁二醇的投料比,合成了末端为亲水羟基的聚丁二酸丁二醇酯PBS。然后利用PBS末端羟基的反应活性,和自制的二氯磷酸-2-氯乙酯反应使末端羟基磷酯化,随后再将提纯过的该聚合物水解,得到了磷酯化的聚丁二酸丁二醇酯PBS-Cl。最后,以无水的三甲胺为季铵化试剂,在高压釜中实现了对PBS-Cl的季铵化,得到了末端为磷酰胆碱基团的聚丁二酸丁二醇酯PBS-PC。~1H NMR、FT-IR和X-射线光电子能谱(XPS)结果证实了所有合成的聚合物的结构。根据XPS测试数据计算知道,平均每一个PBS链上约有1.9个PC基团。(3)采用示差扫描量热法(DSC)和热重法(TGA)测试了合成聚合物的热性能。与PBS相比,末端磷酯(PBS-Cl)和PC(PBS-PC)基团的存在,一定程度上使得聚合物分子在晶格中的有序排列变得困难,阻碍其结晶;同时,主链的柔顺性降低,使得聚合物的熔点和熔融焓降低(PBS-PC＜PBS-Cl＜PBS),而玻璃化温度升高(PBS-PC＞PBS-Cl＞PBS)。动态接触角结果证实,PC基团的引入很大程度上提高了聚合物PBS的亲水性(后退角PBS:33.8°;PBS-PC:8.4°),且目标聚合物PBS-PC的降解速率、吸水率以及以中性红为模型药物释药速率得到了很大的改善。(4)通过溶血、细胞毒性(L929细胞)、血小板黏附及蛋白质吸附(牛血清白蛋白和牛血浆纤维蛋白原为模型蛋白)实验,系统研究了聚合物PBS、PBS-Cl和PBS-PC的血液相容性和细胞相容性。溶血实验表明,上述三种聚合物的溶血率均小于5%,不会引起溶血反应。且相对于聚合物PBS和PBS-Cl来说,PBS-PC的溶血率更低,性能更好。以小鼠成纤维细胞L929为对象进行细胞毒性实验发现,不论是三种聚合物本身还是它们的浸提液,均无明显的细胞毒性。而且,聚合物PBS-PC具有比聚合物PBS和PBS-Cl更好的细胞增值率,说明聚合物PBS-PC具有更优良的细胞亲和性。以牛血清白蛋白(BSA)和牛血浆纤维蛋白原(BPF)为模型蛋白,研究了合成聚合物对蛋白质的吸附性能。BSA在PBS表面的吸附量是0.21μg/cm~2,而在PBS-PC表面的吸附量是0.1μg/cm~2,BSA的吸附量减少了大约52%。BPF在PBS表面的吸附量是0.46μg/cm~2,而在PBS-PC表面的吸附量是0.13μg/cm~2,BPF的吸附量减少了大约72%。血小板黏附实验表明,血小板在疏水聚合物PBS涂层产生了激活、凝聚。与此相比,血小板在两亲聚合物PBS-PC涂层基本没有黏附。综上所述,PBS-PC可望成为一种新的具有良好生物降解性和生物相容性的高分子材料,在药物控释、基因治疗、组织工程和材料表面改性等生物医用材料领域具有广阔的应用前景。更多还原

【Abstract】 Biodegradable and biocompatible aliphalic polyester is one of the synthetic polymer materials which is widely used in the research and application of biomedical materials and green polymer materials. However, because of its poor surface hydrophilicity and absence of natural molecule acting point, its application as biomaterials especially as drug delivery materials was limited.Polyphosphate is another new biodegradable material with a rapid development. Its main chain phosphate skeleton is similar to nucleic acid and phosphorus acid. The characteristics of degradation at physiological conditions, and vulnerablity and high variability of their structure make them to be modified easily. However, the fast degradation characteristic of polyphosphate restricted its application in drug release.In order to overcome these shortcomings and promote the application to public as better biomedical materials, this dissertation attempts to improve hydrophilicity and drug delivery performance of the aliphatic polyesters through copolymerization of aliphatic ester and phosphate ester, and introduction of the phosphorylcholine （PC） groups on both ends of poly（butylenes succinate）. The results and conclusions are summarized as follows:（1） A series of copolymers containing aliphatic polyester and polyphosphoester segments in the repeat units were synthesized via condensation polymerization reaction with adipoyl chloride, ethyl dicholorophosphate and triethylene glycol as the beginning materials. The effects of reaction conditions on polymerization were studied and the structures of final polymers were characterized by ¹H NMR, FT-IR and MALDI-TOF MS. Dynamic contact angle was used to characterize the surface capability of the polymers. The controlled release character of the copolymers was studied by a fluorescence method using neutral red as a model drug. The experimental data displayed that strong hydrophilic polyphosphate has the fastest release rate, about 90% neutral red was released within 10 days; and strong hydrophobic aliphatic polyester has the slowest release rate, only 50% neutral red was released for 10 days. Hydropholicity and drug release rate of aliphalic polyester indeed can be regulated through the copolymerization of phosphate and aliphatic polyester. （2） A new