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標題: | 利用脂質體傳輸阿黴素–順鉑共軛抗癌藥物 Doxorubicin–Cisplatin Conjugated Anticancer Drug for Liposomal Co-Delivery |
作者: | Chia-Yun Hsu 許嘉云 |
指導教授: | 方俊民(Jim-Min Fang) |
關鍵字: | 癌症,藥物,脂質體,傳輸,阿黴素,順鉑,共軛, cancer,drug,liposome,delivery,doxorubicin,cisplatin,conjugated, |
出版年 : | 2018 |
學位: | 碩士 |
摘要: | 隨著全球人口的增加及老化,癌症發生的事件量及頻率攀升。根據世界衛生組織(WHO),癌症在2015年造成880萬人死亡,是當年總死亡人口的1/6。為了有效的治療癌症,除了手術之外,也開發了許多的治療方法來同時進行治療。然而,由於現有的化療方法缺乏選擇性,造成用藥量的限制,使得癌症的治癒率仍有進步的空間。
阿黴素是美國食品藥品監督管理局(FDA)核准並用於治療多種癌症的抗癌藥物。其毒殺癌細胞的機制有多種可能,其一是透過抑制拓樸異構酶(TOP II),使得DNA雙股螺旋因為無法接合而斷裂,進而破壞細胞,達到毒殺癌細胞的效果。然而,過量的阿黴素會與氧氣作用大量產生具毒性的活性氧類,造成致命的心肌病,使得給藥量必須限制在一定的範圍。 順鉑亦為FDA核准多年的抗癌藥物。其作用機制是透過與DNA形成共價鍵,使得DNA扭曲不穩定,而破壞細胞。由於阿黴素與順鉑均針對DNA大量複製的細胞,除了癌細胞之外,皮膚、黏膜等正常細胞亦會受影響。利用藥物傳遞系統,選擇性能被大幅改善,而減少副作用。 外表具PEG的脂質體藥物傳輸系統,因其大小及表面的修飾,能夠累積在腫瘤組織之間(EPR effect)、增加在體內循環的時間,使得副作用與投藥次數減少,表現不同的藥物動力學。 為了解決抗藥性、增加殺死癌細胞的機率,科學家們曾嘗試將兩種藥物同時包覆進脂質體,然而這樣的方法無法使兩種藥物的比例固定。因此,若透過生物可代謝的酯鍵來連接兩種抗癌藥物,預期此目標分子能夠在進入細胞之後釋放出兩個有效的藥物,達到加成或協同效應。 在這部分的工作中,我們利用琥珀酸二酯連接及順鉑,合成出阿黴素‒順鉑共軛抗癌藥物20。而脂質體包覆好的阿黴素‒順鉑共軛抗癌藥物20,便用於ES-2及SKOV-3兩種卵巢癌細胞的活性測試。實驗結果顯示,脂質體包覆的20比脂質體包覆的阿黴素有效抑制癌細胞生長,在ES-2中抑制能力好3倍,在SKOV-2中好9倍。這個數據支持了我們的理論–脂質體包覆的共軛抗癌藥物能夠達到協同作用,有效地毒殺癌細胞。 Cancer is a leading cause of death worldwide and is expected to become even more problematic due to the expanding population and aging. Although several kinds of treatments have been introduced to kill cancer cells, there is still a lot of room for improvement of effectiveness and selectivity in cancer treatments. Doxorubicin is one of the most frequently used anticancer drugs. After inserting into DNA double strands, doxorubicin stabilizes the topoisomerase II (TOP II) and inhibits TOP II from ligation, which leads to cell death. However, the reactive oxygen species (ROS), which are generated through redox reaction, have been implicated to cause severe side effects when reacting with normal cells. Cisplatin, another frequently used anticancer drug, targets nucleus to inhibit cancer cells from duplicating. Nevertheless, the lack of selectivity between cancer cells and normal cells also causes several side effects. To reduce these side effects, proper drug delivery systems are introduced. The previous research has found that using PEGylated nano-liposomes to encapsulate doxorubicin can afford prolonged drug circulation time and allow drug released at specific tumor site. These characters of drug delivery system lead to better selectivity, reduced side effects, desired biodistribution, and different pharmacodynamics. As for enhancing the effectiveness of killing cancer cells, one would like to encapsulate two kinds of anticancer drugs in each liposome. Nevertheless, simply mixing two drugs in a solution for encapsulation cannot precisely control the proportion, which is not allowed in drug development. It is desirable to conjugate two anticancer drugs through a bio-cleavable covalent bond, which can be broken in the environment inside cells and then release the two drugs to attain additive or synergistic effect. In this work, doxorubicin and oxoplatin, which is the oxidized form of cisplatin, were linked by succinate diester to give doxorubicin–oxoplatin conjugate (20). Compound 20 was then encapsulated in liposome to give liposomal 20, which was then used in the cytotoxicity assay. Liposomal 20 showed better inhibition than liposomal doxorubicin in two ovarian cancer cell lines, ES-2 and SKOV-3. The results suggested that conjugation of two anticancer drugs with liposomal delivery system can attain synergistic effect and increase the chance of killing cancer cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71928 |
DOI: | 10.6342/NTU201804064 |
全文授權: | 有償授權 |
顯示於系所單位: | 化學系 |
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