本文主要研究内容
作者陈路锋（2019）在《新型核-壳结构磁性介孔二氧化锆纳米颗粒的制备及其用于肿瘤磁靶向性CT/MRI双模态成像与药物递送的实验研究》一文中研究指出：目的:基于氧化铁的核-介孔壳状磁性纳米颗粒具有良好的生物安全性、磁共振成像功能、具有简便易行的物理性肿瘤磁靶向性功能、具有磁热疗功能,而且还具有较高的载药能力,已广泛应用于多个肿瘤诊治领域。目前常用的制备方法为“先核后壳法”,这种方法对合成壳所需的前驱物与磁核之间的界面化学特性要求较高,其形貌和大小主要受预先合成的氧化铁所影响,而且大部分MNPs仅具有单一磁共振成像功能。本研究提出一种新的“先壳后核法”合成策略用于核-介孔壳结构MNPs的制备,使用既具有较高载药能力又具有CT成像功能的中空介孔ZrO2纳米颗粒作为壳层,然后在ZrO2球内生长出磁核,构建一种新型的具有介孔壳层结构的磁性纳米颗粒。并通过体内实验与体外实验对其CT/MRI双模态成像功能、磁靶向性、载药释药性能进行评价,并通过对阿霉素的递送探讨其用于磁靶向性肿瘤治疗的效果。方法:1.使用模板法合成中空介孔二氧化锆纳米颗粒,通过强制渗透法在二氧化锆内装载二价铁盐和三价铁盐,然后根据化学共沉淀法的原理在二氧化锆的内部空间内生长出四氧化三铁纳米颗粒,然后进行表面PEG化修饰,得到磁性介孔二氧化锆纳米颗粒（M-MZNs）,并对其理化表征、CT/MRI成像性能、载药释药性能进行检测。2.使用不同浓度M-MZNs与HepG2进行孵育24小时和48小时,通过CCK-8法检测其细胞毒性。使用普鲁士蓝染色检测M-MZNs的细胞内吞情况及外磁场对内吞的影响,使用透射电镜验证细胞内吞。使用共聚焦荧光显微镜及流式细胞术检测M-MZNs-DOX在细胞内的DOX聚集情况。使用CCK-8法检测游离DOX、M-MZNs-DOX、M-MZNs-DOX+磁场等三种处理对HepG2细胞的杀伤作用。3.使用H22肝癌细胞系构建昆明小白鼠皮下瘤模型,分别于经瘤内注射M-MZNs-DOX前后进行CT扫描和MRI扫描,然后又使用经静脉注射途径给药,并设置磁靶向性组,分别于给药前和给药后3小时后进行CT扫描和MRI扫描。使用普鲁士蓝染色进行磁靶向性和生物分布评价。将15只荷瘤鼠分为5组,按照给药处理的不同分为五组,分别为:对照组、M-MZNs组、DOX组、M-MZNs-DOX组及M-MZNs-DOX加外磁场组,经静脉给药,每四天给药一次共四次。检测各组小鼠的体重、肿瘤生长情况,治疗结束后使用TUNEL染色进行组织学评价,使用HE染色进行安全性评价。结果:1.成功制备出Fe3O4@ZrO2,为多核-介孔壳结构,平均粒径约为155.23±7.10nm,Zeta电位为16.9mV,水合粒径为218.6nm。经PEG化修饰后,即M-MZNs,Zeta电位为-17.9mV,水合粒径231.4nm。M-MZNs呈超顺磁性,其饱和磁化强度为26.5emu/g。其比表面积为307.066 m2/g,介孔直径为3.803nm,介孔容积分别为0.783cm3/g。2.使用DOX进行载药和释药检测,载药率及包封率分别为,20.2%和49.5%,在pH=5.5的条件下DOX释放能力高于pH=7.2的条件,在50小时,前者的释放率>25%,而后者的释放率<15%.3.M-MZNs具有CT/MRI双模态成像功能,弛豫效率r2值为79.88mM/s。4.M-MZNs具有良好的细胞相容性,0.78-100μg/mL浓度范围内未造成明显的细胞抑制作用。5.与Hep G2细胞孵育4小时后,M-MZNs可以被细胞内吞,外磁场可以增加细胞内吞量。6.M-MZNs-DOX可以在细胞内释放DOX,各组的细胞内荧光强度分别为（×104）:对照组1.257±0.014,DOX组15.201±0.154,M-MZNs-DOX M-组:20.589±0.433,M-MZNs-DOX M+组:29.949±1.096。各组之间比较P值均小于0.05.7.M-MZNs-DOX可以明显抑制Hep G2细胞的增殖,外磁场可以提高对Hep G2细胞的抑制作用。8.经瘤内注射后,M-MZNs-DOX可以使肿瘤部位在CT图像上呈显著强化,而在MRI图像上肿瘤信号明显下降。经静脉注射M-MZNs-DOX纳米复合体可以使肿瘤部位的CT值上升,非磁靶向性组肿瘤部位CT值从44.35±4.35HU增高至53.67±3.66HU HU（P<0.05）,增高21.25±3.55%;而在磁靶向性组,CT值从42.70±2.80HU增高至61.39±1.90HU（P<0.05）,CT值增高44.03±6.18%.经静脉注射M-MZNs-DOX纳米复合体可以使肿瘤部位T2信号值减低,非磁靶向性组从1116.63±197.27下降至929.54±155.22,下降率为16.64±1.56%;而在磁靶向性组,从1141.59±81.95下降至795.54±120.20（P<0.05）,下降率为30.59±5.74%.9.普鲁士蓝染色结果显示,经静脉注射纳米药物后,肿瘤部位有明显的蓝染颗粒,而对照组没有蓝染颗粒。磁靶向组（M+）的蓝染颗粒明显多于非磁靶向组（M-）。蓝染颗粒主要位于肝和脾内,肺内亦可见少量蓝染颗粒,而脑、心、肾、肌肉等组织没有出现蓝染颗粒。10.