臺灣博碩士論文加值系統

就癌症藥物載體而言，利用微脂粒包覆抗癌藥物用以治療癌症一直是臨床上很有興趣之研究。本研究首先利用光反應作用先行合成一專一性標靶分子，再利用標靶分子所形成之標靶微脂粒包覆癌症藥物以開發所謂標靶抗癌微脂粒。
首先，我們將Octreotide 與RGD 分子分別與DSPE-PEG做鍵結，再將DSPE-
PEG-Octerotide以及DSPE-PEG-RGD分別嵌入微脂粒脂雙層表面，形成所謂Octreotide(RGD)-PEG-liposome；其中，微脂粒內所包覆之抗癌藥物為二氫丹參酮。
實驗結果顯示，標靶分子Octerotide及RGD分別與DSPE-PEG鍵結之部份，其接枝率分別為69%及85%。此外鍵結後之標靶分子分別製作成不同組成之微脂粒(分別為Octreotide-PEG-liposome, RGD-PEG-liposome, PEG-liposome及Octreotide/RGD-PEG-liposome)，對於胃癌細胞株AGS進行細胞毒性以及腫瘤移殖老鼠實驗。在24小時的細胞毒性實驗部份，Octerotide/RGD-PEG-liposome抑制細胞增生的效果明顯優於其他組成(其細胞存活率分別為Octreotide：12.8%、RGD：20.1%, PEG：15.7%, Octreotide/RGD：2.3%)；在腫瘤移殖老鼠的實驗裡，使用Octerotide/RGD-PEG-liposome也有明顯抑制腫瘤細胞的生長(給藥後腫瘤細胞的體積與原始大小相比為Octreotide：64.8%, RGD：102.9%, PEG：92.8%, Octreotide/RGD：61.2%)。
本研究結果認為，使用複合型標靶式微脂粒藥物，其抑制腫瘤細胞增生的效果更優於使用單一型標靶式微脂粒藥物，我們認為複合型標靶式微脂粒將可會是未來微脂粒發展的新方向。

Liposome as a carrier encapsulate anti-cancer drugs has always regard as an interesting topic in clinical research. In this study, we develop a targeting anti-cancer liposome that has a specific target molecule by synthesis, which has potential to directly target to the specific cancer. First, we made Octreotide and RGD respectively conjugated with DSPE-PEG, and then we made DSPE-PEG-Octreotide and DSPE-PEG-RGD integrated to lipid bilayer, which is called Octreotide(RGD)-PEG-liposome, also we encapsulated dihydrotanshinone I as the anti-cancer drug.The results showed that the graft density of DSPE-PEG-Octreotide and DSPE-PEG-RGD was 69% and 85%. In addition, we made liposome with different composition (Octreotide-PEG-liposome, RGD-PEG-liposome, PEG-liposome, and Octreotide/RGD-PEG-liposome, with 10mM lipid concentration). The anti-cancer activity was investigating by in virto and in vivo test. The in vitro study we used different liposomes treat with AGS human gastric adenocarcinoma. Cytotoxicity effect showed that Octreotide/RGD-PEG-liposome is obviously superior to other component (the survival rate of Octreotide：12.8%, RGD：20.1%, PEG：15.7% and Octreotide/RGD：2.3%, respectively) after 24 hours treatment. Also in vivo study result showed that tumor bearing mice i.v. injected with Octreotide/RGD-PEG-liposome also evident to inhibit growth of tumor size (the tumor volume after treatment/original volume of Octreotide：64.8%, RGD：102.9%, PEG：92.8%, Octreotide/RGD：61.2%, respectively).
In these results, multi-targeted liposomal drug has better potential to inhibit tumor cell proliferation than single-targeted liposomal drug, it may be a new direction of liposomal development in the future.

中文摘要………………………………………………………………………i
英文摘要………………………………………………………………………ii
誌謝……………………………………………………………………………iii
目錄……………………………………………………………………………iv
表目錄 v
圖目錄 vi
第一章 緒論 1
1.1 前言 1
1.1.1 胃癌化療的演進 1
1.2 微脂粒介紹 3
1.2.1 微脂粒 3
1.2.2 微脂粒的分類 4
1. 多層微泡微脂粒 4
2. 單層大微泡微脂粒 4
3. 單層中微泡微脂粒 4
4. 單層小微泡微脂粒 4
1.2.3 微脂粒現今應用的分類方式 4
1. 傳統式微脂粒 5
2. 帶電式微脂粒 5
3. 立體穩定微脂粒 5
4. 標靶式微脂粒 5
1.2.4 標靶式微脂粒藥物的發展 8
1.2.5 微脂粒與化學治療 9
1.3 體抑素介紹 11
1.3.1 體抑素 11
1.3.2 體抑素受體 11
1.3.3 Octreotide 14
1.4 血管新生介紹 15
1.4.1 血管新生 15
1.4.2 血管新生的兩種形式 15
1. 生長的血管新生 15
2. 非生長的血管新生 16
1.4.3 腫瘤與血管新生 16
1.4.4 細胞外基質 17
1.4.5 黏合分子 19
1.4.6 結合蛋白與 RGD 序列 19
1.5 丹參及丹參萃取物 21
第二章 研究動機 22
第三章 材料與方法 23
3.1 材料 23
3.2 儀器 24
3.3 實驗方法 25
3.3.1 DSPE-PEG接枝方式 25
3.3.2 接枝後的分析 25
3.3.3 微脂粒之製備 26
3.3.4 二氫丹參酮溶液之製備 27
3.3.5 細胞毒性及細胞增生測量方法 27
3.3.6 人類胃癌細胞異種移植入鼠體方式 27
3.3.7 活體內抗癌效果 28
3.3.8 體內細胞增生測量方法 29
3.3.9 體內血管測量方法 29
第四章 結果 30
4.1 DSPE-PEG接枝 30
4.1.1檢量線製作 30
4.1.2 DSPE-PEG 接枝率分析 31
1. DSPE-PEG-RGD接枝率 31
2. DSPE-PEG-Octreotide接枝率 31
4.2微脂粒之特性 32
4.3細胞毒性 33
4.3.1 二氫丹參酮對於胃癌細胞(AGS)之細胞毒性 33
4.3.2 不同成分微脂粒對於胃癌細胞(AGS)之細胞毒性 34
1. 不同成分微脂粒在10mM濃度下對於胃癌細胞之細胞毒性 34
2. 不同成分微脂粒在5mM濃度下對於胃癌細胞之細胞毒性 36
3. 不同組成微脂粒對於胃癌細胞型態之影響 37
4.4 體內毒性 40
4.4.1 各組成微脂粒在體內之體重變化 40
4.4.2 各組成微脂粒在體內之抗癌效應 41
1. Control組 41
2. Free組 41
3. PEG組 41
4. Octreotide組 41
5. RGD組 41
6. RGD/Octreotide組 42
4.4.3 組織免疫染色 44
第五章 討論 47
5.1 微脂粒包覆二氫丹參酮對於細胞之毒性 47
5.2 單純微脂粒對於細胞之毒性 47
5.3複合型標靶式微脂粒與單一型比較 48
5.4 胃癌細胞的轉殖 49
5.5 微脂粒腹腔注射 49
5.6 各組成微脂粒對於腫瘤之效應 50
5.7 生長激素的過度分泌 51
第六章 結論 52
參考文獻 53

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