基于葫芦脲超双亲分子构筑光响应功能纳米囊泡

发布时间：2018-02-21 09:43

本文关键词： 超两亲分子葫芦[8]脲光刺激响应胞吞机制靶向释放　出处：《吉林大学》2017年硕士论文　论文类型：学位论文

【摘要】：葫芦[n]脲系列大环化合物(Cucurbit[n]uril,CB[n])是由n个甘脲分子通过2n个亚甲基桥连而形成的具有稳定蜂窝状空间结构的大环化合物家族。由于葫芦[n]脲内部空腔为疏水环境,且空腔的上下开口处均匀排布若干羰基基团,因而又具有一定亲水性,可与某些特殊的客体分子(如:FGG短肽)存在氢键相互作用或电荷-偶极相互作用(如:带正电荷的紫精分子),使得CB[n]分子通常具有较强的配体结合能力。相较于其它葫芦脲分子,CB[8]分子具有较大的内部空腔,可与两个客体分子形成1:2复合物或1:1:1三元复合物,使得以CB[8]复合物为构筑基元的自组装研究更为多样化,引起了科学工作者们极大的兴趣。在超两亲分子组装方面,CB[8]分子更是具有一定的优势,其主客体复合过程中可逆的相互作用有利于构筑智能响应性的超两亲分子,实现组装体的功能调控。最近研究发现,CB[8]与其客体分子的结合与解结合可受多种环境刺激调控,特别是光刺激响应的远程调控使其在主客体化学中独具魅力。因此,本论文开展了基于CB[8]超两亲分子的组装及其组装体光响应载药性能的研究:1.基于CB[8]超两亲分子自组装构筑光刺激响应纳米囊泡CB[8]与二价紫精分子(MV2+)可以形成一种稳定的水溶性复合物,在此基础上,该复合物可以进一步结合一个反式的偶氮苯分子形成更加稳定的三元复合物。但当偶氮苯受到365nm紫外光照刺激后就会发生顺反异构变化,变为顺式偶氮苯,而顺式偶氮苯与紫精CB[8]复合物的空腔在空间结构上不匹配,会从复合物的空腔中解离出来。利用这种光刺激可调节解结合的特性,可以设计以单修饰马来酰亚胺分子的紫精衍生物作为第一客体分子,以带有三条疏水尾链的偶氮苯衍生物作为第二客体分子构筑一种具有光刺激响应的超两亲分子。该超两亲分子在水溶液中自组装形成囊泡结构,并在365nm紫外光刺激下可以实现解散。在此基础上以罗丹明B及5(6)羧基荧光素为药物分子对该囊泡的载药性能和释放性能进行了体外研究,达到了对不同药物分子的包覆及快速释放的效果。2.CB[8]超两亲囊泡的表面修饰及靶向载药性能的研究由于马来酰亚胺具有亲水性,会暴露于囊泡的表面,便于对囊泡进行修饰,因此可以设计带有巯基靶向分子,利用巯基与马来酰亚胺双键的click反应在水溶液中对该囊泡进行功能化。基于这样的设计思路,在上一章工作基础上,合成Cys-i RGD及巯基修饰的透明质酸作为靶向分子对囊泡表面进行功能化,实现包覆抗癌药物囊泡的快速进膜,选择性投送,及可控释放,系统的研究了其进入细胞的跨膜机制;对肿瘤细胞的选择性;并在之前该囊泡体外载药及光控释放研究的基础上,利用细胞存活率实验及细胞凋亡实验对囊泡细胞内释放的药物进行药效评估,证明释放的抗癌药物对癌细胞起到抑制作用。
[Abstract]:Cucurbit [n] uriline CB [n] Urea family is a family of macrocyclic compounds with stable honeycomb space structure, which is formed by connecting n glycoluril molecules through 2n methylene bridges. Because the inner cavity of cucurbita [n] urea is hydrophobic, Moreover, the upper and lower opening of the cavity is evenly arranged with several carbonyl groups, so it has a certain hydrophilicity. Hydrogen bond interaction or charge-dipole interaction can be found with some special guest molecules (e.g.: FGG short peptide), such as the positively charged purple molecule, which makes CB [n] molecule usually have strong ligand binding ability. Other cucurbituride molecules have larger internal cavities. It can form a 1: 2 complex or a 1: 1: 1 ternary complex with two guest molecules, which makes the self-assembly study of CB [8] complex as the building unit more diversified. The CB [8] molecule has a certain advantage in the super amphiphilic molecular assembly, and the reversible interaction in the process of host and guest compound is beneficial to the construction of intelligent and responsive super amphiphilic molecules. Recent studies have found that the binding and unbinding of CB [8] with its guest molecules can be regulated by a variety of environmental stimuli, especially the remote regulation of the photostimuli response, which makes it attractive in host-guest chemistry. In this paper, the assembly of CB [8] ultraamphiphilic molecules and their photoresponse to drug loading were studied. 1. The photostimuli response of CB [8] ultraamphiphilic molecules to nano-vesicles (CB [8] and divalent violet molecules (MV2)) can be formed by the self-assembly of CB [8] superamphiphilic molecules. A stable water-soluble complex, On this basis, the complex can further combine with a trans-azobenzene molecule to form a more stable ternary complex, but when the azobenzene is stimulated by 365 nm ultraviolet light, the cis-azobenzene changes into cis-azobenzene. However, the cavity of cis azobenzene complex with purple essence CB [8] does not match in space structure and will be dissociated from the cavity of the complex. Purple derivatives with single modified Maleimide molecules can be designed as the first guest molecule. Using azobenzene derivatives with three hydrophobic tail chains as the second guest molecule, an ultraamphiphilic molecule with photostimulation response was constructed. The ultraamphiphilic molecule self-assembled in aqueous solution to form vesicle structure. On the basis of the dissolution of Rhodamine B and 5 ~ (6) carboxyfluorescein as drug molecules, the drug loading and release properties of the vesicles were studied in vitro. The surface modification of CB [8] ultraamphiphilic vesicles and their targeting drug loading properties have been achieved. Due to their hydrophilicity, Maleimide will be exposed to the surface of the vesicles, thus facilitating the modification of the vesicles. Therefore, the thiol targeted molecule can be designed to functionalize the vesicle in aqueous solution by the click reaction of mercapto and maleimide. Cys-i RGD and sulfhydryl modified hyaluronic acid were synthesized as target molecules to functionalize the vesicle surface to realize the rapid entry, selective delivery and controllable release of the vesicles coated with anticancer drugs. On the basis of previous studies on drug delivery and light-controlled release of the vesicle, cell viability test and apoptosis test were used to evaluate the efficacy of the drugs released in the vesicle cells. The release of anti-cancer drugs has been shown to inhibit cancer cells.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O641.3

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