本文主要研究内容
作者邓荣（2019）在《多功能纳米粒子在癌症的SERS检测和精准治疗中的应用》一文中研究指出：目前,癌症依旧是威胁人类健康的一大杀手,攻克癌症已经是迫在眉睫的任务。虽然传统的癌症治疗方式,如,手术、化疗、放疗等可以有效的杀死肿瘤细胞、抑制肿瘤的转移,但是癌症的治愈率仍然很低。导致该现状主要的原因有:癌细胞未能及时被发现和诊断;化疗小分子药物的靶向性差,癌细胞未被彻底清除;引起疾病发生的机制不明,无法实现个性化的治疗;人体耐药性产生引起的药物疗效下降等。因此,为了提高癌症患者的生存率,开发更加灵敏、高效的诊疗手段极其重要。随着纳米技术的发展,纳米医学的兴起,越来越多新颖的治疗理念和治疗方法被运用到癌症的诊治中。其中,纳米粒子作为纳米医学重要的组成部分得到了极大的开发和利用,在癌症的早期诊断、精准治疗或新型诊疗一体化平台的构建中发挥着重要的作用。在本论文中,我们以实现癌症的灵敏检测和精准治疗为中心,针对癌症治疗过程中存在的难题,开发了两种超灵敏SERS(Surface Enhanced Raman Spectroscopy)纳米探针和两种多重靶向纳米载药体系,进一步实现了对癌细胞的靶向识别、揭示了靶向复合药物在癌细胞在核内的作用机制、通过调控表观遗传通路中异常基因的表达克服了白血病细胞的耐药性,实现了白血病的精准治疗。主要研究内容如下:1.由于唾液酸在癌细胞表面通常都处于过度表达水平,因此,它已经成为癌症早期诊断的一种重要生物标志物。为了显著放大唾液酸在癌细胞和正常细胞表面的表达差异,在本章中,基于拉曼信标分子4-巯基苯硼酸(MPBA)对唾液酸的靶向识别能力,我们以葡萄糖为桥连分子诱导MPBA修饰的Ag NPs的可控聚集,制备了一种低细胞毒性、高灵敏度的SERS纳米探针(glucose-MPBA@Ag NPs)用于癌细胞的靶向识别。在聚集的glucose-MPBA@Ag NPs纳米结构中形成了三维SERS热点效应,其SERS信号增强能力是单分散MPBA@Ag NPs的10倍以上。更重要的是,glucose-MPBA@Ag NPs间接地将两种细胞表面唾液酸表达量差异放大了5-7倍,提高了癌细胞检测的灵敏度,为肿瘤的早期诊断提供一种新的方法。2.药物在体内能否顺利地到达肿瘤区域决定了药物的治疗效果。目前,为了提高药物的传输效率,减少药物的非特异性作用,越来越多的靶向载体用于小分子药物的传递,但是,这种靶向复合药物的作用机制却很少被研究。在本章中,我们首先构筑了靶向复合药物TLS11a-GC-Dox,然后结合SERS技术和荧光暗场成像,利用核靶向SERS纳米粒子对靶向药物(TLS11a-GC-Dox)的作用过程进行实时光谱监测。通过分析细胞核内生物分子的SERS光谱以及细胞形貌的变化可以推测出,随着Dox的逐渐释放,细胞核内蛋白和DNA的结构均发生了显著的变化,这种变化影响细胞的正常分裂和增殖。这是首次在分子层次分析靶向复合药物的作用过程。3.表观遗传异常是白血病发生发展的重要原因。在本章中,通过对急性髓性白血病(AML)细胞中mi RNA的表达水平进行分析,我们发现mi R-221在AML细胞中显著过度表达且mi R-221参与的NCL/mi R-221/NF?B/DNMT1信号通路作为一种新的表观遗传通路促进了AML白血病发生和发展。基于此机制,我们制备了具有细胞核靶向、同时负载两种基因药物anti-221和AS1411的多功能金纳米粒子NPs N-AS1411/a221用于调控NCL/mi R-221/NF?B/DNMT1的表达。AS1411和anti-221的协同作用从根源上抑制了NCL与mi R-221的过度表达,同时激活了抑癌基因p27kip1和p15ink4b,有效的减缓白血病细胞的增殖速度。动物模型实验也证明NPs N-AS1411/a221可以通过抑制表观遗传通路NCL/mi R-221/NF?B/DNMT1的表达,实现对白血病的精准治疗。总之,我们的研究结果表明,靶向纳米药物体系为临床上白血病的治愈提供了更多的可能。4.白血病难以攻克的一大主因是白血病细胞会对化疗药物产生耐药性。在本章中,我们发现并证明在耐Dox的白血病细胞K562DR中,mi R-221与P-gp的表达均被激活,且二者之间具有显著的正相关性。基于此机制,我们设计合成了同时载有AS1411,anti-221和Dox三种药物的多功能金纳米粒子(NPs FA-AS1411/Dox/a221)。NPs FA-AS1411/Dox/a221作用于耐药细胞后显著下调了mi R-221以及mi R-221介导的DNMT1和P-gp的表达,激活抑癌基因p27kip1和p15ink4b,有效克服K562DR细胞的耐药性,提高了白血病治疗效果。此外,我们进一步利用NPs FA-AS1411/Dox/a221作用于耐药、复发型白血病患者的原代细胞,结果表明,病人原代细胞对阿霉素的敏感度显著提高,这也证明了新型的纳米载药体系可以成功逆转临床模型中白血病细胞的耐药性。
Abstract
mu qian ,ai zheng yi jiu shi wei xie ren lei jian kang de yi da sha shou ,gong ke ai zheng yi jing shi pai zai mei jie de ren wu 。sui ran chuan tong de ai zheng zhi liao fang shi ,ru ,shou shu 、hua liao 、fang liao deng ke yi you xiao de sha si zhong liu xi bao 、yi zhi zhong liu de zhuai yi ,dan shi ai zheng de zhi yu lv reng ran hen di 。dao zhi gai xian zhuang zhu yao de yuan yin you :ai xi bao wei neng ji shi bei fa xian he zhen duan ;hua liao xiao fen zi yao wu de ba xiang xing cha ,ai xi bao wei bei che de qing chu ;yin qi ji bing fa sheng de ji zhi bu ming ,mo fa shi xian ge xing hua de zhi liao ;ren ti nai yao xing chan sheng yin qi de yao wu liao xiao xia jiang deng 。yin ci ,wei le di gao ai zheng huan zhe de sheng cun lv ,kai fa geng jia ling min 、gao xiao de zhen liao shou duan ji ji chong yao 。