多功能介孔硅基纳米共载药体系的构建及其体外抗肿瘤作用初步研究

发布时间：2018-05-28 09:15

本文选题：介孔二氧化硅 + 磁靶向　；参考：《福建中医药大学》2017年硕士论文

【摘要】：肿瘤是现代社会威胁人类健康的重大疾病,化疗是肿瘤临床治疗的重要手段之一。新型肿瘤部位靶向和控释药物递送系统可将抗肿瘤药物更有效地转运到病灶部位,提高抗肿瘤效果,降低其全身性毒副作用,成为目前肿瘤治疗领域的研究热点。在本论文中我们以新型双孔道介孔硅球为基础,通过功能化设计构建合成了具有磁靶向、核磁成像能力和pH敏感释药功能的新型光敏剂与阿霉素共载药多功能纳米载药体系,并对其体外抗肿瘤作用进行了初步研究。此外,我们还合成了新型螺旋棒状介孔二氧化硅纳米材料并对其细胞摄取能力及细胞毒性进行了研究。因此本论文主要分为以下三部分:第一部分研究中,我们以正硅酸四乙酯(TEOS)为硅源、十六烷基三甲基溴化铵(CTAB)为模板剂、正己烷为扩孔剂,采用改性Stober法合成了具有核壳结构的双孔道介孔二氧化硅纳米球,并对其进行功能化设计,通过亲核取代修饰外部嵌合超顺磁Fe3O4,以DCC为缩合剂进行酰胺化连接光敏剂Ce6,并交联嵌段共聚物PAsp-b-PEG以改善纳米复合物的生物相容性和控制药物释放,同时负载化药DOX,构建出具有磁靶向性和pH控制释放能力的光敏剂和化药共载纳米复合物Ce6@MSN-Fe3O4/DOX@PAsp-b-PEG,该共载药纳米复合物DOX的载药量为23.67%,且有明显的pH控制释放性能,酸性条件下在96h时,DOX累积释放率高达90.26%,并具有良好的超顺磁性和核磁成像能力,有应用于磁靶向和临床磁共振成像诊断的潜能。第二部分研究中,我们通过生物透射电镜考察了 MSN-Fe3O4磁性纳米载体的细胞摄取能力,利用荧光显微镜考察了共载药纳米复合物的细胞摄取能力,利用流式细胞仪测定了载光敏剂纳米复合物的体外磁靶向性,采用CCK-8法考察了共载药纳米复合物对B16和MCF-7/ADR细胞增殖的抑制作用。结果表明,MSN-Fe3O4、Ce6@MSN-Fe3O4、Ce6@MSN-Fe3O4/DOX@PAsp-b-PEG均具有良好的细胞摄取能力。载光敏剂纳米复合物Ce6@MSN-Fe3O4具有明显的体外靶向性。共载药纳米复合物对B16细胞和MCF-7/ADR均具有细胞增殖抑制作用,体外光动力抗肿瘤作用可能与诱导活性氧产生有关。第三部分研究中,我们成功合成了不同长径比的新型螺旋棒状介孔二氧化硅纳米材料,研究表明不同长径比螺旋形貌的介孔二氧化硅棒均具有良好的细胞摄取能力,并发现不同长径比的纳米材料中,比表面积大的螺旋介孔二氧化硅棒的细胞毒性相对较大,随载体浓度的增加明显提高了细胞的氧化应激水平,初步表明螺旋介孔二氧化硅纳米材料的比表面积增大可能是引起细胞毒性的关键因素。综上所述,本课题成功设计并合成了具有磁靶向性和pH控制释放能力的光敏剂Ce6和化药DOX共载药纳米复合物Ce6@MSN-Fe3O4/DOX@PAsp-b-PEG,该纳米复合物具有良好的超顺磁性和核磁成像能力,在细胞水平表现出良好的肿瘤细胞靶向性和增殖抑制作用。此外我们还成功合成了不同长径比的新型螺旋棒状介孔二氧化硅纳米材料,研究表明不同长径比螺旋形貌的介孔二氧化硅棒均具有良好的细胞摄取能力,螺旋介孔二氧化硅纳米材料的比表面积增大可能是引起细胞毒性的关键因素。
[Abstract]:Tumor is a major disease that threatens human health in modern society. Chemotherapy is one of the important means of cancer clinical treatment. The new tumor site targeting and controlled release drug delivery system can transfer antitumor drugs more effectively to the site of the focus, improve the effect of anti-tumor and reduce its systemic toxic and side effects, and become the research field of tumor at present. In this paper, based on the new double pass mesoporous silica sphere, we constructed a new photosensitizer and adriamycin co carrier multifunction nano drug delivery system with magnetic target, nuclear magnetic imaging ability and pH sensitive release function based on a new double pass mesoporous silica sphere. A new spiral rod like mesoporous silica nanomaterial was synthesized and its cell uptake and cytotoxicity were studied. This paper is divided into three parts: in the first part, we use four ethyl orthosilicate (TEOS) as silicon source, sixteen alkyl three methyl ammonium bromide (CTAB) as a template, hexane as a reamer, mining The double pass mesoporous silica nanospheres with nuclear shell structure were synthesized by the modified Stober method, and the functionalized design was carried out. The outer chimeric superparamagnetic Fe3O4 was modified by nucleophilic substitution and DCC was used as the condensation agent to connect the photosensitizer Ce6, and the block copolymer PAsp-b-PEG was crosslinked to improve the biocompatibility of the nanocomposites. Control drug release, and load the drug