本文主要研究内容
作者李忆卉（2019）在《羟乙基淀粉紫杉醇前药自组装纳米药物研究》一文中研究指出：恶性肿瘤是威胁人类生命健康的一类重大疾病。尽管抗肿瘤药物研究已经取得诸多进展,这些抗肿瘤药在临床使用时仍存在重大缺陷,如水溶性差、半衰期短、毒副作用大、无特异的肿瘤靶向性等。纳米载药系统由于其增强渗透-滞留(EPR)效应以及表面可修饰性,在提高药物生物利用度、增强肿瘤靶向及减小副作用等方面具有重要作用。特别是随着精准医疗的提出,纳米载药系统由于其可负载分子的多样性而成为实现肿瘤诊断和治疗一体化的重要工具。传统的纳米药物通常以纳米颗粒为载体,通过亲疏水作用、静电作用、范德华力等分子间弱相互作用将治疗性药物包载于其中。然而,这一类基于药物-载体非共价键相互作用的纳米药物仍存在制备工艺复杂、贮存及体内输送时药物易泄漏、共递送纳米粒载药量均一性差等多种不足。具有自组装能力的高分子前药为解决上述问题提供了新的机遇。这一类纳米载药系统基于共价键偶联的两亲性高分子前药。一方面,高分子前药能够有效改善药物的溶解性,增加药物在体内的循环时间,从而提高药效并降低毒副作用。另一方面,两亲性高分子前药本身能作为药物递送载体,可进一步以非共价键相互作用负载其它诊疗剂,从而构建结构简单但功能多样化的共输送系统,并能实现结构可控和载药、释药可控。尽管具有自组装能力的高分子前药在构建用于肿瘤诊疗一体化的复合型载药系统中具有重要的价值和发展前景,但在高分子前药自组装载药系统的设计中,仍存在一些亟待解决的问题:(1)如何选取合适的高分子,使其既能有效改善药物的动力学行为,又具有良好的生物相容性,从而更有利于临床转化;(2)如何选取合适的诊疗分子,通过尽可能简单的组分实现多样化的功能。针对上述问题,结合我们团队在代血浆中分子量羟乙基淀粉的工作基础,本文设计了一种基于羟乙基淀粉紫杉醇前药的自组装纳米粒(HES-SS-PTX NPs),并将其用于乳腺癌诊断和治疗。羟乙基淀粉优越的水溶性能有效解决紫杉醇的难溶问题,其良好的生物相容性也增加了载药系统的安全性。特别地,利用羟乙基淀粉的可降解性可使纳米颗粒在体内循环过程中逐渐变小,从而实现肿瘤的深部穿透。此外,本文引入二硫键连接臂,让紫杉醇能够在肿瘤细胞内高还原性条件下从纳米粒中释放,发挥抗肿瘤药效。进一步地,本文将一种多功能近红外荧光分子DiR负载于HES-SS-PTX NPs疏水核心中,制备了具有多功能的智能型纳米药物。该纳米药物能利用DiR荧光的聚集淬灭效应和恢复动态监测紫杉醇的释放行为,同时利用DiR的近红外吸收和光热转换能力实现荧光-光声双模态成像及化疗-光热抗肿瘤综合治疗。主要研究内容和结论如下:(1)酶-还原双重响应型羟乙基淀粉紫杉醇前药自组装纳米粒的构建及其在乳腺癌治疗中的应用。本章通过超声-高压均质两步乳化法制备了基于羟乙基淀粉紫杉醇前药的自组装纳米粒(HES-SS-PTX NPs)。HES-SS-PTX NPs显著改善了紫杉醇的水溶性,具有核-壳型结构,粒径约160 nm。该纳米粒的HES外壳能在α-淀粉酶催化下降解,粒径减小,进而增强了纳米粒的肿瘤深部穿透能力。在还原剂作用下,前药上的二硫键断裂,释放出游离PTX,从而能特异杀伤胞内高GSH水平的肿瘤细胞。药物动力学及组织分布研究表明,静脉给药后,HES-SS-PTX NPs半衰期显著高于市售紫杉醇注射液(Taxol~?),并能通过EPR效应被动靶向至肿瘤部位,呈现出更显著的体内抗肿瘤效果。(2)载DiR羟乙基淀粉紫杉醇前药自组装载药系统的构建及其药物示踪行为研究。针对HES-SS-PTX NPs功能单一的问题,以HES-SS-PTX NPs为载体,负载近红外荧光分子DiR,构建了载DiR的羟乙基淀粉紫杉醇前药自组装纳米粒(DHP)。与HES-SS-PTX NPs相比,负载DiR后纳米粒尺寸无明显变化,但疏水核变大。位于内核的DiR产生聚集诱导荧光淬灭(ACQ)现象;当DHP纳米粒处于高还原性条件时,二硫键断裂,释放PTX,PTX构成的疏水核被破坏,DiR聚集体解组装后释放出游离DiR,荧光恢复。改变胞内GSH浓度时,DHP纳米粒荧光强度变化与细胞杀伤作用呈正相关。基于上述特性,DHP纳米粒荧光可用于示踪胞内药物的释放及对肿瘤细胞的杀伤作用。(3)载DiR羟乙基淀粉紫杉醇前药自组装载药系统用于体内双模态成像及化疗-光热抗肿瘤作用研究。基于DiR具有近红外吸收及光热转换的特性,考察DHP纳米粒荧光-光声双模态成像能力,以及利用其光热效应进行化疗-光热抗肿瘤综合治疗的效果。DHP纳米粒在近红外激光照射下,光热转换效率显著高于游离光敏剂DiR,并可使静脉注射DHP纳米粒的小鼠肿瘤部位升温至约43°C。在成像功能上,DHP纳米粒近红外荧光成像灵敏度显著高于游离DiR探针,在瘤内产生的光声信号分辨率和信噪比高,能清晰观察到肿瘤的轮廓。因此,DHP纳米粒可应用于肿瘤荧光-光声双模态成像。此外,利用DHP纳米粒进行的化疗-光热治疗具有增强的综合抑瘤效果。综上,本文构建了一种基于羟乙基淀粉紫杉醇前药的酶-还原双重响应型自组装纳米载药系统,并利用这一自组装体负载多功能分子DiR,应用于肿瘤的诊疗。这些研究有望为更好实现药物共输送和诊疗一体化提供新的思路。
Abstract