biodegradable and biocompatible polymer, phosphorylcholine functionalized poly（butylene succinate） （PBS-PC） was synthesized via a four-step synthetic strategy. First, chloroethyl phosphoric acid dichloride was synthesized from POCl₃ and 2-chloroethanol. Second, hydroxyl functionalized poly（butylene succinate） （PBS） was synthesized through a condensation polymerization of dimethyl succinate and 1,4-butadiol. Then, the one-pot end capping reaction of the polymer hydroxyl was conducted and chloroethylphosphorate functionalized poly（butylene succinate） （PBS-Cl） was obtained. Finally, the target polymer bearing PC groups on PBS both ends （PBS-PC） was attained by quaterisation reaction. The results of NMR, FT-IR, GPC and XPS demonstrated a successful construction of the product of PBS-PC. As both the PBS-Cl and PBS-PC polymers contain phosphorus atom in their end groups, the P elemental composition is used to estimate the average number of the end functional groups of the polymer chains. The calculated numbers are 1.9 for both the PBS-Cl and PBS-PC polymers.（3） Thermal analysis of the synthesized PBS, PBS-Cl and PBS-PC were tested using differential scanning calorimetry （DSC） and thermal gravimetric analysis （TGA）. Compared with the PBS, phosphatidate and PC groups on the PBS chain significantly retarded the crystallizability and the flexibility. The melting point and melting enthalpy of PBS-Cl and PBS-PC were lowed （PBS-PC<PBS-Cl<PBS）, but the glass transition temperature （PBS-PC >PBS-Cl>PBS） was increased. Dynamic contact angle results showed that the introduction of PC groups increased the hydropholicity of the PBS （receding contact angle: 33.8°for PBS and 8.4°for PBS-PC）. Dynamic contact angle, in vitro degradation, swelling behavior and drug release measurements revealed that the PBS-PC showed improved hydrophilicity, degradation, swelling and faster drug release rates by compared with PBS.（4） From hemolysis, cytotoxicity, platelet adhesion and protein adsorption （bovine serum albumin and bovine plasma fibrinogen） experiments, hemocompatibility and cell compatibility of polymers PBS, PBS-Cl and PBS-PC were studied systematically. Hemolysis experiment showed that hemolytic rate of the three polymers were all less than 5%, and compared to PBS and PBS-Cl, hemolytic rate of PBS-PC was the lowest. The results of cytotoxicity experiment using mouse L929 fibroblast cells as showed that whether the three polymers themselves or their extracts, no significant cytotoxicity was found. Compared with PBS and PBS-Cl, PBS-PC has a better cell affinity. The results of platelet adhesion test showed that the adhered platelets on the surface coated with PBS showed large sizes, which suggested the aggregation and agglomeration of platelet. This result indicated the activation of the platelets by the hydrophobic surface. On the other hand, the surface coated with PBS-PC almost no platelet adhesion, suggesting excellent anti-coagulation property. Protein adsorption test showed that the amounts of bovine serum albumin （BSA） and bovine plasma fibrinogen （BPF） absorbed on the PBS-PC coated surface were 0.1μg/cm² and 0.13μg/cm², respectively, which were 52% and 72% reduction compared with that on PBS surface.These results suggest that PBS-PC may have potential applications in biological environments as new carrier for controlled drug release, scaffold for tissue engineering or temporary coating for the endovascular implant systems.更多还原