DOX, construct a photosensitizer with the ability of magnetic targeting and pH control release, the co loaded nano complex Ce6@MSN-Fe3O4/DOX@PAsp-b-PEG, the drug loading amount of the co carrier nano complex DOX is 23.67%, and there is a clear pH controlled release energy. The cumulative release rate of DOX is up to 96h under the acidic condition, and the cumulative release rate of DOX is up to high. 90.26%, with good superparamagnetic and magnetic imaging capabilities and potential for magnetic targeting and clinical magnetic resonance imaging. In the second part, we examined the cell uptake of MSN-Fe3O4 magnetic nanoscale by biological transmission electron microscopy, and investigated the cell uptake of CO loaded nanocomposites by fluorescent microscopes. By using the flow cytometry, the magnetic targeting of the photosensitizer nanocomposites was measured in vitro. The inhibitory effects of the co loaded nanocomposites on the proliferation of B16 and MCF-7/ADR cells were investigated by CCK-8. The results showed that MSN-Fe3O4, Ce6@MSN-Fe3O4, Ce6@MSN-Fe3O4/DOX@ PAsp-b-PEG had good cell uptake. The rice complex Ce6@MSN-Fe3O4 has obvious in vitro targeting. The co loaded nanocomposites can inhibit the proliferation of B16 cells and MCF-7/ADR, and the photodynamic anti-tumor effect in vitro may be related to the production of reactive oxygen species. In the third part, we successfully synthesized a new spiral rod like mesoporous two oxidation, which is different from the length to diameter ratio. Silicon nanomaterials have shown that the mesoporous silica rods with different length and diameter ratio have good cell uptake ability. In the nanomaterials with different length to diameter ratio, the cytotoxicity of the mesoporous silica rods with large surface area is relatively large, and the oxidative stress level of the cells is obviously increased with the increase of the carrier concentration. It is preliminarily indicated that the increase of the specific surface area of the mesoporous silica nanomaterials may be the key factor causing cytotoxicity. In summary, the subject has successfully designed and synthesized the photosensitizer Ce6 with the magnetic targeting and pH control release ability and the drug DOX co nanoparticle Ce6 @MSN-Fe3O4/DOX@PAsp-b-PEG, the nanocomposite. It has good superparamagnetic and nuclear magnetic imaging capabilities, and shows good tumor cell targeting and proliferation inhibition at the cell level. In addition, we have also successfully synthesized a new type of spiral rod mesoporous silica nanomaterials with different length to diameter ratio. The study shows that the mesoporous silica rods with different length and diameter ratio are good. Good cell uptake ability, the specific surface area of spiral mesoporous silica nanomaterials may be a key factor to induce cytotoxicity.
【学位授予单位】：福建中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96

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