e xing zhong liu shi wei xie ren lei sheng ming jian kang de yi lei chong da ji bing 。jin guan kang zhong liu yao wu yan jiu yi jing qu de zhu duo jin zhan ,zhe xie kang zhong liu yao zai lin chuang shi yong shi reng cun zai chong da que xian ,ru shui rong xing cha 、ban cui ji duan 、du fu zuo yong da 、mo te yi de zhong liu ba xiang xing deng 。na mi zai yao ji tong you yu ji zeng jiang shen tou -zhi liu (EPR)xiao ying yi ji biao mian ke xiu shi xing ,zai di gao yao wu sheng wu li yong du 、zeng jiang zhong liu ba xiang ji jian xiao fu zuo yong deng fang mian ju you chong yao zuo yong 。te bie shi sui zhao jing zhun yi liao de di chu ,na mi zai yao ji tong you yu ji ke fu zai fen zi de duo yang xing er cheng wei shi xian zhong liu zhen duan he zhi liao yi ti hua de chong yao gong ju 。chuan tong de na mi yao wu tong chang yi na mi ke li wei zai ti ,tong guo qin shu shui zuo yong 、jing dian zuo yong 、fan de hua li deng fen zi jian ruo xiang hu zuo yong jiang zhi liao xing yao wu bao zai yu ji zhong 。ran er ,zhe yi lei ji yu yao wu -zai ti fei gong jia jian xiang hu zuo yong de na mi yao wu reng cun zai zhi bei gong yi fu za 、zhu cun ji ti nei shu song shi yao wu yi xie lou 、gong di song na mi li zai yao liang jun yi xing cha deng duo chong bu zu 。ju you zi zu zhuang neng li de gao fen zi qian yao wei jie jue shang shu wen ti di gong le xin de ji yu 。zhe yi lei na mi zai yao ji tong ji yu gong jia jian ou lian de liang qin xing gao fen zi qian yao 。yi fang mian ,gao fen zi qian yao neng gou you xiao gai shan yao wu de rong jie xing ,zeng jia yao wu zai ti nei de xun huan shi jian ,cong er di gao yao xiao bing jiang di du fu zuo yong 。ling yi fang mian ,liang qin xing gao fen zi qian yao ben shen neng zuo wei yao wu di song zai ti ,ke jin yi bu yi fei gong jia jian xiang hu zuo yong fu zai ji ta zhen liao ji ,cong er gou jian jie gou jian chan dan gong neng duo yang hua de gong shu song ji tong ,bing neng shi xian jie gou ke kong he zai yao 、shi yao ke kong 。jin guan ju you zi zu zhuang neng li de gao fen zi qian yao zai gou jian yong yu zhong liu zhen liao yi ti hua de fu ge xing zai yao ji tong zhong ju you chong yao de jia zhi he fa zhan qian jing ,dan zai gao fen zi qian yao zi zu zhuang zai yao ji tong de she ji zhong ,reng cun zai yi xie ji dai jie jue de wen ti :(1)ru he shua qu ge kuo de gao fen zi ,shi ji ji neng you xiao gai shan yao wu de dong li xue hang wei ,you ju you liang hao de sheng wu xiang rong xing ,cong er geng you li yu lin chuang zhuai hua ;(2)ru he shua qu ge kuo de zhen liao fen zi ,tong guo jin ke neng jian chan de zu fen shi xian duo yang hua de gong neng 。zhen dui shang shu wen ti ,jie ge wo men tuan dui zai dai xie jiang zhong fen zi liang qiang yi ji dian fen de gong zuo ji chu ,ben wen she ji le yi chong ji yu qiang yi ji dian fen zi sha chun qian yao de zi zu zhuang na mi li (HES-SS-PTX NPs),bing jiang ji yong yu ru xian ai zhen duan he zhi liao 。