【作者】 苟鹏飞；

【导师】 沈之荃； 朱蔚璞；

【作者基本信息】 浙江大学 ， 高分子化学与物理， 2010， 博士

【摘要】 本论文综合应用可控开环聚合、ATRP、"Click"反应等技术系统地合成了一系列以杯芳烃和环糊精为核的两亲嵌段、杂臂星形聚合物和药物键合两亲星形聚合物,并初步研究了这些聚合物在水溶液中的自组装行为以及药物键合两亲星形聚合物的载药性能。设计了两种含八个醇羟基的间苯二酚杯芳烃衍生物引发剂,并以芳氧基钇配合物[Y(DBMP)3]为催化剂,通过可控开环聚合首次在温和条件下合成了一系列分子量不同的八臂星形聚已内酯。通过1HNMR和SEC-MALLS等测试证明了其为结构明确的八臂星形聚合物,溶解性较好的杯芳烃引发剂所合成的星形聚合物更接近设计结构。随后以这些八臂星形聚已内酯为基础,通过ATRP、"Click"反应和选择性水解反应首次合成了结构新颖的两亲八臂三嵌段ABA型星形共聚物(SPCL-PAA-PCL),其每条臂都由PCL-b-PAA-b-PCL线型三嵌段两亲共聚物组成。同时,应用DLS和TEM对这些两亲星形聚合物在水溶液中通过自组装形成的聚集体形貌进行了表征。考虑到引发剂溶解性对合成结构明确星形聚合物的影响,利用选择性取代反应合成了十四个低活性仲羟基被酯化而七个高活性伯羟基被保留的具备良好溶解性的p-环糊精衍生物(per-2,3-acetyl-p-CD),并以其为引发剂,辛酸亚锡为催化剂通过可控开环聚合合成了结构明确,分子量分布小于1.15的以环糊精为核的七臂星形聚已内酯,该类星形聚合物的“核”与“臂”皆具可生物降解性。随后以这些七臂星形聚已内酯为原料,设计了两种类型的两亲七臂星形嵌段共聚物：一类为通过七臂星形聚已内酯和羧基修饰的聚乙二醇之间的酯化偶联反应合成的两亲七臂两嵌段星形共聚物(CDSPCL-b-PEG),该共聚物在水溶液中能自组装形成10-40 nm的球形胶束；另一类为通过ATRP和"Click"反应合成的两亲七臂三嵌段ABC型星形聚合物(CDSPCL-PtBA-PEG),其每条臂包括疏水段PCL-b-PtBA嵌段共聚物和亲水段PEG,符合一定组成比例的该星形三嵌段共聚物在水溶液中能自组装形成奇特的“核-壳-冠”胶束和“多壁”囊泡,通过DLS, TEM和AFM等方法对这些胶束和囊泡进行了表征,并提出了疏水链PCL和PtBA之间的结晶差异性可能为这些奇特聚集体的形成提供了附加驱动力。通过三氟乙酸选择性水解CDSPCL-PtBA-PEG得到了具有PAA和PEG两种类型亲水链段的七臂三嵌段星形聚合物CDSPCL-PAA-PEG,该聚合物在水溶液中自组装形成的聚集体具有pH响应性,改变pH值可调控这些聚集体的形貌和尺寸。以大环化合物为核且结构明确的杂臂星形聚合物并不多见,本论文利用对叔丁基杯[4]芳烃和p-环糊精在特定条件下的选择性取代反应分别设计了基于对叔丁基杯[4]芳烃和p-环糊精的A2B2和A14B7杂官能团引发剂,并通过可控开环聚合,ATRP或‘’Click"反应分别合成了以对叔丁基杯[4]芳烃为核的两亲A2B2杂臂星形聚合物[C4S(PCL)2-(PEG)2]和以环糊精为核的两亲A14B7杂臂星形聚合物[CDS(PCL-PAA)]。通过1HNMR, SEC-MALLS,FT-IR等方法证明了这些杂臂星形聚合物结构明确,分子量可控,分子量分布较窄。DLS, TEM和AFM等方法研究这些杂臂星形聚合物在水溶液中自组装行为表明亲水链的重量百分数是影响自组装聚集体形貌的重要因素之一：亲水链重量百分数较小的杂臂星形聚合物趋向于形成较大的聚集体,如蠕虫,囊泡等；亲水链重量百分数较大的杂臂星形聚合物趋向于形成较小的聚集体,如球形胶束等。以二澳新戊二醇和β-环糊精衍生物[per-6-(tert-butyldimethylsilyl)-β-CD)]为起始原料,通过可控开环聚合和‘’Click"反应合成了疏水链PCL末端药物键合的两亲A2B2杂臂星形聚合物[(PCL)2-(PEG)2-D]和A14B7杂臂星形聚合物[CDS(PCL)14-(PEG)7-D]。通过1HNMR, SEC-MALLS, FT-IR等方法证明了这些药物键合杂臂星形聚合物结构明确,分子量可控。应用DLS和TEM等方法研究这些药物键合杂臂星形聚合物在水溶液中的自组装行为表明,通过改变亲水链段的重量百分数能调控聚集体的形貌,获得诸如球形,蠕虫状,片状等多种形貌的药物键合聚集体。此外,首次发现药物键合杂臂星形聚合物对疏水药物的载药效率明显高于相对应的非药物键合杂臂星形聚合物。合成了药物键合量可调控且结构明确的主链药物键合两亲七臂星形聚合物[CDS-P(CL-co-DTC)-D-b-PEG]。其合成过程如下：首先设计了一种新型的含溴六元环环碳酸酯单体(DBTC),通过其和CL单体在环糊精衍生物(per-2,3-acetyl-p-CD)引发下的可控开环共聚合合成了主链含溴的七臂星形聚合物[CDS-P(CL-co-DBTC)]。然后,通过CDS-P(CL-co-DBTC)和羧基封端PEG之间的酯化偶联反应合成了两亲七臂星形聚合物CDS-P(CL-co-DBTC)-b-PEG。随后将CDS-P(CL-co-DBTC)-b-PEG疏水链上的溴基团在NaN3的处理下等当量地转化为叠氮基团。最后,通过"Click"反应将炔基修饰的布洛芬接枝到了聚合物疏水主链上获得了目标产物CDS-P(CL-co-DTC)-D-b-PEG。通过1HNMR, SEC, FT-IR等方法证明了CDS-P(CL-co-DTC)-D-b-PEG具有和设计相吻合的明确结构。此外,CDS-P(CL-co-DTC)-D-b-PEG根据组成的不同在水溶液中能自组装形成球形胶束、蠕虫和直径达数百个纳米的囊泡等聚集体。更多还原

【Abstract】 In this dissertation, a series of amphiphilic star block, miktoarm star copolymers and drug-conjugated amphiphilic star copolymers based on resorcinarene, calixarene and cyclodextrin cores have been synthesized by combination of CROP, ATRP and "Click" reaction. Primary studies on the self-assembly behaviors of these copolymers and drug-loading capacities of the drug-conjugated amphiphilic star copolymers have been performed.Two kinds of novel multifunctional resorcinarene precursors with eight alcoholic hydroxyls were