【作者】 王晶晶；

【导师】 蒋锡群； 武伟；

【作者基本信息】 南京大学 ， 高分子化学与物理， 2013， 博士

【摘要】 环糊精(cyclodextrin, CD)是直链淀粉在芽孢杆菌产生的环糊精葡萄糖基转移酶作用下产生的一系列的环状低聚糖的总称,其结构是葡萄糖单元通过1,4-α-糖苷键连接的环状分子,环糊精具有的良好的生物相容性,且疏水性空腔具有对小分子客体的包合能力,因此,基于环糊精的新型功能材料越来越受关注。设计合成基于环糊精的精确控制的拓扑结构,利用环糊精空腔的包合作用组装纳米粒子作为药物载体,并且运用特定基团对外界环境的刺激响应性来控制药物的释放,可以为药物载体的合成领域提供一个新的思路。环糊精的强大的功能化的能力,使其可以作为核,合成星形聚合物,其独特的拓扑结构,是合成高载药量的载体的优良前体。富勒烯具有独特的笼状结构和很好的物理化学性能,但是其疏水性限制了其在生物学方面的应用,因此,设计合成富勒烯水溶性衍生物并且研究其生物性能具有重要的意义。富勒烯上的双键可以发生1,3-偶极环加成反应,Diels-Alder反应等等,这使富勒烯成为药物设计的理想基体,因此,用共价连接方法引入环糊精来提高富勒烯的水溶性,且研究其在细胞以及生物体内性能具有重要的生物学意义。本论文利用化学合成手段,设计合成了具有特殊性能的含环糊精的纳米药物载体,且研究了其体内外的行为,主要包括以下内容：(1)我们合成了由p-环糊精封端的多臂聚合物,通过p-环糊精/金刚烷的包合作用,将聚合物组装成为纳米粒子。纳米粒子中设计引入了酯键,通过酯键的水解可以使纳米粒子解离为多臂聚合物。因此,这一体系具有多级载体的特点,纳米粒子作为第一级载体,多臂聚合物作为第二级载体。多臂聚合物是通过原子转移自由基聚合的方法合成的,因此,其分子量及多分散度可控。且这一多臂聚合物在其端基β-环糊精上有大量的羟基,可以用来连接药物及其他的生物活性分子。(2)合成了以二氨基三乙二醇为间隔臂的新型水溶性环糊精-富勒烯结合物,这一物质在小鼠肿瘤中有着很好的富集效果,由于C60部分可以在光照条件下产生活性氧,因此在光照条件下,这一物质可以有效剪切DNA,有作为光动力学药物的潜在应用。(3)用原子转移自由基聚合方法,合成了以环糊精为核,丙烯酸叔丁酯为链的星形聚合物。水解后的产物星形聚丙烯酸,在4-二甲氨基吡啶/N,N’-二环己基碳二亚胺催化下连接抗肿瘤药物紫杉醇,结果表明,随着聚合物分子量的升高,载药量随之升高,最高可达到59%,且随着分子量的升高,粒子趋向于在肿瘤富集。更多还原

【Abstract】 Cyclodextrins (CDs) is a series of cyclic oligosaccharides in general. They are produced from amylose under the action of cyclodextrin glycosyltransferase which is produced by Bacillus. Their structures of the cyclic molecules are made up of the glucose unit bound together by1,4-a-glycosidic linkage. Cyclodextrins have good biocompatibility, and the hydrophobic cavity has the ability to inclusion small molecules. Therefore, new functional materials based on cyclodextrins get increasingly attention. Design and synthesis of cyclodextrin-based precise topology, nanoparticles assembled via host-guest interactions, and specific groups which are stimuli-responsive to the external environment to control drug release, provide new ideas for the field of drug vector synthesis. The powerful functionalization capacity of cyclodextrins makes them attractive to be used as nuclears and synthesize star polymer whose unique topology can be used as excellent precursors for high drug loading carriers.Fullerene has a unique structure and excellent physical and chemical properties, but their hydrophobicity limits its applications in biology, therefore, the design of water-soluble fullerene derivatives and study its biological properties have important significance. The double bond of fullerene can occur the1,3-dipolar cycloaddition, Diels-Alder reaction, etc., which makes fullerene an ideal matrix in drug carrier design. Therefore, covalently attach cyclodextrin to fullerene to increase the water solubility of fullerene and study the in vitro and in vivo properties have important biological significance.In this dissertation, we designed cyclodextrin-containing drug carriers utilizing a variety of chemical synthesis techniques and intermolecular interactions. The main contents are described as below:(1) We present the synthesis of a giant multiarm polymer terminated by β-cyclodextrin (β-CD) and the assembly of this polymer into nanoparticles via the β-CD/adamantane inclusion complex. Ester linkage is introduced to the nanoparticles by design, which enables the nanoparticles to decompose into the multiarm polymers again by hydrolysis of the ester linkage. Thus, this system has the characteristics of MSVs with the nanoparticle as the first stage vector and the giant multiarm polymer as the second stage vector. The multiarm polymer is synthesized by atom transfer radical polymerization (ATRP). Thus, the preparation is facile, and its molecular weight and distribution can be well controlled. The multiarm polymer has abundant hydroxyl groups in the peripheral β-CD moieties which can be used to conjugate drug or other bioactive molecules.(2) We present the synthesis of a novel water soluble C60-CD conjugate containing a hydrophilic spacer of diaminotriethylene glycol. This compound can accumulate in tumor and exhibits an effective DNA cleavage ability under visible light irradiation thanks to the reactive oxygen species generated by the photoexcitation of the C60moiety.(3) A multiarm polymer with β-cyclodextrin as the core, poly (t-butyl acrylate) as arms was synthesized by atom transfer radical polymerization. After hydrolysis, the product of multiarm poly(acrylic acid) was combined with PTX under the catalyst of DMAP/DCC. The results showed that with the increase of polymer molecular weight, the amount of the drug increased, up to59%, and the particles tend to be accumulated in the tumor more easily.更多还原