qiang yi ji dian fen you yue de shui rong xing neng you xiao jie jue zi sha chun de nan rong wen ti ,ji liang hao de sheng wu xiang rong xing ye zeng jia le zai yao ji tong de an quan xing 。te bie de ,li yong qiang yi ji dian fen de ke jiang jie xing ke shi na mi ke li zai ti nei xun huan guo cheng zhong zhu jian bian xiao ,cong er shi xian zhong liu de shen bu chuan tou 。ci wai ,ben wen yin ru er liu jian lian jie bei ,rang zi sha chun neng gou zai zhong liu xi bao nei gao hai yuan xing tiao jian xia cong na mi li zhong shi fang ,fa hui kang zhong liu yao xiao 。jin yi bu de ,ben wen jiang yi chong duo gong neng jin gong wai ying guang fen zi DiRfu zai yu HES-SS-PTX NPsshu shui he xin zhong ,zhi bei le ju you duo gong neng de zhi neng xing na mi yao wu 。gai na mi yao wu neng li yong DiRying guang de ju ji cui mie xiao ying he hui fu dong tai jian ce zi sha chun de shi fang hang wei ,tong shi li yong DiRde jin gong wai xi shou he guang re zhuai huan neng li shi xian ying guang -guang sheng shuang mo tai cheng xiang ji hua liao -guang re kang zhong liu zeng ge zhi liao 。zhu yao yan jiu nei rong he jie lun ru xia :(1)mei -hai yuan shuang chong xiang ying xing qiang yi ji dian fen zi sha chun qian yao zi zu zhuang na mi li de gou jian ji ji zai ru xian ai zhi liao zhong de ying yong 。ben zhang tong guo chao sheng -gao ya jun zhi liang bu ru hua fa zhi bei le ji yu qiang yi ji dian fen zi sha chun qian yao de zi zu zhuang na mi li (HES-SS-PTX NPs)。HES-SS-PTX NPsxian zhe gai shan le zi sha chun de shui rong xing ,ju you he -ke xing jie gou ,li jing yao 160 nm。gai na mi li de HESwai ke neng zai α-dian fen mei cui hua xia jiang jie ,li jing jian xiao ,jin er zeng jiang le na mi li de zhong liu shen bu chuan tou neng li 。zai hai yuan ji zuo yong xia ,qian yao shang de er liu jian duan lie ,shi fang chu you li PTX,cong er neng te yi sha shang bao nei gao GSHshui ping de zhong liu xi bao 。yao wu dong li xue ji zu zhi fen bu yan jiu biao ming ,jing mai gei yao hou ,HES-SS-PTX NPsban cui ji xian zhe gao yu shi shou zi sha chun zhu she ye (Taxol~?),bing neng tong guo EPRxiao ying bei dong ba xiang zhi zhong liu bu wei ,cheng xian chu geng xian zhe de ti nei kang zhong liu xiao guo 。(2)zai DiRqiang yi ji dian fen zi sha chun qian yao zi zu zhuang zai yao ji tong de gou jian ji ji yao wu shi zong hang wei yan jiu 。zhen dui HES-SS-PTX NPsgong neng chan yi de wen ti ,yi HES-SS-PTX NPswei zai ti ,fu zai jin gong wai ying guang fen zi DiR,gou jian le zai DiRde qiang yi ji dian fen zi sha chun qian yao zi zu zhuang na mi li (DHP)。