sui zhao na mi ji shu de fa zhan ,na mi yi xue de xing qi ,yue lai yue duo xin ying de zhi liao li nian he zhi liao fang fa bei yun yong dao ai zheng de zhen zhi zhong 。ji zhong ,na mi li zi zuo wei na mi yi xue chong yao de zu cheng bu fen de dao le ji da de kai fa he li yong ,zai ai zheng de zao ji zhen duan 、jing zhun zhi liao huo xin xing zhen liao yi ti hua ping tai de gou jian zhong fa hui zhao chong yao de zuo yong 。zai ben lun wen zhong ,wo men yi shi xian ai zheng de ling min jian ce he jing zhun zhi liao wei zhong xin ,zhen dui ai zheng zhi liao guo cheng zhong cun zai de nan ti ,kai fa le liang chong chao ling min SERS(Surface Enhanced Raman Spectroscopy)na mi tan zhen he liang chong duo chong ba xiang na mi zai yao ti ji ,jin yi bu shi xian le dui ai xi bao de ba xiang shi bie 、jie shi le ba xiang fu ge yao wu zai ai xi bao zai he nei de zuo yong ji zhi 、tong guo diao kong biao guan wei chuan tong lu zhong yi chang ji yin de biao da ke fu le bai xie bing xi bao de nai yao xing ,shi xian le bai xie bing de jing zhun zhi liao 。zhu yao yan jiu nei rong ru xia :1.you yu tuo ye suan zai ai xi bao biao mian tong chang dou chu yu guo du biao da shui ping ,yin ci ,ta yi jing cheng wei ai zheng zao ji zhen duan de yi chong chong yao sheng wu biao zhi wu 。wei le xian zhe fang da tuo ye suan zai ai xi bao he zheng chang xi bao biao mian de biao da cha yi ,zai ben zhang zhong ,ji yu la man xin biao fen zi 4-qiu ji ben peng suan (MPBA)dui tuo ye suan de ba xiang shi bie neng li ,wo men yi pu tao tang wei qiao lian fen zi you dao MPBAxiu shi de Ag NPsde ke kong ju ji ,zhi bei le yi chong di xi bao du xing 、gao ling min du de SERSna mi tan zhen (glucose-MPBA@Ag NPs)yong yu ai xi bao de ba xiang shi bie 。zai ju ji de glucose-MPBA@Ag NPsna mi jie gou zhong xing cheng le san wei SERSre dian xiao ying ,ji SERSxin hao zeng jiang neng li shi chan fen san MPBA@Ag NPsde 10bei yi shang 。geng chong yao de shi ,glucose-MPBA@Ag NPsjian jie de jiang liang chong xi bao biao mian tuo ye suan biao da liang cha yi fang da le 5-7bei ,di gao le ai xi bao jian ce de ling min du ,wei zhong liu de zao ji zhen duan di gong yi chong xin de fang fa 。2.yao wu zai ti nei neng fou shun li de dao da zhong liu ou yu jue ding le yao wu de zhi liao xiao guo 。mu qian ,wei le di gao yao wu de chuan shu xiao lv ,jian shao yao wu de fei te yi xing zuo yong ,yue lai yue duo de ba xiang zai ti yong yu xiao fen zi yao wu de chuan di ,dan shi ,zhe chong ba xiang fu ge yao wu de zuo yong ji zhi que hen shao bei yan jiu 。zai ben zhang zhong ,wo men shou xian gou zhu le ba xiang fu ge yao wu TLS11a-GC-Dox,ran hou jie ge SERSji shu he ying guang an chang cheng xiang ,li yong he ba xiang SERSna mi li zi dui ba xiang yao wu (TLS11a-GC-Dox)de zuo yong guo cheng jin hang shi shi guang pu jian ce 。