聚合物复合胶束的制备及其作为可控载体的研究

【作者】 熊德安；

【导师】 史林启；

【作者基本信息】 南开大学 ， 高分子化学与物理， 2009， 博士

【摘要】 嵌段共聚物复合胶束将具有不同性质的聚合物嵌段引入到同一胶束中,使其具有复合的“核”或“壳”结构,能更好地满足药物控制释放、催化剂载体等方面的应用。本论文利用嵌段共聚物之间的氢键和/或静电相互作用设计并制备了多种聚合物复合胶束。并在复合胶束调控所包裹药物的释放速率和所负载的金纳米催化剂的催化活性方面开展了研究。主要内容包括:1、利用聚丙烯酸和聚（4-乙烯基吡啶）之间的氢键作用,将聚（N-异丙基丙烯酰胺）-b-聚（4-乙烯基吡啶）（PNIPAM-b-P4VP）与聚乙二醇-b-聚丙烯酸（PEG-b-PAA）在乙醇中自组装,首次制备了一种纤维状复合胶束。该胶束具有PAA/P4VP的复合核和一个PEG&PNIPAM的混合壳层。通过改变溶液中两种聚合物的质量比(W_{PNIPAM-b-P4VP}/W_PEG-b-PAA)可以调节所形成的纤维状胶束的长度,并且,该纤维状胶束的端基是“活的”,新加入的PNIPAM-b-P4VP链可以继续沿端基生长,并可以在两个胶束聚集体之间起到一种桥连作用,将两个聚集体连接起来,使得纤维状胶束的长度增加。2、巧妙地运用了层层自组装的方式,通过PAA和P4VP之间的氢键作用,在乙醇中将分别具有温度和pH值敏感的聚合物嵌段引入到聚苯乙烯-b-聚丙烯酸（PS-b-PAA）聚合物胶束的表面,制备了一种多层胶束。胶束的冠层由PNIPAM链和过量的P4VP链段组成。将胶束转移到酸性水中时,其多层复合结构不会发生变化。多层胶束具有pH和温度双重敏感性,升高溶液的温度到最低临界溶液温度（LCST）以上时,PNIPAM塌缩到PAA/P4VP复合层上而过量的P4VP链依然伸展到酸性水溶液中,形成一种冠层反转胶束。3、用1,2-二氯乙烷作辅助,在水中制备了一种PS-b-PAA空心胶束,胶束的空腔被1,2-二氯乙烷所占据。向胶束溶液中加入PNIPAM-b-P4VP和PEG-b-P4VP时,高分子链会通过PAA和P4VP之间的静电和氢键作用组装在胶束表面。这样,就形成了一种多层复合胶束,胶束具有一个相对独立的空腔、PAA/P4VP复合壳层以及由PEG和PNIPAM的混合物构成的冠层。将体系的温度升高到LCST以上时,PNIPAM塌缩在复合层上。与此同时,PEG依然伸展到水溶液中,在塌缩的PNIPAM层中构筑了一种亲水性通道,为小分子,尤其是亲水性小分子进出胶束提供了一条有效的途径。通过改变胶束冠层PNIPAM和PEG链的比例可以调节胶束表面通道的数量和密度,进而可以有效地调控所包裹药物的释放速率。4、利用PAA和P4VP之间的静电和氢键作用,通过层层组装的方式,制备了一种新型的以PS为核、PAA/P4VP复合层为壳、PNIPAM和PEG的混合物为冠的核-壳-冠胶束,并将金纳米粒子负载到胶束的壳层中。升温后,PNIPAM塌缩,对小分子的扩散形成一种障碍,同时也使得所负载的金粒子不易从胶束中脱落。PEG链穿过塌缩层伸展到水溶液中,形成允许小分子通过的亲水性通道。这种通道可以用来调控所负载金催化剂的催化活性:通过改变PEG链在冠层中的比例可以调节胶束表面的PEG通道的数量和密度,进而可以调节小分子进出胶束的速率和催化反应的速率。这种在胶束表面制备亲水性通道的同时又保持了胶束在溶液中的稳定性的方法在许多疏水性药物的传输、控制释放以及基因治疗等方面有着十分广泛的应用前景。5、将传统的乳液聚合和原子转移自由基聚合结合起来,利用乳液作为模版制备了具有空心结构的杂臂交联聚合物。在乳液体系中,单体和催化体系在油相中,含有疏水端基的水溶性大分子引发剂在水相中。大分子引发剂的疏水端基进入到油相中后就可以引发聚合。所得聚合物具有一个空腔,并且同时含有PEG和PNIPAM的臂,这两种臂的比例可以通过改变引发剂中二者的质量比来控制,所得聚合物中空腔的大小也可以通过改变聚合体系的水油比来调控。这种具有空心结构的多臂交联聚合物具有其他核交联聚合物所具备的特性,其在药物释放、催化剂载体、涂料添加剂以及材料的改性方面有极其重要的应用价值。更多还原