yu HES-SS-PTX NPsxiang bi ,fu zai DiRhou na mi li che cun mo ming xian bian hua ,dan shu shui he bian da 。wei yu nei he de DiRchan sheng ju ji you dao ying guang cui mie (ACQ)xian xiang ;dang DHPna mi li chu yu gao hai yuan xing tiao jian shi ,er liu jian duan lie ,shi fang PTX,PTXgou cheng de shu shui he bei po huai ,DiRju ji ti jie zu zhuang hou shi fang chu you li DiR,ying guang hui fu 。gai bian bao nei GSHnong du shi ,DHPna mi li ying guang jiang du bian hua yu xi bao sha shang zuo yong cheng zheng xiang guan 。ji yu shang shu te xing ,DHPna mi li ying guang ke yong yu shi zong bao nei yao wu de shi fang ji dui zhong liu xi bao de sha shang zuo yong 。(3)zai DiRqiang yi ji dian fen zi sha chun qian yao zi zu zhuang zai yao ji tong yong yu ti nei shuang mo tai cheng xiang ji hua liao -guang re kang zhong liu zuo yong yan jiu 。ji yu DiRju you jin gong wai xi shou ji guang re zhuai huan de te xing ,kao cha DHPna mi li ying guang -guang sheng shuang mo tai cheng xiang neng li ,yi ji li yong ji guang re xiao ying jin hang hua liao -guang re kang zhong liu zeng ge zhi liao de xiao guo 。DHPna mi li zai jin gong wai ji guang zhao she xia ,guang re zhuai huan xiao lv xian zhe gao yu you li guang min ji DiR,bing ke shi jing mai zhu she DHPna mi li de xiao shu zhong liu bu wei sheng wen zhi yao 43°C。zai cheng xiang gong neng shang ,DHPna mi li jin gong wai ying guang cheng xiang ling min du xian zhe gao yu you li DiRtan zhen ,zai liu nei chan sheng de guang sheng xin hao fen bian lv he xin zao bi gao ,neng qing xi guan cha dao zhong liu de lun kuo 。yin ci ,DHPna mi li ke ying yong yu zhong liu ying guang -guang sheng shuang mo tai cheng xiang 。ci wai ,li yong DHPna mi li jin hang de hua liao -guang re zhi liao ju you zeng jiang de zeng ge yi liu xiao guo 。zeng shang ,ben wen gou jian le yi chong ji yu qiang yi ji dian fen zi sha chun qian yao de mei -hai yuan shuang chong xiang ying xing zi zu zhuang na mi zai yao ji tong ,bing li yong zhe yi zi zu zhuang ti fu zai duo gong neng fen zi DiR,ying yong yu zhong liu de zhen liao 。zhe xie yan jiu you wang wei geng hao shi xian yao wu gong shu song he zhen liao yi ti hua di gong xin de sai lu 。
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论文详细介绍
论文作者分别是来自华中科技大学的李忆卉，发表于刊物华中科技大学2019-10-11论文，是一篇关于羟乙基淀粉论文,紫杉醇论文,高分子前药论文,刺激响应性论文,药物递送系统论文,诊疗一体化论文,华中科技大学2019-10-11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，资料来自华中科技大学2019-10-11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：羟乙基淀粉论文; 紫杉醇论文; 高分子前药论文; 刺激响应性论文; 药物递送系统论文; 诊疗一体化论文; 华中科技大学2019-10-11论文;