摘要
纳米药物载体具有提高难溶性药物的溶解度、稳定性、改善药物在体内分布特征、延长药物循环时间等优点,但是其综合性能有待进一步提高。例如：通过物理吸附在纳米载体上的药物在控制释放中存在“突释”现象,介孔硅材料要求药物尺寸和孔隙尺寸匹配,这使纳米粒子在药物负载和控制释放方面的应用受到限制。因此,制备具有特殊结构和功能的纳米药物载体以克服上述问题具有重要理论意义和应用价值。本文将聚合物胶束和生物膜通道的性质结合起来,制备了结构新颖的具有通道结构的核-壳-冠三层胶束,研究了其对药物的负载和控制释放行为,胶束疏水的壳层可避免药物的“突释”和防止生物酶对内核的降解；利用通道结构控制了药物释放的速率；另外,以温度敏感的复合胶束为模板,制备了带有通道结构的空心杂化纳米粒子。
利用可逆加成裂解链转移自由基聚合(RAFT)方法合成了分子量窄分布的带有梳状结构的聚乙二醇-b-聚(甲基丙烯酸羟基乙酯-g-聚乳酸)-b-聚异丙基丙烯酰胺(PEG45-b-P(HEMA-g-PLA10)11-b-PNIPAM430)。常温下,嵌段聚合物在水溶液中自组装形成以PLA为核,PEG和PNIPAM为混合壳的胶束,透射电镜表明胶束呈球形结构,光散射表征粒径为140 nm左右。升高温度,PNIPAM链段由亲水变为疏水并塌缩在PLA核表面,胶束由核壳结构转变为核-壳-冠结构,PEG链穿过疏水的PNIPAM层形成通道,并对聚合物胶束起到稳定作用。以抗癌药物阿霉素(DOX)为模型药物,研究了嵌段聚合物胶束对DOX的控制释放行为。结果表明：在37℃时,含有通道结构的PEG-b-P(HEMA-g-PLA)-b-PNIPAM胶束能够很好的控制药物DOX释放。
利用RAFT和开环聚合(ROP)方法合成了分子量窄分布的嵌段聚合物PLA-b-PNIPAM;利用ROP合成了生物可降解的嵌段聚合物PEG-b-PLA。在常温下,PEG45-b-PLA100和PLA125-b-PNIPAM180在水溶液中自组装形成以PLA为核,以PEG和PNIPAM为混合壳的复合胶束；升高温度,混合壳层中的PNIPAM链段塌缩在PLA核表面,胶束转变成核-壳-冠结构,PEG链段穿过疏水的PNIPAM层形成通道,并对胶束起到稳定作用。实验研究表明：亲水性PEG通道可以使小分子(如水分子和小分子药物)穿过,而大分子物质(如生物酶等)很难穿过,从而可以保护胶束结构在体内循环中的稳定存在；通过改变两种嵌段聚合物的比例可以很容易地调节胶束表面的PEG通道数量和密度,从而达到控制释放目的。
利用具有温度响应性的复合胶束为模板,制备了带有通道结构的空心杂化纳米粒子。首先利用原子转移自由基聚合方法(ATRP)合成了分子量窄分布的嵌段聚合物聚乙二醇-b-聚异丙基丙烯酰胺(PEG-b-PNIPAM)和聚异丙基丙烯酰胺-b-聚4-乙烯基吡啶(PNIPAM-b-P4VP)。常温下,将两种嵌段聚合物溶解在酸水中(pH 4.0),升高溶液温度至45℃,嵌段聚合物形成以PNIPAM为核、以PEG和P4VP为混合壳的复合胶束。1,2-二(碘乙氧基)乙烷(BIEE)交联P4VP后,四乙氧基硅烷(TEOS)选择性沉积在P4VP链段上并发生溶胶凝胶反应,形成以PNIPAM为核,以P4VP/Silica为混合壳,PEG为冠的核-壳-冠三层结构的杂化纳米粒子。降低溶液温度,PNIPAM发生溶胀直至溶解,由于PEG与Silica之间的作用力比较弱以及PNIPAM的溶胀作用,嵌段聚合物PEG-b-PNIPAM会从杂化纳米粒子中逃逸出来,形成内部含有I(?)NIPAM、P4VP/Silica层带有通道结构的杂化空心纳米粒子,通道有利于杂化纳米粒子内外物质发生交换。
制备了具有多层结构的多功能的磁性纳米药物载体,该载体的内核是Fe304纳米粒子,Si02包裹在Fe304上能够保护其不被腐蚀氧化；中间层是生物相容性的聚天冬氨酸(PAsp)载药层；最外层是亲水的聚乙二醇(PEG)稳定层。磁性纳米复合粒子各层都是生物相容的,利用静电作用将抗癌药物阿霉素(DOX)负载在磁性纳米复合粒子中,通过PAsp的pH响应调节了DOX的释放速率。
Nanoparticles have attracted enormous attention in controlled drug release because they could improve the solubility and stability of drugs. Polymeric micelles and mesoporous silica are the most studied materials for controlled drug release. Block copolymer can self-assemble into core-shell structure in aqueous solution. Hydrophobic drugs can be loaded into micellar core to lower their toxicity in human body. However, polymeric micelles are easily to be biodegraded and disaggregated in the blood. As far as silica is concerned, size-matching between drugs and mesopore is usally necessary for efficient loading and controlled release of drugs, which in fact restrict the application of mesoporous silica as drug carrier. Thus, it is desirable to prepare nanoparticles with novel structures and multi-functions for controlled drug release. Inspired by protein channels in biomembranes, polymeric micelles with tunable channels are constructed and used for controlled drug release, and polymer/silica hybrid hollow nanoparticles with tunable channels are prepared using complex micelles as a template.