治疗结束后,对照组肿瘤体积为4057.1±166.4mm3,M-MZNs组为4028±418.1mm3,与对照比较统计学差异（P>0.05）;DOX组为2833.7±376.7mm3,与对照组比较有统计学差异（P<0.05）;M-MZNs-DOX M-组为2021.8±265.7mm3,低于对照组和DOX组（P值均小于0.05）;M-MZNs-DOX M+组为1286.9±166.2mm3,低于M-MZNs-DOX M-组（P<0.05）。在整个治疗期间,各组小鼠体重逐渐增加,在各时间点均没有明显差异（P>0.05）。TUNEL染色结果显示各组凋亡细胞比率用对照进行标化后分别为,对照组:1.00±0.24;NPs组:1.10±0.27,与对照组比较无统计学差异（P>0.05）;DOX组:6.98±1.16,与对照组比较有统计学差异（P<0.05）;M-组:17.83±1.31,与对照组和DOX组比较均有统计学差异（P<0.05）;M+组:33.36±3.20,与对照组、DOX组和M-组比较均有统计学差异（P<0.05）。各组小鼠主要器官的HE染色结果显示,脑、心、肺、肝、脾、肾、肌肉等均未见到明显的组织学损伤。结论:本研究使用“先壳核后”的策略成功制备出具有介孔壳层与多磁核的新型多功能磁性纳米颗粒,即磁性介孔二氧化硅纳米颗粒M-MZNs。其具有良好的理化性能,可用于CT/MRI双模态成像,具有良好的载药能力,并可用于磁靶向性、pH敏感性阿霉素递送。体内实验证实M-MZNs-DOX可以实现磁靶向性肿瘤CT/MRI双模态成像及化疗,并且该纳米载药系统可以提高阿霉素的化疗效果,同时具有良好的生物安全性。本研究为新型MNPs的研制及其用于CT/MRI双模态影像引导下化疗提供了新的研究思路。
Abstract
mu de :ji yu yang hua tie de he -jie kong ke zhuang ci xing na mi ke li ju you liang hao de sheng wu an quan xing 、ci gong zhen cheng xiang gong neng 、ju you jian bian yi hang de wu li xing zhong liu ci ba xiang xing gong neng 、ju you ci re liao gong neng ,er ju hai ju you jiao gao de zai yao neng li ,yi an fan ying yong yu duo ge zhong liu zhen zhi ling yu 。mu qian chang yong de zhi bei fang fa wei “xian he hou ke fa ”,zhe chong fang fa dui ge cheng ke suo xu de qian qu wu yu ci he zhi jian de jie mian hua xue te xing yao qiu jiao gao ,ji xing mao he da xiao zhu yao shou yu xian ge cheng de yang hua tie suo ying xiang ,er ju da bu fen MNPsjin ju you chan yi ci gong zhen cheng xiang gong neng 。ben yan jiu di chu yi chong xin de “xian ke hou he fa ”ge cheng ce lve yong yu he -jie kong ke jie gou MNPsde zhi bei ,shi yong ji ju you jiao gao zai yao neng li you ju you CTcheng xiang gong neng de zhong kong jie kong ZrO2na mi ke li zuo wei ke ceng ,ran hou zai ZrO2qiu nei sheng chang chu ci he ,gou jian yi chong xin xing de ju you jie kong ke ceng jie gou de ci xing na mi ke li 。bing tong guo ti nei shi yan yu ti wai shi yan dui ji CT/MRIshuang mo tai cheng xiang gong neng 、ci ba xiang xing 、zai yao shi yao xing neng jin hang ping jia ,bing tong guo dui a mei su de di song tan tao ji yong yu ci ba xiang xing zhong liu zhi liao de xiao guo 。