具有癌细胞靶向性的碳基荧光介孔硅复合纳米颗粒的制备及生物应用

发布时间：2018-02-09 23:52

本文关键词： 介孔硅碳点近红外成像靶向治疗　出处：《中北大学》2017年硕士论文　论文类型：学位论文

【摘要】：介孔二氧化硅纳米颗粒(MSNs)除了具有表面易功能化、细胞易于吸收、可生物降解、低毒性和优良的生物相容性这些传统的性能外,还具有独特的性能,例如高比表面积、大的孔体积、可调的孔结构和良好的物理化学稳定性等,因此MSNs在生物医学方面的应用受到了研究者的特别关注,已经被广泛应用于靶向药物输送、诊断、治疗等其他的生物医学方面。近二十年来,有大量的研究将荧光蛋白和荧光染料等不同种类的荧光物质与介孔硅掺杂,但是这些材料容易光漂白,不适合在血液内长期循环以及实时追踪。碳点(CDs)作为一种新型的荧光纳米材料,其制备方法简单,原料成本低,具有可调的发光范围、良好的光稳定性、易功能化以及良好的生物相容性和水溶性等性质,和半导体量子点比较,其最大的优点就是毒性低,使其在光催化、传感器、太阳能电池和生物成像等方面具有广泛的应用。本论文将MSNs和CDs复合得到碳基荧光介孔硅材料,不仅同时具有CDs和MSNs的优良性能,还可以作为良好的药物载体对病变细胞达到靶向治疗的目的。本论文主要通过两种不同的方法制备具有不同荧光性能的碳基荧光介孔硅,以实现生物成像与靶向治疗一体化,主要工作如下:(1)通过原位合成法将荧光碳点和靶向剂同时作用到MSNs上,此方法制备过程简单,原料成本低,将叶酸(FA)和氨基化MSNs(MSNs-NH2)混合,一步微波法制备出具有靶向性的荧光介孔硅(FA-CDs-MSNs),其中FA既为CDs来源又可以作为靶向剂。通过系统的研究,其产物具有低毒性、良好的荧光性能和细胞靶向性,被应用于细胞成像和靶向治疗,也被用来区别癌细胞和正常细胞,为了验证FA-CDs-MSNs对癌细胞有治疗的效果,将其承载药物阿霉素(DOX),DOX@FA-CDs-MSNs有选择性地靶向肿瘤组织和抑制癌细胞的生长,作为药物载体提高了其药物利用率和抗癌能力,减小了对其他组织的毒副作用。本论文合成的具有靶向性的的荧光介孔硅为细胞靶向和治疗构建了一个新的纳米平台。(2)通过共缩聚法将近红外碳点(NIR-CDs)合成到MSNs的骨架结构里,再在其表面嫁接线粒体靶向剂(3-羧丙基)三苯基溴化磷(TPP),得到具有线粒体靶向性的近红外介孔硅(NIR-MSNs-TPP)。首先将近红外碳点与异氰酸丙基三乙氧基硅烷(IPTS)共轭得到NIR-硅烷,再与TEOS共缩聚反应合成近红外介孔硅(NIR-MSNs),将其氨基化后和TPP通过酰胺反应得到最终产物。NIR-CDs在近红外区域同时具有激发和发射双光子性能,毒性非常低,可用来双光子生物成像,近红外光还具有高组织渗透性和生物友好型等特性,比低渗透性的紫外或者可见光具有非常大的优势,能够克服紫外可见光在光活化等生物应用方面的局限性。将其与MSNs复合之后,其产物不仅可以用来高渗透双光子成像还可以用于药物输送,将其修饰靶向剂TPP之后,可将药物输送至线粒体从而实现更高效的靶向治疗。
[Abstract]:In addition to the traditional properties of mesoporous silica nanoparticles, such as easy surface functionalization, easy absorption of cells, biodegradability, low toxicity and excellent biocompatibility, they also have unique properties, such as high specific surface area. Because of its large pore volume, adjustable pore structure and good physical and chemical stability, the application of MSNs in biomedicine has attracted special attention and has been widely used in targeted drug delivery and diagnosis. Treatment and other biomedical aspects. Over the last two decades, a lot of research has been done on doping different kinds of fluorescent substances, such as fluorescent proteins and fluorescent dyes, with mesoporous silicon, but these materials are easy to photobleach. As a new kind of fluorescent nanomaterials, the method of preparation is simple, the cost of raw material is low, the luminescence range is adjustable, and the photostability is good. Easy functionalization and good biocompatibility and water-solubility properties, compared with semiconductor quantum dots, its greatest advantage is low toxicity, making it in photocatalysis, sensors, Solar cells and biometric imaging are widely used. In this paper, MSNs and CDs are combined to produce carbon-based fluorescent mesoporous silicon materials, which not only have the excellent properties of CDs and MSNs, but also have good properties. It can also be used as a good drug carrier for targeted therapy of diseased cells. In this paper, two different methods were used to prepare carbon-based fluorescent mesoporous silicon with different fluorescence properties, so as to realize the integration of biologic imaging and targeted therapy. The main work is as follows: (1) the fluorescent carbon spot and the target agent are simultaneously applied to MSNs by in situ synthesis. The process of preparation is simple and the cost of raw material is low. The fluorescent mesoporous silicon (FA-CDs-MSNs) was prepared by one-step microwave method. FA is both a source of CDs and a targeting agent. Through systematic study, the products have low toxicity, good fluorescence properties and cell targeting. It has been used in cell imaging and targeted therapy, and also used to distinguish cancer cells from normal cells. In order to verify the effect of FA-CDs-MSNs on the treatment of cancer cells, the carrier drug DOXDX FA-CDs-MSNs is selectively targeted at tumor tissues and inhibits the growth of cancer cells. As a drug carrier, the drug utilization rate and anticancer ability are improved. The target fluorescent mesoporous silicon synthesized in this paper has constructed a new nano-platform for cell targeting and treatment. It is synthesized into the skeleton structure of MSNs by means of near infrared carbon dots (NIR-CDss). NIR-silane was obtained by grafting the mitochondrial targeting agent 3-carboxypropyl) triphenyl phosphorous bromide (TPPN) on its surface to obtain near-infrared mesoporous silicon (NIR-MSNs-TPPN) with mitochondrial targeting. First, NIR-silane was obtained by conjugation of near-infrared carbon point with isocyanate triethoxy silane (IPTSs). Near-infrared mesoporous silicon (NIR-MSNsN) was synthesized by copolycondensation with TEOS. The final product, .NIR-CDs, was obtained by amination with TPP through amide reaction. The product, .NIR-CDs, has the properties of excitation and emission of two photons in the near infrared region, and its toxicity is very low, so it can be used for two-photon imaging. Near-infrared light also has high tissue permeability and biological friendliness, and has a great advantage over ultraviolet or visible light with low permeability. It can overcome the limitations of ultraviolet and visible light in biological applications such as photoactivation. When combined with MSNs, the product can be used not only for high permeable two-photon imaging, but also for drug delivery and modification of target agent TPP. Drugs can be transported to mitochondria to achieve more efficient targeted therapy.
【学位授予单位】：中北大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TB383.1;TQ460.1

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