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標題: | pH值敏感型中孔洞二氧化矽奈米材料之設計與藥物傳遞應用 Designing a pH-Responsive Mesoporous Silica Nanoparticle Drug Delivery System |
作者: | Tzu-Ting Tseng 曾子庭 |
指導教授: | 牟中原(Chung-Yuan Mou) |
關鍵字: | 中孔洞二氧化矽奈米材料,殼-核結構,酸鹼值敏感,泛艾黴素,乳腺癌細胞,雞胚胎尿絨毛膜動物模型, mesoporous silica nanoparticles,core-shell structure,pH-responsive nanocarrier,epirubicin,chick embryo chorioallantoic membrane tumor model, |
出版年 : | 2019 |
學位: | 碩士 |
摘要: | 近幾年,奈米材料在生物醫學的應用上受到相當大的重視,由於其高生物相容性、易調控的尺寸大小、利於表面修飾等特性,經常被用來當作藥物或是生物顯影劑的載體。目前,最廣泛使用的奈米材料包含金屬氧化物、奈米碳材、半導體材料等,而本實驗中,將使用中孔洞二氧化矽奈米材料作為主要載體。中孔洞二氧化矽奈米材料擁有相當高的表面積以及可調控的孔洞大小利於搭載藥物,並可利用多種矽烷偶合劑 (silane coupling agent) 來進行表面修飾。此外,酸鹼值敏感型藥物載體的研究日趨增加,由於腫瘤環境較為酸性,可利用酸鹼值的差異來控制藥物釋放。
本研究中,我們將設計一種對酸鹼值敏感的中孔洞二氧化矽奈米材料,以靜電吸附的方式搭載抗癌藥物泛艾黴素(Epirubicin),並利用腫瘤微酸環境的特性,於材料表面修飾對酸鹼值值敏感的官能基進而達到標靶的效果。首先,我們嘗試並成功合成出具有酸鹼值敏感的官能基,且利用一步合成的方式將其修飾在表面,形成一種核-殼的中孔洞二氧化矽奈米材料 (core-shell structure)。為了增加材料的懸浮性以及增加材料在生物體內的循環時間,我們在對酸鹼值敏感的殼層上修飾長碳鏈的有機官能機。當材料經血液循環至腫瘤微酸環境時,由於其酸鹼值敏感的特性,酸鹼值敏感殼層會崩解,使得殼層上的長碳鏈一併掉落,進而讓材料互相聚集,達到累積在腫瘤的效果,並增加細胞吞噬的可能性。此外,我們於材料骨架內修飾具有一級胺及二級胺的官能基來調整材料的表面電荷,使其在中性環境下帶負電並於酸性環境中帶正電,來增加材料對藥物吸附力以及優化藥物釋放效果。 細胞實驗方面,我們使用小鼠乳腺癌細胞 (4T1 cell) 為細胞株。在細胞毒性實驗結果中,酸鹼值敏感的中孔洞二氧化矽奈米材料具有良好的生物相容性,且搭載藥物後對於腫瘤細胞的生長有相當高的抑制效果。此外,其較小的材料尺寸 (約50奈米) 及骨架內修飾的胺基官能基有利於細胞的吞噬,進而在像胞內體 (endosome) 更酸性的胞器中釋放藥物。 動物實驗方面,我們利用雞胚胎尿絨毛膜模型 (chick embryo CAM) 作為動物實驗體。相較於小鼠模型,雞胚胎腫瘤模型花費更少的時間與金錢,且不受數量限制,操作上也較為方便及容易。實驗結果中,酸鹼值敏感的中孔洞二氧化矽奈米材料搭載抗癌藥物具有良好的腫瘤抑制效果,且相對於一般中孔洞二氧化矽奈米材料有更好的標靶性及高滲透長滯留效應 (EPR effect),大大提升材料於生物醫學應用的潛力。 In the past decades, nanoparticles have been highly promising in biomedical studies for drug delivery or cell tracking due to their biocompatibility, multifunction, tunable size, and so on. There is a wide variety of nano-materials, including metal oxide, carbon, semiconductors. Among these materials, we will focus on the mesoporous silica nanoparticles (MSNs). Mesoporous silica nanoparticles (MSNs) have gained significant attention in nanomedicine research owing to its high surface area, tunable pore size, easy functionalization, exceptional stability. Besides, pH-responsive nanocarriers have been recently developed to control drug release between healthy areas and the tumor microenvironment. In this study, we synthesized pHR-MSN-PEG/DA@EPIs, in which pH-responsive (pHR) core-shell MSNs were utilized as nanocarriers, and the anti-tumor drug epirubicin (EPI) was encapsulated by electrical absorption. To promote the application in biomedicine, PEGylation was use to increase the suspension properties of the nanoparticles and enhance circulation time in organisms. Though the PEGylated nanoparticles have well enhanced permeability and retention effect, they are not easily uptaken by cells. Hence, the strategy of designation is that the PEGylated pH-responsive shell degrade and cause a decrease in the suspension properties when the nanoparticles arrives to acidic tumor microenvironment. Due to the degradation of PEGylated pH-responsive shell, the nanoparticles aggregated and accumulated in tumor site, also increasing the cell uptake. Furthermore, we modified the functional groups with primary and secondary amines to control the loading and release of the chemodrug. Test tube studies showed the zeta potential of nanoparticles to be negative in neutral environments, which increased the attraction towards EPI. On the other hand, pHR-MSN-PEG/DA became positively charged under lower pH conditions, and consequently induced drug release. In vitro studies showed that the carrier pHR-MSN-PEG/DA is non-toxic and cellular uptake is pretty facile. Cytotoxicity of pHR-MSN-PEG/DA@EPIs were evaluated in 4T1 cells, showing considerable cytotoxicity towards tumor cells. For in vivo studies, a chicken embryo model was developed, and pHR-MSN-PEG/DA exhibited excellent passive targeting behavior due to permeability and retention (EPR) effect. In a chicken embryo chorioallantoic membrane (CAM) tumor model, pHR-MSN-PEG/DA@EPIs were shown to have potential tumor-targeting ability and strong effects as drug carriers for tumor inhibition. Due to these behaviors, pHR-MSN-PEG/DA@EPIs are promising nanoparticles for chemotherapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78604 |
DOI: | 10.6342/NTU201903122 |
全文授權: | 有償授權 |
顯示於系所單位: | 化學系 |
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