fang fa :1.shi yong mo ban fa ge cheng zhong kong jie kong er yang hua gao na mi ke li ,tong guo jiang zhi shen tou fa zai er yang hua gao nei zhuang zai er jia tie yan he san jia tie yan ,ran hou gen ju hua xue gong chen dian fa de yuan li zai er yang hua gao de nei bu kong jian nei sheng chang chu si yang hua san tie na mi ke li ,ran hou jin hang biao mian PEGhua xiu shi ,de dao ci xing jie kong er yang hua gao na mi ke li （M-MZNs）,bing dui ji li hua biao zheng 、CT/MRIcheng xiang xing neng 、zai yao shi yao xing neng jin hang jian ce 。2.shi yong bu tong nong du M-MZNsyu HepG2jin hang fu yo 24xiao shi he 48xiao shi ,tong guo CCK-8fa jian ce ji xi bao du xing 。shi yong pu lu shi lan ran se jian ce M-MZNsde xi bao nei tun qing kuang ji wai ci chang dui nei tun de ying xiang ,shi yong tou she dian jing yan zheng xi bao nei tun 。shi yong gong ju jiao ying guang xian wei jing ji liu shi xi bao shu jian ce M-MZNs-DOXzai xi bao nei de DOXju ji qing kuang 。shi yong CCK-8fa jian ce you li DOX、M-MZNs-DOX、M-MZNs-DOX+ci chang deng san chong chu li dui HepG2xi bao de sha shang zuo yong 。3.shi yong H22gan ai xi bao ji gou jian kun ming xiao bai shu pi xia liu mo xing ,fen bie yu jing liu nei zhu she M-MZNs-DOXqian hou jin hang CTsao miao he MRIsao miao ,ran hou you shi yong jing jing mai zhu she tu jing gei yao ,bing she zhi ci ba xiang xing zu ,fen bie yu gei yao qian he gei yao hou 3xiao shi hou jin hang CTsao miao he MRIsao miao 。shi yong pu lu shi lan ran se jin hang ci ba xiang xing he sheng wu fen bu ping jia 。jiang 15zhi he liu shu fen wei 5zu ,an zhao gei yao chu li de bu tong fen wei wu zu ,fen bie wei :dui zhao zu 、M-MZNszu 、DOXzu 、M-MZNs-DOXzu ji M-MZNs-DOXjia wai ci chang zu ,jing jing mai gei yao ,mei si tian gei yao yi ci gong si ci 。jian ce ge zu xiao shu de ti chong 、zhong liu sheng chang qing kuang ,zhi liao jie shu hou shi yong TUNELran se jin hang zu zhi xue ping jia ,shi yong HEran se jin hang an quan xing ping jia 。jie guo :1.cheng gong zhi bei chu Fe3O4@ZrO2,wei duo he -jie kong ke jie gou ,ping jun li jing yao wei 155.23±7.10nm,Zetadian wei wei 16.9mV,shui ge li jing wei 218.6nm。jing PEGhua xiu shi hou ,ji M-MZNs,Zetadian wei wei -17.9mV,shui ge li jing 231.4nm。M-MZNscheng chao shun ci xing ,ji bao he ci hua jiang du wei 26.5emu/g。ji bi biao mian ji wei 307.066 m2/g,jie kong zhi jing wei 3.803nm,jie kong rong ji fen bie wei 0.783cm3/g。