本文主要研究内容
作者陈少青（2019）在《环境响应型脂质纳米载体的构建及其应用于肿瘤和炎症治疗的研究》一文中研究指出：脂质纳米粒作为近十几年来被广泛关注的纳米载体,在肿瘤的化疗治疗、基因治疗等方面的靶向递送中发挥着重要作用。脂质纳米载体具有长效、缓控释作用,其药物释放存在双相释放的特点,前期突释,后期缓释,在靶部位的缓慢释放可能影响了药效的发挥。环境响应型药物递释系统可在维持其体循环稳定的同时,特异性响应物理、化学、生物等内源性或外源性的刺激,实现靶部位的响应性药物递释,提高疗效并降低毒副作用。但目前通过这些手段进行改造的药物递释系统主要是结构有较大可调控改造性的聚合物胶束,由于脂质基本都为天然成分,可改造结构不多,少有具有敏感特性的脂质纳米粒的报道。本文设计了环境响应型脂质纳米载体用于肿瘤治疗,并在其基础上进行修饰设计了另外一种功能响应型脂质纳米载体用于炎症治疗,内容如下:首先利用含二硫键的二硫代二丙酸(DTPA)两端共价连接辛癸酸甘油酯(Gcc)和具有P-gp抑制作用的槲皮素(Qu)得到槲皮素-辛癸酸甘油酯脂质纳米粒(Qu-SS-Gcc LNPs),设计了具有还原敏感及P-糖蛋白(P-gp)抑制作用的脂质纳米给药系统。Qu-SS-Gcc LNPs的粒径大小约为87.8 nm。以化疗药物紫杉醇(PTX)为模型药物制备载紫杉醇槲皮素-辛癸酸甘油酯脂质纳米粒(PTX/Qu-SS-Gcc LNPs)。PTX/Qu-SS-Gcc LNPs的载药量和包封率分别为8.6%和93.5%。不同还原条件下体外药物释放和荧光共振能量转移率测定的结果表明Qu-SS-Gcc LNPs仅在10 mM GSH条件下能够实现载体快速裂解,迅速完全释放包载药物,差示扫描量热分析也检测到了 Qu的存在,说明Qu-SS-Gcc LNPs具有典型的还原响应性。以肝正常细胞L-02和鼠乳腺癌细胞4T1细胞分别作为正常细胞和肿瘤细胞模型。荧光共振能量转移结果显示PTX/Qu-SS-Gcc LNPs在肿瘤细胞中响应高浓度还原物质,载体裂解快速释放包载药物,同时裂解产生的Qu通过与P-gp位点的结合抑制P-gp,减少药物外排,具有优异的体外抑制肿瘤细胞生长效果。而PTX/Qu-SS-Gcc LNPs不会在正常细胞内发生载体大量裂解,毒性较低。以荷4T1原位瘤小鼠为模型动物,活体成像技术表明Qu-SS-Gcc LNPs静脉注射后在体内主要分布于肿瘤、肝和脾部位。模型动物药效学结果显示,与Taxol(?)和非还原敏感脂质纳米制剂载紫杉醇单甘脂固体脂质纳米粒相比,PTX/Qu-SS-Gcc LNPs具有更好的抗肿瘤效果,抑瘤率能达到73.1%,生物安全性高。进一步的研究利用Qu-SS-Gcc LNPs中DTPA与Qu和Gcc共价连接的酯键具有酯酶敏感的特点,对其进行壳聚糖(CSO)表面修饰,设计了具有结肠靶向作用的环境响应型给药系统。以地塞米松为模型药物得到CSO修饰载地塞米松槲皮素-辛癸酸甘油酯脂质纳米粒(CSO/Dex/LNPs)用于溃疡性结肠炎的治疗。高效液相色谱法测定CSO/Dex/LNPs的包封率和载药量分别为93.1%和8.1%。体外释放结果显示Dex/LNPs和CSO/Dex/LNPs都有酯酶响应的特性,能够在含酯酶的人工肠液中快速释放药物。以人结肠癌细胞Caco-2细胞单层为肠细胞屏障模型,跨膜电阻值的测定和渗透实验结果表明CSO/Dex/LNPs脱去外壳后的Dex/LNPs对脂多糖(LPS)刺激的Caco-2细胞单层具有保护作用,同时能增加LPS刺激后的Caco-2细胞中E-钙黏蛋白的表达。酶联免疫分析法和Griess法考察Dex/LNPs对LPS刺激后的小鼠单核巨噬细胞白血病细胞Raw 264.7的抗炎作用,结果表明Dex/LNPs能显著降低LPS刺激后Raw 264.7中炎性因子TNF-α,IL-6和NO的表达。以C57BL/6小鼠构建结肠炎小鼠动物模型,体内分布结果显示CSO/LNPs具有结肠靶向作用,在结肠炎动物结肠部位有较强的的滞留能力。模型动物体内抗炎效果表明CSO/Dex/LNPs比游离Dex具有更好的抗炎作用,能减少结肠的萎缩和组织形态学的变化,增加结肠表面E-钙黏蛋白的表达,其结肠部位炎性因子TNF-α,IL-6及NO的表达分别是结肠炎小鼠的37.4%,35.5%和33.2%。本研究构建的还原敏感及P-gp抑制脂质纳米给药系统和在其基础上修饰后的结肠靶向酯酶敏感脂质纳米给药系统能够在分别在肿瘤部位和结肠炎症部位实现快速响应性释药,为环境响应型脂质纳米载体的构建与应用提供了新策略和新思路。
Abstract
zhi zhi na mi li zuo wei jin shi ji nian lai bei an fan guan zhu de na mi zai ti ,zai zhong liu de hua liao zhi liao 、ji yin zhi liao deng fang mian de ba xiang di song zhong fa hui zhao chong yao zuo yong 。zhi zhi na mi zai ti ju you chang xiao 、huan kong shi zuo yong ,ji yao wu shi fang cun zai shuang xiang shi fang de te dian ,qian ji tu shi ,hou ji huan shi ,zai ba bu wei de huan man shi fang ke neng ying xiang le yao xiao de fa hui 。huan jing xiang ying xing yao wu di shi ji tong ke zai wei chi ji ti xun huan wen ding de tong shi ,te yi xing xiang ying wu li 、hua xue 、sheng wu deng nei yuan xing huo wai yuan xing de ci ji ,shi xian ba bu wei de xiang ying xing yao wu di shi ,di gao liao xiao bing jiang di du fu zuo yong 。