tong guo fen xi xi bao he nei sheng wu fen zi de SERSguang pu yi ji xi bao xing mao de bian hua ke yi tui ce chu ,sui zhao Doxde zhu jian shi fang ,xi bao he nei dan bai he DNAde jie gou jun fa sheng le xian zhe de bian hua ,zhe chong bian hua ying xiang xi bao de zheng chang fen lie he zeng shi 。zhe shi shou ci zai fen zi ceng ci fen xi ba xiang fu ge yao wu de zuo yong guo cheng 。3.biao guan wei chuan yi chang shi bai xie bing fa sheng fa zhan de chong yao yuan yin 。zai ben zhang zhong ,tong guo dui ji xing sui xing bai xie bing (AML)xi bao zhong mi RNAde biao da shui ping jin hang fen xi ,wo men fa xian mi R-221zai AMLxi bao zhong xian zhe guo du biao da ju mi R-221can yu de NCL/mi R-221/NF?B/DNMT1xin hao tong lu zuo wei yi chong xin de biao guan wei chuan tong lu cu jin le AMLbai xie bing fa sheng he fa zhan 。ji yu ci ji zhi ,wo men zhi bei le ju you xi bao he ba xiang 、tong shi fu zai liang chong ji yin yao wu anti-221he AS1411de duo gong neng jin na mi li zi NPs N-AS1411/a221yong yu diao kong NCL/mi R-221/NF?B/DNMT1de biao da 。AS1411he anti-221de xie tong zuo yong cong gen yuan shang yi zhi le NCLyu mi R-221de guo du biao da ,tong shi ji huo le yi ai ji yin p27kip1he p15ink4b,you xiao de jian huan bai xie bing xi bao de zeng shi su du 。dong wu mo xing shi yan ye zheng ming NPs N-AS1411/a221ke yi tong guo yi zhi biao guan wei chuan tong lu NCL/mi R-221/NF?B/DNMT1de biao da ,shi xian dui bai xie bing de jing zhun zhi liao 。zong zhi ,wo men de yan jiu jie guo biao ming ,ba xiang na mi yao wu ti ji wei lin chuang shang bai xie bing de zhi yu di gong le geng duo de ke neng 。4.bai xie bing nan yi gong ke de yi da zhu yin shi bai xie bing xi bao hui dui hua liao yao wu chan sheng nai yao xing 。zai ben zhang zhong ,wo men fa xian bing zheng ming zai nai Doxde bai xie bing xi bao K562DRzhong ,mi R-221yu P-gpde biao da jun bei ji huo ,ju er zhe zhi jian ju you xian zhe de zheng xiang guan xing 。ji yu ci ji zhi ,wo men she ji ge cheng le tong shi zai you AS1411,anti-221he Doxsan chong yao wu de duo gong neng jin na mi li zi (NPs FA-AS1411/Dox/a221)。NPs FA-AS1411/Dox/a221zuo yong yu nai yao xi bao hou xian zhe xia diao le mi R-221yi ji mi R-221jie dao de DNMT1he P-gpde biao da ,ji huo yi ai ji yin p27kip1he p15ink4b,you xiao ke fu K562DRxi bao de nai yao xing ,di gao le bai xie bing zhi liao xiao guo 。ci wai ,wo men jin yi bu li yong NPs FA-AS1411/Dox/a221zuo yong yu nai yao 、fu fa xing bai xie bing huan zhe de yuan dai xi bao ,jie guo biao ming ,bing ren yuan dai xi bao dui a mei su de min gan du xian zhe di gao ,zhe ye zheng ming le xin xing de na mi zai yao ti ji ke yi cheng gong ni zhuai lin chuang mo xing zhong bai xie bing xi bao de nai yao xing 。
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论文作者分别是来自吉林大学的邓荣，发表于刊物吉林大学2019-06-25论文，是一篇关于纳米医学论文,多功能纳米粒子论文,癌症论文,白血病论文,表观遗传学论文,吉林大学2019-06-25论文的文章。本文可供学术参考使用，各位学者可以免费参考阅读下载，文章观点不代表本站观点，资料来自吉林大学2019-06-25论文网站，若本站收录的文献无意侵犯了您的著作版权，请联系我们删除。
标签：纳米医学论文; 多功能纳米粒子论文; 癌症论文; 白血病论文; 表观遗传学论文; 吉林大学2019-06-25论文;