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標題: 利用近紅外光促發奈米碳管光熱效應來克服人類乳癌 MCF-7 細胞抗藥性
Overcomes the Drug Resistance by Carbon Nanotubes-mediated Photothermal Effects in Human Breast Cancer MCF-7 Cells
作者: 陳奕君
Chen, Yi-Chun
關鍵字: 奈米碳管
出版社: 化學系所
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摘要: 癌症是導致全球人類的死亡的主因之一,雖然有許多科學家努力研究來對抗此疾病,然而在癌症治療過程中細胞的多重抗藥性常導致的治療失效。其中有一項多重抗藥性的機制為在細胞表面過度表現輸出幫浦,像是輸運蛋白(ABC-transporter)中的P-醣蛋白,此蛋白能將化療藥物傳輸至細胞外,降低細胞內的藥物累積,因此減少藥物的作用。此外,在多重抗藥性的癌細胞會擁有比一般癌細胞較酸性的胞器,導致anthracycline藥物會被質子化並累積於胞器內。此現象稱為質子化、侷限、分泌模式 (protonation, sequestration and secretion, PPS)並說明了細胞對於弱鹼性藥物的抗藥性原因之一。 在我們先前的研究中發現,利用光內化策略成功的破壞多重抗藥性細胞內的酸性胞器,因此克服阿黴素因PPS所顯現的抗藥性問題。在本篇研究中,單壁奈米碳管不只能做為藥物輸送的載體,將藥物送至具抗藥性的癌細胞中,也能利用光熱特性,來進行光熱治療。我們首先利用硫酸與硝酸溶液氧化單壁奈米碳管的表面,之後在修飾上聚乙二醇來增加碳管的水溶性。阿黴素則經由π-π stacking貼附於奈米碳管表面。在光熱性質的部份,我們將奈米碳管水溶液暴露於808 nm雷射,並用熱像儀記錄溫度,結果顯示,碳管水溶液隨著照光時間增加,溫度也有上升的趨勢,一般的水溶液暴露於同樣光源下則沒有太大的變化。在螢光共軛焦顯微鏡下發現,阿黴素在多重抗藥性細胞內產生紅色點狀物,而聚乙二醇修飾的阿黴素-單壁奈米碳管在照光前一樣於細胞內呈現紅色點狀結構,經由照光之後明顯看見阿黴素累積於細胞核內,照光之後細胞存活率中也有明顯下降的趨勢。因此,修飾上聚乙二醇的單壁奈米碳管仍然具有光熱特性,並具有藥物傳輸載體的功能,甚至可將藥物輸送至有抗藥性的癌細胞中,可作為一個有潛力的藥物傳遞系統。
Cancer is the leading cause of human death worldwide. Although many scientists work to fight this disease, multiple drug resistance (MDR) is a predominant obstacle for effective cancer therapy. One well studied mechanism of MDR involves over-expression of efflux pumps, such as the ABC-transporter family P-glycoprotein (P-gp), on the cell surface. Because efflux pumps transport chemotherapeutic agents out of cells, the over-expression of efflux pumps prevents the intracellular accumulation of chemotherapeutics, thereby decreasing efficacy. In addition, the lower than normal pH value of the acidic organelles in MDR cells can cause the protonation of anthracycline drugs, inducing drug accumulation in these organelles. We have previously shown that the photochemical internalisation (PCI) strategy, a specific branch of photodynamic therapy (PDT), can overcome the doxorubicin resistance in MCF-7/ADR cells in vitro and in vivo by successfully disrupting endosomal and lysosomal compartments. In this study, single-walled carbon nanotubes (SWNTs) were utilised as light-activated drug carriers for doxorubicin delivery in MCF-7/ADR cells. SWNTs were first oxidised using nitric acid/sulfuric acid and the surface of the SWNTs was further modified using polyethylene glycol (PEG) phospholipids to increase solubility in aqueous solutions. Doxorubicin (Dox) was also attached to the surface of PEGylated SWNTs via π-π stacking. Our results showed that a concentration-dependent temperature increase was observed in a solution of PEGylated SWNTs with 808-nm laser irradiation, whereas a water solution showed no significant changes in temperature under a thermal camera using the same irradiation. Interestingly, PEGylated Dox-SWNTs enhanced the nuclear accumulation of doxorubicin with light irradiation. In contrast, free doxorubicin or PEGylated Dox-SWNTs revealed discrete red spots in MCF-7/ADR cells using confocal microscopic observation. Cell viability of PEGylated SWNTs-treated cells was significantly decreased after light irradiation. Thus, photothermally activated PEGylated SWNTs can be a potential nanocarrier to deliver doxorubicin to drug-resistant breast cancer cells.
其他識別: U0005-0907201214380300
Appears in Collections:化學系所



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