pH响应核壳式磁性介孔硅纳米复合物的构建及其在光动力治疗中的应用

发布时间：2018-03-05 06:04

  本文选题：p　切入点：H响应性　出处：《河北北方学院》2017年硕士论文　论文类型：学位论文

【摘要】：核壳式磁性介孔硅纳米复合物是以磁性纳米粒为核,介孔硅材料为壳而形成的纳米复合材料。它不仅具备了磁性纳米粒及介孔硅材料各自所具有的特性如磁靶向性、高的比表面积、易于修饰的内表面等,而且还克服了磁性纳米容易团聚、氧化的缺点,使其在生物医药、环境、化工等研究领域有着良好的应用。光动力疗法(Photodynamic Therapy,PDT)是一种新型肿瘤治疗方法,主要利用光敏剂在特定波长光的作用下,产生单线态氧,对肿瘤细胞进行杀伤,达到肿瘤治疗目的。光动力疗法在治疗黑素瘤、乳腺癌等表浅性肿瘤方面有很好的应用,同时在治疗HPV病毒感染如内、外阴阴道尖锐湿疣等方面也有重要作用,目前光敏剂已成为新型抗肿瘤药物研究的热点之一。但PDT目前仍存在一些问题,主要是患者在治疗过程中需要全程避光,否则会产生严重的全身性光毒副作用,使用非常不便;另一方面,光敏剂的体内分布缺少明确的肿瘤靶向,肿瘤部位有效浓度不高,影响光动力治疗的效果并导致毒副作用的产生。本课题针对光动力治疗中的该主要问题,采用现代纳米技术构建出能够把光敏剂有效靶向肿瘤部位的响应性纳米载药系统,达到光敏剂有效靶向肿瘤部位,并在肿瘤局部响应释放,以有效提高肿瘤组织药物浓度,降低全身毒副作用。首先我们设计合成了核壳式磁性Fe3O4介孔硅纳米复合物(MMSN),利用其负载光敏剂孟加拉红(RB),并在介孔硅表面功能性的修饰具有pH响应的嵌段聚合物聚乙二醇-b-聚天冬氨酸(PEG-b-PAsp),形成pH响应核壳式磁性介孔硅纳米复合物(RB-MMSNs),并对其进行了相关表征。通过透射电镜观察合成的MMSN的微观形态,其纳米粒径在190nm左右,具有规则的球状形貌且介孔特性良好。通过在介孔硅表面修饰PEG-b-PAsp使RB-MMSNs具有一定的pH响应性,并在实验过程中发现其也可以增加介孔硅层对RB的载药,使得RB负载率高达36%左右。体外测得RB-MMSNs的磁饱和强度约达26.6emu/g,弛豫率接近52.52S-1mM-1,具有较好的磁靶向作用,并有可能用于磁共振成像。其次通过体外细胞实验考察了RB-MMSNs的体外磁靶向性及光动力效果。CCK-8的检测结果可知RB-MMSNs无显著的暗毒性,相较于游离的RB,该材料能很好的被小鼠黑色素瘤B16细胞摄取,且在施加外部磁场部位的纳米复合物细胞摄取量显著增加。经LED绿光灯照射,RB-MMSNs对B16细胞的半数抑制浓度为4.85μg/mL,而游离RB高达48.86μg/mL。CCK-8及流式凋亡细胞检测结果均显示RB-MMSNs对B16细胞杀伤能力高于同浓度的游离RB10倍左右,因此RB-MMSNs能极大程度的提高体外光动力杀伤B16细胞的效率。最后通过体内动物实验进一步研究了RB-MMSNs对小鼠B16黑色素移植瘤的PDT效果。小鼠磁共振成像(MRI)及普鲁士染色实验结果均表明RB-MMSNs在外磁场作用下具有体内肿瘤靶向性。动物实验结果显示,在施加了磁场并结合光疗的实验小鼠组中,肿瘤体积最小,并具有统计学差异,同时该组小鼠的生存期相对最长,TUNEL凋亡检测结果也辅助证明了这一点,表明RB-MMSNs具有良好的体内肿瘤治疗效果。总之,我们构建合成的RB-MMSNs纳米复合物具有较高的光敏剂负载率,明显的体内外磁靶向性和pH响应释放特性,以及低的毒副作用,很大程度的解决了绝大多数光敏剂在肿瘤组织部位有效浓度不高,体内运输过程中易泄露而导致毒副作用大等问题,有望成为一种集磁靶向性、pH响应性于一身的多功能纳米载体,增强光动力治疗肿瘤的效果。
[Abstract]:Core-shell magnetic mesoporous silica nanocomposite with magnetic nanoparticles as core and nano composite mesoporous silica shell formed. It not only has the magnetic nanoparticles and mesoporous silica materials with their properties such as magnetic targeting, high specific surface area, easy modification of the inner surface, but also overcome the magnetic nanoparticles are easy to agglomerate, oxidation defects, the environment in the field of chemical, biological medicine, and so on. It has a good application of photodynamic therapy (Photodynamic Therapy PDT) is a new method for tumor therapy, mainly using photosensitizer in the light of a specific wavelength under the action of singlet oxygen the tumor cell killing, achieve tumor therapy. Photodynamic therapy in the treatment of melanoma, a very good application of breast cancer and other superficial tumor, at the same time in the treatment of HPV infection, such as, vulvovaginal condyloma acuminatum has The important role the photosensitizer has become one of the hot research of new anti-tumor drug. But the PDT still has some problems, mainly the whole patients need light in the treatment process, or will cause severe systemic side effects of light, use very inconvenient; on the other hand, the lack of photosensitizer distribution in vivo tumor target clear to the tumor site, effective concentration is not high, influence the effect of photodynamic treatment and lead to the emergence of side effects. Aiming at the main problems in photodynamic therapy, can construct the light sensitive agent effective targeting of tumor response nano drug carrier system by modern nanotechnology, to achieve effective targeting photosensitizer the tumor site, and in response to the release of local tumor, improve the drug concentration of tumor tissue and reduce systemic side effects. First we design a core-shell Fe3O4 magnetic mesoporous silica nanoparticles synthesized Compound (MMSN), using the load of photosensitizer Rose Bengal (RB), and pH response of block copolymer polyethylene glycol -b- polyaspartic acid on modified functional mesoporous silicon surface (PEG-b-PAsp), the formation of pH response core-shell mesoporous silica nanocomposite (RB-MMSNs), and the the characterization of morphology observed by transmission electron microscopy. The synthesis of MMSN, the nano particle size of about 190nm, with regular spherical morphology and mesoporous characteristics are good. Through surface modification of mesoporous silica PEG-b-PAsp RB-MMSNs has a pH response, and in the course of the experiment found that it can also increase the mesoporous silicon layer the RB loading, the RB load rate as high as 36%. RB-MMSNs test in vitro magnetic saturation intensity of about 26.6emu/g, the relaxation rate is close to 52.52S-1mM-1, has good effect to the magnetic target, and may be used in magnetic resonance imaging. Followed by fine in vitro 鑳炲疄楠岃，

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