dan mu qian tong guo zhe xie shou duan jin hang gai zao de yao wu di shi ji tong zhu yao shi jie gou you jiao da ke diao kong gai zao xing de ju ge wu jiao shu ,you yu zhi zhi ji ben dou wei tian ran cheng fen ,ke gai zao jie gou bu duo ,shao you ju you min gan te xing de zhi zhi na mi li de bao dao 。ben wen she ji le huan jing xiang ying xing zhi zhi na mi zai ti yong yu zhong liu zhi liao ,bing zai ji ji chu shang jin hang xiu shi she ji le ling wai yi chong gong neng xiang ying xing zhi zhi na mi zai ti yong yu yan zheng zhi liao ,nei rong ru xia :shou xian li yong han er liu jian de er liu dai er bing suan (DTPA)liang duan gong jia lian jie xin gui suan gan you zhi (Gcc)he ju you P-gpyi zhi zuo yong de hu pi su (Qu)de dao hu pi su -xin gui suan gan you zhi zhi zhi na mi li (Qu-SS-Gcc LNPs),she ji le ju you hai yuan min gan ji P-tang dan bai (P-gp)yi zhi zuo yong de zhi zhi na mi gei yao ji tong 。Qu-SS-Gcc LNPsde li jing da xiao yao wei 87.8 nm。yi hua liao yao wu zi sha chun (PTX)wei mo xing yao wu zhi bei zai zi sha chun hu pi su -xin gui suan gan you zhi zhi zhi na mi li (PTX/Qu-SS-Gcc LNPs)。PTX/Qu-SS-Gcc LNPsde zai yao liang he bao feng lv fen bie wei 8.6%he 93.5%。bu tong hai yuan tiao jian xia ti wai yao wu shi fang he ying guang gong zhen neng liang zhuai yi lv ce ding de jie guo biao ming Qu-SS-Gcc LNPsjin zai 10 mM GSHtiao jian xia neng gou shi xian zai ti kuai su lie jie ,xun su wan quan shi fang bao zai yao wu ,cha shi sao miao liang re fen xi ye jian ce dao le Qude cun zai ,shui ming Qu-SS-Gcc LNPsju you dian xing de hai yuan xiang ying xing 。yi gan zheng chang xi bao L-02he shu ru xian ai xi bao 4T1xi bao fen bie zuo wei zheng chang xi bao he zhong liu xi bao mo xing 。ying guang gong zhen neng liang zhuai yi jie guo xian shi PTX/Qu-SS-Gcc LNPszai zhong liu xi bao zhong xiang ying gao nong du hai yuan wu zhi ,zai ti lie jie kuai su shi fang bao zai yao wu ,tong shi lie jie chan sheng de Qutong guo yu P-gpwei dian de jie ge yi zhi P-gp,jian shao yao wu wai pai ,ju you you yi de ti wai yi zhi zhong liu xi bao sheng chang xiao guo 。er PTX/Qu-SS-Gcc LNPsbu hui zai zheng chang xi bao nei fa sheng zai ti da liang lie jie ,du xing jiao di 。yi he 4T1yuan wei liu xiao shu wei mo xing dong wu ,huo ti cheng xiang ji shu biao ming Qu-SS-Gcc LNPsjing mai zhu she hou zai ti nei zhu yao fen bu yu zhong liu 、gan he pi bu wei 。mo xing dong wu yao xiao xue jie guo xian shi ,yu Taxol(?)he fei hai yuan min gan zhi zhi na mi zhi ji zai zi sha chun chan gan zhi gu ti zhi zhi na mi li xiang bi ,PTX/Qu-SS-Gcc LNPsju you geng hao de kang zhong liu xiao guo ,yi liu lv neng da dao 73.1%,sheng wu an quan xing gao 。