2.shi yong DOXjin hang zai yao he shi yao jian ce ,zai yao lv ji bao feng lv fen bie wei ,20.2%he 49.5%,zai pH=5.5de tiao jian xia DOXshi fang neng li gao yu pH=7.2de tiao jian ,zai 50xiao shi ,qian zhe de shi fang lv >25%,er hou zhe de shi fang lv <15%.3.M-MZNsju you CT/MRIshuang mo tai cheng xiang gong neng ,chi yu xiao lv r2zhi wei 79.88mM/s。4.M-MZNsju you liang hao de xi bao xiang rong xing ,0.78-100μg/mLnong du fan wei nei wei zao cheng ming xian de xi bao yi zhi zuo yong 。5.yu Hep G2xi bao fu yo 4xiao shi hou ,M-MZNske yi bei xi bao nei tun ,wai ci chang ke yi zeng jia xi bao nei tun liang 。6.M-MZNs-DOXke yi zai xi bao nei shi fang DOX,ge zu de xi bao nei ying guang jiang du fen bie wei （×104）:dui zhao zu 1.257±0.014,DOXzu 15.201±0.154,M-MZNs-DOX M-zu :20.589±0.433,M-MZNs-DOX M+zu :29.949±1.096。ge zu zhi jian bi jiao Pzhi jun xiao yu 0.05.7.M-MZNs-DOXke yi ming xian yi zhi Hep G2xi bao de zeng shi ,wai ci chang ke yi di gao dui Hep G2xi bao de yi zhi zuo yong 。8.jing liu nei zhu she hou ,M-MZNs-DOXke yi shi zhong liu bu wei zai CTtu xiang shang cheng xian zhe jiang hua ,er zai MRItu xiang shang zhong liu xin hao ming xian xia jiang 。jing jing mai zhu she M-MZNs-DOXna mi fu ge ti ke yi shi zhong liu bu wei de CTzhi shang sheng ,fei ci ba xiang xing zu zhong liu bu wei CTzhi cong 44.35±4.35HUzeng gao zhi 53.67±3.66HU HU（P<0.05）,zeng gao 21.25±3.55%;er zai ci ba xiang xing zu ,CTzhi cong 42.70±2.80HUzeng gao zhi 61.39±1.90HU（P<0.05）,CTzhi zeng gao 44.03±6.18%.jing jing mai zhu she M-MZNs-DOXna mi fu ge ti ke yi shi zhong liu bu wei T2xin hao zhi jian di ,fei ci ba xiang xing zu cong 1116.63±197.27xia jiang zhi 929.54±155.22,xia jiang lv wei 16.64±1.56%;er zai ci ba xiang xing zu ,cong 1141.59±81.95xia jiang zhi 795.54±120.20（P<0.05）,xia jiang lv wei 30.59±5.74%.9.pu lu shi lan ran se jie guo xian shi ,jing jing mai zhu she na mi yao wu hou ,zhong liu bu wei you ming xian de lan ran ke li ,er dui zhao zu mei you lan ran ke li 。ci ba xiang zu （M+）de lan ran ke li ming xian duo yu fei ci ba xiang zu （M-）。lan ran ke li zhu yao wei yu gan he pi nei ,fei nei yi ke jian shao liang lan ran ke li ,er nao 、xin 、shen 、ji rou deng zu zhi mei you chu xian lan ran ke li 。