A novel and well-defined triblock copolymer, poly (ethylene glycol)-b-poly(2-hydroxyethyl methacrylate-g-lactide)-b-poly(N-isopropylacrylamide) (PEG45-b-P(HEMA-g-PLA10)11-b-PNIPAM430), containing a biodegradable PLA block and a thermo-sensitive PNIPAM block, was synthesized by a combination of ring opening polymerization (ROP) and reversible addition-fragmentation chain transfer polymerization (RAFT). In aqueous solution, the copolymer could self-assemble into core-shell micelle with the inner hydrophobic PLA block as the biodegradable core and outer bis-hydrophilic PEG/PNIPAM block as the mixed shell at room temperature. Increasing the temperature above the lower critical solution temperature (LCST) of PNIPAM, the micelle converted into a core-shell-corona (CSC) structure due to the collapsed of PNIPAM block. The soluble PEG chains could stretch out the PNIPAM shell forming hydrophilic PEG channels. Doxorubicin (Dox), an anticancer drug, was used as a model drug for controlled release experiments. The DOX-drug loaded micelle with PEG channels displayed well controlled release behaviors.
Two well-defined diblock copolymers of PLA-b-PNIPAM and PEG-b-PLA were synthesized by a combination of ROP and RAFT, In aqueous solution, comicellization of these two diblock copolymers at room temperature resulted in complex micelles with a biodegradable hydrophobic PLA core and a mixed hydrophilic PEG/PNIPAM shell. Above the LCST of PNIPAM, complex micelles could be converted into a core-shell-corona structure composed of a PLA core, a collapsed PNIPAM shell, and a soluble PEG corona. The PEG chains acted as channels in the PNIPAM shell for the exchange of substance between the core and external environment, through which small molecule such as drug could pass and macromolecules such as enzyme could not. The release of a model small molecule drug, ibuprofen, loaded in the micellar core was investigated. The release rate depended on the composition of the mixed shell. Higher content of PNIPAM in the mixed shell led to slower release of ibuprofen. Compared with core-shell micelles, complex micelles with the core-shell-corona structure avoided burst release of ibuprofen and inhibited degradation of PLA by lipase, a macromolecular enzyme.
It is an efficient method to synthesize the hybrid hollow nanoparticles with tunable channels using thermo-responsive complex micelles (PEG-b-PNIPAM/PNIPAM-b-P4VP) as a template. Two well-defined diblock copolymers, poly(ethylene glycol)-b-poly(N-isopropylacrylamide) (PEG-b-PNIPAM) and poly(N-isopropylacrylamide)-b-poly(4-vinylpyridine) (PNIPAM-b-P4VP), were first synthesized by atom transfer radical polymerization (ATRP). With increasing the temperature (45℃) of their mixed aqueous solution, the complex micelles formed with the PNIPAM block as the core and the mixed soluble PEG/P4VP blocks as the shell at pH 4.0. Shell cross-linking of the complex micelles was achieved using 1,2-bis(2-iodoethoxy)ethane (BIEE) as a bifunctional agent. Silica was selectively well deposited on the P4VP block of the complex micelles forming a core-shell-corona structure with PNIPAM as the core, P4VP/silica as the hybrid shell, and PEG as the corona. The soluble PEG chains penetrated the hybrid shell as the corona to avoid the hybrid nanoparticle further aggregates. The PEG channels through which H2O molecule could pass formed due to the phase separation between the silica shell and the PEG chains. Decreasing the temperature to 4℃, the PNIPAM block became swollen and further soluble, the PEG-b-PNIPAM block copolymer escaped from the nanoparticles as a result of swelled PNIPAM and weak interaction between PEG and silica within the pH range of 2.0-7.0. Thus hollow nanoparticles formed. It should be noted that in situ channels were obtained simultaneously in the silica shell due to the escape of PEG chains. These channels, which connected the inner space and the outer milieu, were promising for substance exchange.
A new type of multifunctional nanoparticles containing magnetic Fe3O4@SiO2 sphere and biocompatible block copolymer poly(ethylene glycol)-b-poly(aspartate acid) (PEG-b-PAsp) was prepared. Silica coated on the superparamaagnetic core was able to not only achieve a magnetic dispersivity, but also protect Fe3O4 against oxidation and acid corrosion. The PAsp block was grafted onto the surface of the Fe3O4@SiO2 nanoparticles by amido bonds, and the PEG block formed the outermost shell. The anticancer agent doxorubicin (DOX) was loaded into the hybrid nanoparticles via electrostatic interaction between DOX and PAsp. The release rate of DOX could be adjusted by manipulating the pH value.
引文
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