功能化介孔二氧化硅纳米载药体系的制备及其在治疗肿瘤骨转移方面的应用研究

发布时间：2018-05-15 20:21

本文选题：肿瘤骨转移 + 介孔二氧化硅纳米颗粒　；参考：《河北大学》2017年硕士论文

【摘要】：肿瘤骨转移一旦发生,癌症患者的生存几率与生活质量都将大大降低。随着纳米技术的迅猛发展,纳米材料由于其纳米尺度所固有的独特物理性质,在肿瘤治疗方面发挥着重要的作用,其可以通过EPR效应被动选择肿瘤细胞进行治疗。然而,由于转移病灶并未形成血管漏洞,所以EPR效应并不能应用于肿瘤骨转移,如何靶向转移病灶尤其是骨转移病灶依旧迫切需要解决。目前临床当中采用化疗药与双磷酸盐联合给药的模式进行肿瘤骨转移的治疗,但传统的治疗技术很难达到理想效果,受限于化疗药物和双磷酸盐很难同时到达肿瘤部位,协同发挥作用。本课题设计并构建了一种新型的基于介孔二氧化硅纳米颗粒(MSNs)的肿瘤化疗-双磷酸盐/热疗-双磷酸盐联合治疗靶向递释系统。该系统利用MSNs孔道高效负载药物或包覆纳米金棒实现近红外光热转换,并通过修饰双磷酸盐主动靶向骨及骨的微环境。本文第一部分为DOX@MSNs-ZOL的构建、表征和肿瘤骨转移的治疗评价。合成了粒径为40 nm的单分散介孔二氧化硅纳米颗粒,表面修饰ZOL后负载抗肿瘤药DOX,构建了一种可以靶向骨的可控释药体系。由于合适的介孔孔道和巨大的比表面积,MSNs-ZOL在pH=7.4的PBS溶液中负载DOX药量为77.34%。DOX释放为pH依赖型,在酸性环境中释放较快,通过能量依赖介导的方式进入细胞后定位到细胞溶酶体,并且对肿瘤细胞有明显的协同治疗作用,能有效抑制肿瘤转移。第二部分为采用晶种法合成均一的金纳米棒(Au),然后利用Au表面的CTAB作为模板剂,加入TEOS形成MSNs包覆Au的核壳结构,有两个SPR峰,横向SPR峰为530 nm,纵向SPR峰为808 nm。纳米颗粒比表面积为176.06 m2/g,平均孔道直径2.4 nm。同样在纳米颗粒表面进行了ZOL的修饰。Au@MSNs-ZOL可吸收近红外激光并将其转换成大量的热能,发热效率与纳米粒的浓度、激光照射强度、激光照射时间相关。Au@MSNs-ZOL的细胞摄取和肿瘤靶向特性考察,共聚焦荧光显微镜和流式细胞仪直观结果显示MDA-MB-231细胞对Au@MSNs-ZOL的孵育时间越长,细胞摄取越多。体内及体外实验证明,该体系对肿瘤细胞有明显的协同治疗作用,能有效抑制肿瘤转移,且具有良好的光声成像作用,可用于体内监测。
[Abstract]:Once tumor bone metastases occur, the survival rate and quality of life of cancer patients will be greatly reduced. With the rapid development of nanotechnology, nanomaterials play an important role in tumor therapy because of their unique physical properties in nanometer scale. They can be used to treat tumor cells passively through EPR effect. However, due to the absence of vascular loopholes in metastatic lesions, the EPR effect cannot be applied to tumor bone metastasis. How to target metastatic lesions, especially bone metastases, still needs to be solved urgently. At present, chemotherapy drugs combined with bisphosphates are used to treat tumor bone metastases in clinical practice. However, the traditional treatment techniques are difficult to achieve the desired results, which are limited by the difficulty of both chemotherapy drugs and bisphosphates reaching the tumor site at the same time. Play a synergistic role. A novel tumor chemotherapy-bisphosphate / hyperthermal-bisphosphate targeted delivery system based on mesoporous silica nanoparticles was designed and constructed. The system uses MSNs channels to efficiently load drugs or coated nanocrystalline gold rods to achieve near infrared photothermal conversion and by modifying bisphosphates to actively target bone and bone microenvironment. The first part of this paper is the construction, characterization of DOX@MSNs-ZOL and evaluation of the treatment of tumor bone metastasis. The monodisperse mesoporous silica nanoparticles with the diameter of 40 nm were synthesized and the antitumor drug DOX was loaded on the surface modified by ZOL. A controlled release drug system was constructed which could target the bone. Due to the suitable mesoporous channels and large specific surface area of MSNs-ZOL in PBS solution of pH=7.4, the amount of DOX loaded with 77.34%.DOX was released as a pH dependent type, and released rapidly in acidic environment. The lysosomes of the cells were located after entering the cells in an energy-dependent manner. And has the obvious synergistic effect to the tumor cell, can suppress the tumor metastasis effectively. In the second part, the uniform au nanorods were synthesized by the method of crystal seeding, and then TEOS was added to the au surface as template to form the core-shell structure of au coated with MSNs. There were two SPR peaks, the transverse SPR peak was 530nm, and the longitudinal SPR peak was 808 nm. The specific surface area of nanoparticles is 176.06 m2 / g, and the average pore diameter is 2.4 nm. The surface of nanoparticles was also modified by ZOL. Aur MSNs-ZOL absorbed near infrared laser and converted it into a large amount of heat energy. The heating efficiency, the concentration of nanoparticles, the intensity of laser irradiation, The cell uptake and tumor targeting characteristics of MSNs-ZOL were investigated. The results of confocal fluorescence microscopy and flow cytometry showed that the longer the incubation time of Au@MSNs-ZOL was, the more the cell uptake was. Experiments in vivo and in vitro show that the system has obvious synergistic effect on tumor cells, can effectively inhibit tumor metastasis, and has a good photoacoustic imaging effect, which can be used for in vivo monitoring.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;TB383.1

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