【Abstract】 Polymeric complex micelles,which were synthesized by introducing more than one kind of polymer blocks with different properties into the same micelle,have a complex core or shell and would match well with the higher requirement of drug release and catalyst carrying.In this thesis,many kinds of complex micelles were designed and synthesized through the hydrogen bonding and/or the electrostatic interactions between differene polymer blocks.The complex micelles were used to control the release velocity of the encapsulated drug and to madulate the catalytic activity of the loaded metallic nanoparticles.The contents of the corresponding research works are shown as follows.Novel kind of worm-like complex micelles were synthesized through the hydrogen bonding between PAA block and P4VP block by adding poly（N-isopropylacrylamide）-block-poly（4-vinylpyridine）（PNIPAM-b-P4VP） into the solution of poly（ethylene glycol）-block-poly（acrylic acid）（PEG-b-PAA） in ethanol.The resulted micelles have a PAA/P4VP complex core and a PEG&PNIPAM mixed shell.The length of worm-like aggregates could be adjusted by changing the weight ratio of W_{（PNIPAM-b-P4VP）}/W_{（PEG-b-PAA）}.The terminal group of the aggregates is "living".The newly added PNIPAM-b-P4VP chains would grow onto the aggregates from the group and acted as a bridge to connect two aggregates, and the length of the micelles increased.Multilayered micelles was synthesized through the electrostatic interaction and the hydrogen bonding between PAA block and P4VP block using the layer by layer assembly method by adding PNIPAM-b-P4VP and PEG-b-P4VP into the polystyrene-block-poly（acrylic acid）（PS-b-PAA） micellar solution.The corona of the micelles consisted of a kind temperature sensitive polymer block and a kind of pH sensitive polymer block.The multi-layered morphology would not change when the micelles were transferred into water.The micelles have both pH and temperature sensitivity.PNIPAM would collapse onto the PAA/P4VP complex layer when the solution was heated above LCST,and the excessive P4VP chains would still extend into the solution.Accordingly,a kind of reverse micelles formed.PS-b-PAA spherical micelle with a liquid core and PAA shell were prepared with the assistance of 1,2-dichloroethane.In the process of adding the mixture of PNIPAM-b-P4VP and PEG-b-P4VP,multi-layered micelles with mixed corona consisted of both PNIPAM and PEG chains were constructed through the electrostatic interaction and hydrogen bonding between PAA block and P4VP block. When heating above LCST,PNIPAM chains collapsed onto the PAA/P4VP complex layer while PEG chains still stretched into the solution through the collapsed PNIPAM layer,leading to the formation of hydrophilic channels around PEG chains. The ratio of the channels in the corona of the micelles can be modified by changing the weight ratio of W_{（PNIPAM-b-P4VP）}/W_{（PEG-b-P4VP）},and accordingly,the release velocity of the drugs encapsulated in the hollow space can be controlled through this method.Polymeric micelles with a PS core,PAA/P4VP complex shell and PEG&PNIPAM mixed corona were synthesized through the layer by layer assembly method and used as the supporter for the gold nanoparticles（GNs）.When heated above LCST,PNIPAM would collapse onto the PAA/P4VP complex layer,acting as a barrier for the diffusion of small molecules and also preventing the sheeding of the GNs.Hydrophilic channels around PEG chains formed when PNIPAM chains collapsed above LCST.The ratio of the channels in the corona can be tuned by changing the weight ratios of PEG chains to PNIPAM chains in the corona and the catalytic activity of the GNs can be modulated by the channels.This concept of constructing the hydrophilic channels in the corona while the micelles were stabilized by the extended PEG chains can be further used in controlled drug delivery, DNA transfer and gene therapy.Hollow crosslinked polymers（HCPs） were synthesized using arm first method via atom transfer radical polymerization.The polymerization process was performed in mini-emulsion system,in which the macro initiators,PEG-Br and PNIPAM-Cl, were in the water phase whileas the vinyl-monomer,4VP,and the cross-linker,DVB, were in the butanone phase.The resulted polymer contained a hollow space,and the volume of the hollow space could be adjusted by changing the ratio of water to butanone.There were two kinds of arms,PEG and PNIPAM,in the polymer,and their ratio can be well controlled.更多还原