synthesized and used as initiators to prepare well-defined eight-arm star-shaped poly(s-caprolactone) (SPCL) in the presence of yttrium tris(2,6-di-tert-butyl-4-methylphenolate) [Y(DBMP)3] under mild conditions. End group 1H NMR and SEC-MALLS analyses confirmed the well-defined eight-arm star structures. Subsequently, novel amphiphilic star triblock copolymers, star poly(ε-caprolactone)-block-poly(acrylic acid)-block-poly(ε-caprolactone)s (SPCL-PAA-PCL) consisting eight PCL-b-PAA-b-PCL triblock arms were prepared by combination of ATRP, "Click" reaction, and selective hydrolysis using SPCL as starting material. These amphiphilic star triblock copolymers could self-assemble into spherical micelles in aqueous solution which were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM).Considering the influence of the initiators’solubilities for preparing well-defined star polymers, per-2,3-acetyl-β-cyclodextrin with seven primary hydroxyl groups was synthesized and used as multifunctional initiator for CROP of CL. Well-defined P-cyclodextrin-centered seven-arm star poly(ε-caprolactone) (CDSPCL) with narrow molecular weight distributions (≤1.15) have been successfully prepared in the presence of Sn(Oct)2 for the first time. Both the "core" and the "arm" of these star polymers are biodegradable. Subsequently, two kinds of amphiphilic seven-arm star block copolymers were synthesized from CDSPCL:one was amphiphilic seven-arm star poly(ε-caprolactone-b-ethylene glycol) (CDSPCL-b-PEG), which was synthesized by the coupling reaction of CDSPCL with carboxyl-terminated mPEGs. CDSPCL-b-PEG could self-assemble into spherical micelles in water with the particle size ranging from 10-40 nm. The other one was amphiphilic seven-arm star poly(ε-caprolactone-b-tert-butyl acrylate-b-ethylene glycol) (CDSPCL-PrBA-PEG), which was synthesized by combination of ATRP, and "Click" reaction from CDSPCL. Some CDSPCL-PtBA-PEG with proper components could self-assemble into novel "core-shell-corona" micelles and "multi-wall" vesicles, which were characterized by DLS, TEM, and AFM. The possible reason for the formation of these novel aggregates was the differential crystallinity between PCL and PtBA. Furthermore, seven-arm amphiphilic star copolymers (CDSPCL-PAA-PEG) with two different hydrophilic chains (PAA and PEG) were synthesized by the selective hydrolysis of CDSPCL-PtBA-PEG, which could self-assemble into pH-response aggregates in water.Only few papers concerned the synthesis of well-defined miktoarm star copolymers based on macrocyclic compounds. In this dissertation, novel heterotetrafunctional A2B2 and A14B7 initiators were synthesized from selective substitution reactions of calix[4]arene and P-cyclodextrin. A2B2 miktoarm star copolymers [C4S(PCL)2-(PEG)2] consisting of two PCL arms and and two PEG arms were synthesized from calix[4]arene-based A2B2 initiator by the combination of CROP, and "Click" reaction; while A14B7 miktoarm star copolymers [CDS(PCL-PAA)] consisting of fourteen PCL arms and seven PAA arms were synthesized by the combination of CROP, and ATRP.1H NMR, SEC-MALLS, FT-IR analyses confirmed that they had well-defined miktoarm star architectures, controlled molecular weight and reasonably narrow molecular weight distribution. DLS, TEM, and AFM were used to characterize the morphologies of the self-assembled aggregates from these amphiphilic A14B7 and A2B2 miktoarm star copolymers. In general, the weight fraction of hydrophilic chains was the keypoint to control the morphologies of the aggregates:amphiphilic star copolymers with low weight fraction of hydrophilic chains preferred to form large aggregates, such as worm like micelles and vesicles; while amphiphilic star copolymers with high weight fraction of hydrophilic chains preferred to form small aggregates, such as spherical micelles.Novel two kinds of drug-conjugated miktoarm star copolymers, A2B2 miktoarm star copolymers (PCL)2-(PEG)2-D and A14B7 miktoarm star copolymers CDS(PCL)14-(PEG)7-D with ibuprofen conjugated on the end of the PCL chains have been synthesized by the combination of CROP and "Click" chemistry using 2,2-bis(bromomethyl)propane-1,3-diol and per-6-(tert-butyldimethylsilyl)-β-CD as starting material, respectively.’H NMR, SEC-MALLS, FT-IR analyses suggested that these copolymers had designed well-defined miktoarm star architectures and controlled molecular weight. These copolymers could self-assemble into various morphologies (such as spherical micelles, lamellar aggregates, and worm-like aggregates) in aqueous solution, which can be controlled by the composition of the copolymers. The drug-loading efficiency and drug-encapsulation efficiency of the drug-conjugated miktoarm star copolymers were significantly higher than those of the corresponding non-drug-conjugated miktoarm star copolymers.Novel main chain drug-grafted amphiphilic seven-arm star copolymers CDS-P(CL-co-DTC)-D-b-PEG with tunable amount of drug molecules have been prepared in this dissertation. The synthetic route was as follows:bromide functionalized cyclic carbonate monomer had been designed and used to copolymerize with CL in the presence of per-2,3-acetyl-β-CD to prepare seven-arm star copolymers [CDS-P(CL-co-DBTC)]. Then, amphiphilic star copolymers CDS-P(CL-co-DBTC)-b-PEG had been synthesized by esterification coupling reaction between CDS-P(CL-co-DBTC) and carboxyl-terminated mPEGs. Subsequently, bromide groups on the main chains of CDS-P(CL-co-DBTC)-b-PEG had been converted into azide groups by treating with NaN3. Finally, the targeted CDS-P(CL-co-DTC)-D-b-PEG had been synthesized by "Click" reation between alkyne functionalized ibuprofen and azide functionalized amphiphilic star copolymers. Furthermore, CDS-P(CL-co-DTC)-D-b-PEG could self-assemble into spherical micelles, worm-like aggregates and vesicles with a diameter of several hundreds nm, according to the composition of the copolymer.更多还原