jin yi bu de yan jiu li yong Qu-SS-Gcc LNPszhong DTPAyu Quhe Gccgong jia lian jie de zhi jian ju you zhi mei min gan de te dian ,dui ji jin hang ke ju tang (CSO)biao mian xiu shi ,she ji le ju you jie chang ba xiang zuo yong de huan jing xiang ying xing gei yao ji tong 。yi de sai mi song wei mo xing yao wu de dao CSOxiu shi zai de sai mi song hu pi su -xin gui suan gan you zhi zhi zhi na mi li (CSO/Dex/LNPs)yong yu hui yang xing jie chang yan de zhi liao 。gao xiao ye xiang se pu fa ce ding CSO/Dex/LNPsde bao feng lv he zai yao liang fen bie wei 93.1%he 8.1%。ti wai shi fang jie guo xian shi Dex/LNPshe CSO/Dex/LNPsdou you zhi mei xiang ying de te xing ,neng gou zai han zhi mei de ren gong chang ye zhong kuai su shi fang yao wu 。yi ren jie chang ai xi bao Caco-2xi bao chan ceng wei chang xi bao bing zhang mo xing ,kua mo dian zu zhi de ce ding he shen tou shi yan jie guo biao ming CSO/Dex/LNPstuo qu wai ke hou de Dex/LNPsdui zhi duo tang (LPS)ci ji de Caco-2xi bao chan ceng ju you bao hu zuo yong ,tong shi neng zeng jia LPSci ji hou de Caco-2xi bao zhong E-gai nian dan bai de biao da 。mei lian mian yi fen xi fa he Griessfa kao cha Dex/LNPsdui LPSci ji hou de xiao shu chan he ju shi xi bao bai xie bing xi bao Raw 264.7de kang yan zuo yong ,jie guo biao ming Dex/LNPsneng xian zhe jiang di LPSci ji hou Raw 264.7zhong yan xing yin zi TNF-α,IL-6he NOde biao da 。yi C57BL/6xiao shu gou jian jie chang yan xiao shu dong wu mo xing ,ti nei fen bu jie guo xian shi CSO/LNPsju you jie chang ba xiang zuo yong ,zai jie chang yan dong wu jie chang bu wei you jiao jiang de de zhi liu neng li 。mo xing dong wu ti nei kang yan xiao guo biao ming CSO/Dex/LNPsbi you li Dexju you geng hao de kang yan zuo yong ,neng jian shao jie chang de wei su he zu zhi xing tai xue de bian hua ,zeng jia jie chang biao mian E-gai nian dan bai de biao da ,ji jie chang bu wei yan xing yin zi TNF-α,IL-6ji NOde biao da fen bie shi jie chang yan xiao shu de 37.4%,35.5%he 33.2%。ben yan jiu gou jian de hai yuan min gan ji P-gpyi zhi zhi zhi na mi gei yao ji tong he zai ji ji chu shang xiu shi hou de jie chang ba xiang zhi mei min gan zhi zhi na mi gei yao ji tong neng gou zai fen bie zai zhong liu bu wei he jie chang yan zheng bu wei shi xian kuai su xiang ying xing shi yao ,wei huan jing xiang ying xing zhi zhi na mi zai ti de gou jian yu ying yong di gong le xin ce lve he xin sai lu 。
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论文作者分别是来自浙江大学的陈少青，发表于刊物浙江大学2019-07-05论文，是一篇关于脂质纳米粒论文,还原敏感论文,抑制论文,酯酶敏感论文,结肠靶向论文,浙江大学2019-07-05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，资料来自浙江大学2019-07-05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。