10.zhi liao jie shu hou ,dui zhao zu zhong liu ti ji wei 4057.1±166.4mm3,M-MZNszu wei 4028±418.1mm3,yu dui zhao bi jiao tong ji xue cha yi （P>0.05）;DOXzu wei 2833.7±376.7mm3,yu dui zhao zu bi jiao you tong ji xue cha yi （P<0.05）;M-MZNs-DOX M-zu wei 2021.8±265.7mm3,di yu dui zhao zu he DOXzu （Pzhi jun xiao yu 0.05）;M-MZNs-DOX M+zu wei 1286.9±166.2mm3,di yu M-MZNs-DOX M-zu （P<0.05）。zai zheng ge zhi liao ji jian ,ge zu xiao shu ti chong zhu jian zeng jia ,zai ge shi jian dian jun mei you ming xian cha yi （P>0.05）。TUNELran se jie guo xian shi ge zu diao wang xi bao bi lv yong dui zhao jin hang biao hua hou fen bie wei ,dui zhao zu :1.00±0.24;NPszu :1.10±0.27,yu dui zhao zu bi jiao mo tong ji xue cha yi （P>0.05）;DOXzu :6.98±1.16,yu dui zhao zu bi jiao you tong ji xue cha yi （P<0.05）;M-zu :17.83±1.31,yu dui zhao zu he DOXzu bi jiao jun you tong ji xue cha yi （P<0.05）;M+zu :33.36±3.20,yu dui zhao zu 、DOXzu he M-zu bi jiao jun you tong ji xue cha yi （P<0.05）。ge zu xiao shu zhu yao qi guan de HEran se jie guo xian shi ,nao 、xin 、fei 、gan 、pi 、shen 、ji rou deng jun wei jian dao ming xian de zu zhi xue sun shang 。jie lun :ben yan jiu shi yong “xian ke he hou ”de ce lve cheng gong zhi bei chu ju you jie kong ke ceng yu duo ci he de xin xing duo gong neng ci xing na mi ke li ,ji ci xing jie kong er yang hua gui na mi ke li M-MZNs。ji ju you liang hao de li hua xing neng ,ke yong yu CT/MRIshuang mo tai cheng xiang ,ju you liang hao de zai yao neng li ,bing ke yong yu ci ba xiang xing 、pHmin gan xing a mei su di song 。ti nei shi yan zheng shi M-MZNs-DOXke yi shi xian ci ba xiang xing zhong liu CT/MRIshuang mo tai cheng xiang ji hua liao ,bing ju gai na mi zai yao ji tong ke yi di gao a mei su de hua liao xiao guo ,tong shi ju you liang hao de sheng wu an quan xing 。ben yan jiu wei xin xing MNPsde yan zhi ji ji yong yu CT/MRIshuang mo tai ying xiang yin dao xia hua liao di gong le xin de yan jiu sai lu 。
论文参考文献
论文详细介绍
论文作者分别是来自中国医科大学的陈路锋，发表于刊物中国医科大学2019-09-19论文，是一篇关于磁性纳米颗粒论文,二氧化锆论文,核壳结构论文,肿瘤论文,磁靶向论文,药物递送论文,中国医科大学2019-09-19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，资料来自中国医科大学2019-09-19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：磁性纳米颗粒论文; 二氧化锆论文; 核壳结构论文; 肿瘤论文; 磁靶向论文; 药物递送论文; 中国医科大学2019-09-19论文;