基于介孔有机氧化硅的三阴性乳腺癌诊疗一体化研究

发布时间：2018-05-18 05:49

本文选题：介孔有机氧化硅 + 三阴性乳腺癌　；参考：《南方医科大学》2017年博士论文

【摘要】：三阴性乳腺癌(TNBC)是同时缺乏ER、PR和HER-2三种类型受体蛋白的乳腺癌亚型,在乳腺癌中最具侵袭性,转移率高且预后不良。完全根除高侵袭性三阴性乳腺癌仍然是当今医学的重大挑战。近年来,基于纳米材料的光学治疗是肿瘤治疗的新方法,具有广阔的临床应用前景。本论文利用介孔有机氧化硅纳米探针开展了三阴性乳腺癌增强光动力治疗及影像指导下光热-化学联合治疗研究。1)构建了蛋黄-蛋壳结构的介孔有机氧化硅偶联二氢卟吩e6(Chlorin e6,Ce6)和过氧化氢酶(Catalase)的多功能纳米平台,用于增强三阴性乳腺癌光动力治疗。构建的蛋黄-蛋壳结构的介孔有机氧化硅偶联二氢卟吩e6和过氧化氢酶的多功能纳米平台(PMO-Ce6@Catalase)具有有机-无机杂化的骨架结构,均一的尺寸,良好的稳定性和生物相容性。体外实验结果表明该纳米平台具有良好的单线态氧产生能力,过氧化氢酶能够将H202转变成02,提高了肿瘤细胞周围氧分子浓度,解决了肿瘤乏氧问题,增强了光动力治疗效果。与游离的Ce6和单纯的PMO-Ce6光动力治疗方式相比,体内实验结果证明PMO-Ce6@Catalase能够显著抑制肿瘤的生长。组织病理学结果也显示该纳米探针的增强光动力治疗方式可在肿瘤区域形成广泛的细胞凋亡和坏死。同时病理组织切片结果显示光动力治疗策略对主要器官没有产生明显的毒副作用。因此PMO-Ce6@Catalase纳米平台在三阴性乳腺癌的光动力治疗方面具有巨大的临床转化潜能。2)开发了介孔有机二氧化硅包裹普鲁士蓝纳米平台(PB@PMO)用于三阴性乳腺癌影像指导下的光热化学联合治疗。合成的PB@PMO具有有机-无机杂化的骨架,粒径均一(125 nm),高比表面积(866 m2 g-1),大的孔径(3.2 nm),高药物装载能力(260 μg mg-1),pH响应性药物释放特性以及良好的磁共振(MR)和光声(PA)成像能力。PB@PMO纳米平台的磁共振和光声成像可提供肿瘤信息,确定精准的光热治疗时机和范围。与单一的光热或化学治疗相比,体内实验结果证明了基于PB@PMO纳米平台的光热-化学联合治疗策略能够显著抑制MDA-MB-231-Luc肿瘤的生长。而且组织病理学结果分析显示光热和化学联合治疗的方法可导致肿瘤区域形成广泛的细胞凋亡和坏死。主要器官的病理组织切片结果显示光热和化学联合治疗策略没有产生明显的毒性作用。这种双模态PA/MR成像能力和光热-化学联合治疗特性的PB@PMO纳米平台在三阴性乳腺癌的治疗方面具有巨大的临床应用前景。
[Abstract]:Tri-negative breast cancer (TNBC) is a subtype of breast cancer lacking both ERPR and HER-2 receptor proteins. It is the most invasive breast cancer with high metastasis rate and poor prognosis. The complete eradication of highly invasive triple negative breast cancer remains a major medical challenge today. In recent years, optical therapy based on nanomaterials is a new method for tumor treatment, which has broad clinical application prospects. In this paper, mesoporous organic silicon oxide nanoprobes were used to develop enhanced photodynamic therapy for three-negative breast cancer and photothermal-chemotherapeutic combined therapy under the guidance of image. 1) mesoporous organic silica coupling with yolk-eggshell structure was constructed. The multifunctional nanoplatforms of porphin e6(Chlorin e6 Ce6 and catalase, Used to enhance photodynamic therapy for triple negative breast cancer. The constructed mesoporous organosilica-coupled porphine e6 and catalase multifunctional nano-platform PMO-Ce6 @ Catalasehave organic-inorganic hybrid skeleton structure, uniform size, good stability and biocompatibility. The results of in vitro experiments showed that the nano-platform had a good ability to produce singlet oxygen and catalase could transform H202 into 02, which increased the concentration of oxygen molecules around tumor cells, solved the problem of tumor hypoxia, and enhanced the effect of photodynamic therapy. Compared with free Ce6 and simple PMO-Ce6 photodynamic therapy, the results of in vivo experiments showed that PMO-Ce6@Catalase could significantly inhibit tumor growth. Histopathological results also showed that the enhanced photodynamic therapy of the nanoprobe could result in extensive apoptosis and necrosis in the tumor area. At the same time, the results of histopathological section showed that photodynamic therapy had no obvious side effects on the main organs. Therefore, PMO-Ce6@Catalase nanoplatform has great clinical transformation potential in the photodynamic therapy of tri-negative breast cancer. 2) the development of mesoporous organic silica coated with Prussian blue nano-platform for the use of tri-negative breast cancer under the guidance of the image. Photothermal chemotherapy combined therapy. The synthesized PB@PMO has organic-inorganic hybrid skeleton. Uniform particle size of 125 nm, high specific surface area of 866 m2 g-1, large pore size of 3.2 nm, high drug loading capacity of 260 渭 g mg-1 / 1 and good magnetic resonance (MRN) and photoacoustic (PAA) imaging ability. Magnetic resonance and photoacoustic imaging of PBBELP PMO nanoplatform Can provide tumor information, Determine the timing and scope of accurate photothermal therapy. Compared with single photothermal or chemotherapeutic therapy, the results of in vivo experiments demonstrated that the photothermal-chemotherapeutic strategy based on PB@PMO nanoplatform could significantly inhibit the growth of MDA-MB-231-Luc tumors. Histopathological analysis showed that the combination of photothermal and chemotherapeutic therapy could lead to extensive apoptosis and necrosis in the tumor area. Histopathological findings of major organs showed that the combination of photothermal and chemical therapy had no obvious toxic effect. The dual-mode PA/MR imaging capability and photothermal-chemotherapeutic properties of the PB@PMO nanoplatform have great clinical application prospects in triple negative breast cancer treatment.
【学位授予单位】：南方医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R737.9

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