硒铂配位组装体：通过活性氧选择性杀死癌细胞

发布时间：2018-11-05 20:44

【摘要】：在科技飞速发展的今天,癌症仍然是威胁人类健康的最大杀手,发展新型抗癌药物极为重要。其中,尤为关键的是提高药物的选择性。科学家尝试使用药物载体来运输药物,包括聚合物胶束、聚合物囊泡、纳米粒子等,利用肿瘤组织的增强渗透滞留效应以达到靶向运输的目的。然而,由于在血液循环中的不稳定性以及肿瘤组织附近复杂的微环境,载体运输并没能实现在保持药物抗癌活性同时降低副作用的目的。除此之外,科学家也尝试用已有抗癌药物的衍生物进行再开发,希望能得到更好的选择性和更好的疗效。然而,由于在抗癌机理上并没有创新,基于已有抗癌药物的衍生物即使在杀伤力上相比原药有一定提升,却依然无法在选择性上有很大提高。硒作为人体必需的微量元素,有着独特的氧化还原特性,在人体内发挥着调节氧化还原平衡的重要作用。研究表明硒在预防癌症方面扮演了重要角色。在生物体内,硒具有双重作用,在低浓度下它可以抑制活性氧基团的生成,而高浓度下则可以诱导活性氧基团的产生。将硒和金属抗癌药物联合起来,有望提供解决增强药物选择性的新思路。在本论文中,我们合成了三臂含硒两亲性分子。此含硒分子表现出了对癌细胞的选择性,但缺乏足够的杀伤力。因此我们将此分子与顺铂配位,希望能够提高它的杀伤力,同时保留其选择性。结果表明含硒分子可以和铂进行配位,且形成1:1的配位体结构。通过诱导癌细胞产生过量活性氧,配位体可以有效地杀死多种癌细胞。同时由于配位体在正常细胞内产生的活性氧浓度较低,配位体对正常细胞的毒性也大大降低。由于这种配位体杀死癌细胞的机理不同于顺铂,它克服了癌细胞对顺铂的耐药性。在对顺铂有较强耐药性的癌细胞系中,配位体表现了远强于顺铂的杀伤力。含硒分子和顺铂的配位成功的提高了对癌细胞的选择性,同时表现出不同于顺铂的抗癌机理,克服了耐药性。我们希望含硒小分子在抗肿瘤方面有更广阔的应用.它不仅可以推广到除顺铂之外其他的铂系列抗肿瘤药物,还可应用在钌类钛类锗类等其他金属系列抗癌药物的改进中。硒和其他金属的配位提供了一种廉价而高效的实现选择性抗癌的途径,将给传统的金属抗癌药物带来新的活力。
[Abstract]:With the rapid development of science and technology, cancer is still the biggest killer threatening human health. It is very important to develop new anticancer drugs. Among them, the most important thing is to improve the selectivity of drugs. Scientists try to use drug carriers to transport drugs, including polymer micelles, polymer vesicles, nanoparticles, and so on, using the enhanced osmotic retention of tumor tissues for targeted transport. However, because of the instability in the blood circulation and the complex microenvironment near tumor tissue, carrier transport failed to achieve the goal of keeping the anticancer activity of the drug while reducing the side effects. In addition, scientists are trying to redevelop existing derivatives of anticancer drugs in the hope of better selectivity and better efficacy. However, because of the lack of innovation in anticancer mechanism, the derivatives based on existing anticancer drugs can not improve their selectivity even though they have a certain increase in killing power compared with the original drugs. Selenium, as a necessary trace element, has unique redox characteristics and plays an important role in regulating redox balance in human body. Studies have shown that selenium plays an important role in preventing cancer. Selenium can inhibit the formation of reactive oxygen group at low concentration and induce the production of active oxygen group at high concentration. The combination of selenium and metal anticancer drugs is expected to provide a new way to enhance drug selectivity. In this paper, we synthesized three-arm selenium-containing amphiphilic molecules. This selenium-containing molecule exhibits selectivity to cancer cells but lacks sufficient lethality. Therefore, we coordinate this molecule with cisplatin in the hope of improving its cytotoxicity while retaining its selectivity. The results show that the selenium molecule can coordinate with platinum and form a 1:1 ligand structure. By inducing cancer cells to produce excess reactive oxygen species, ligands can effectively kill a variety of cancer cells. At the same time, the toxicity of the ligands to normal cells was greatly reduced because of the low concentration of reactive oxygen species produced by the ligands in normal cells. Because the ligand kills cancer cells by a different mechanism than cisplatin, it overcomes the resistance of cancer cells to cisplatin. In cancer cell lines with strong resistance to cisplatin, the ligands are much more lethal than cisplatin. The coordination of selenium molecule and cisplatin improves the selectivity of cancer cells, and it also shows different anticancer mechanism from cisplatin and overcomes drug resistance. We hope that selenium-containing small molecules can be used more widely in anti-tumor. It can be applied not only to other platinum antitumor drugs but also to the improvement of ruthenium titanium germanium and other metal series anticancer drugs. The coordination of selenium and other metals provides a cheap and efficient way to achieve selective anticancer, which will bring new vitality to traditional metal anticancer drugs.
【学位授予单位】：清华大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914;O641.4

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