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研究生:古振安
研究生(外文):Guu Jan An
論文名稱:聚葡萄糖標的型高分子抗癌前驅藥之製備及其性質探討
論文名稱(外文):Preparation and Characterization of Targetable Dextran Polymer Prodrug
指導教授:莊祚敏薛敬和薛敬和引用關係
指導教授(外文):Tzuoh-Min JuangGing-Ho Hsiue
學位類別:博士
校院名稱:國立交通大學
系所名稱:應用化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:167
中文關鍵詞:標的型高分子藥物間隔基木瓜蛋白脢半乳糖胺
外文關鍵詞:targetingpolymer-drug conjugateADR5-FUpapainspacergalactosamine
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本研究在探討高分子型抗癌藥物的合成製備及其應用性。此高分子藥物採用聚葡萄糖當作高分子載體,搭載生物活性試劑如抗癌藥物5-fluorouracil (5-FU)及adriamycin (ADR)和標的性官能基團,為具有導向標的性質的高分子抗癌藥物。抗癌藥物本身經由一段三個氨基酸組成之寡隔離基與高分子骨架結合;另外接上一可導引藥物至肝臟細胞的官能基-半乳糖胺(galactosamine),使高分子前驅藥具有抗癌標的功能。
研究採用生物可分解的天然水溶性高分子聚葡萄糖做為高分子載體。高活性的藥物以特殊設計的間隔基(spacer)與高分子載體連接,使藥物保持安定直到抵達治療部位才被釋放出來發揮作用。本研究依據上述原理所製備的高分子耦合藥物,間隔基是由三個氨基酸所組成的短鏈Gly-Leu-Gly (簡稱GLG),在實驗室中以溶液相合成方法合成得到。使用了兩種一般癌症治療常用的藥物5-fluorouracil (5-FU)和adriamycin (ADR),藉著間隔體與高分子鍵結,同時也以間隔體為橋樑將半乳糖(galactosamine)加入高分子藥物結構中。除了對高分子偶合結構進行鑑定之外,亦分別針對這兩組高分子藥物進行酵素水解釋放性質、生物體外(in vitro)細胞毒性試驗以及小白鼠生物體內(in vivo)毒性測試等方面性質的探討。
製備過程中以核磁共振光譜(NMR)、紅外光譜(FT-IR)及紫外光譜(UV/vis spectrum)進行追蹤鑑定以及確認試劑成份的含量,在5-FU高分子藥物中藥物的含量約為5 mol%;而在另一高分子-藥物共軛體中ADR藥物的含量為3 mol%。酵素水解實驗結果在木瓜蛋白(papain)作用下,DGLG-5FU在48小時後解離出20%左右的5-FU,一週後則有將近50%的5-FU被釋出;DGLGA經過50小時酵素水解之後,ADR的釋放量約為總藥物含量的42%。活體外細胞毒性試驗以肝癌細胞Hep-3B為對象,證實具有Gly-Leu-Gly間隔基的高分子藥物包括DGLG-5FU、DGLGA和DGLGA-Ga均展現明顯的細胞成長抑制效果,而DGLGA-Ga因為攜帶可辨識導向肝臟細胞的基團-半乳糖(galactosamine),使它更容易累積於細胞周圍,而具有比DGLGA還高的細胞毒性效果。動物實驗方面,雖然無法將感染癌症的老鼠完全治癒,但是DGLGA與DGLGA-Ga均能降低ADR的藥物毒性,並且延長老鼠的壽命,兩組藥物治療的老鼠平均壽命皆比未接受藥物治療者及施打ADR者長,50天長時存活者的結果則分別有兩隻(2/6)和一隻(1/6)。顯示出當聚葡萄糖-藥物的共軛結構中含有Gly-Leu-Gly間隔基時,能夠適時釋放出藥物分子,有助於降低藥物副作用及提高治療效果。

In this study preparation and characterization of an anticancer polymer prodrug have been discribed. The polymer prodrugs were obtained by utilizing dextran as the polymer carrier, which was conjugated with drugs, i.e., 5-fluorouracil (5-FU) and adriamycin (ADR) and with a targeting moiety, respectively.
5-FU was fixated to dextran through covalent bonds to provide a water-soluble macromolecular prodrug. A lysosomally digestable tripeptide chain of Gly-Leu-Gly was used as a spacer group between dextran and 5-FU. Moreover, 5-FU was attached to the spacer via amide bonding by the coupling agent, diethylphosphoric cyanide. The content of 5-FU moiety on the polymeric-drug conjugate was about 5mol%. Galactosamine, as a saccharide residue, was used for the targeting effect of the polymer-drug conjugate. Also investigated herein was the release behavior of 5-FU from the conjugate by papain. The total amount of 5-FU released after 48 hr was 20 mol% and about 50 mol% for a week for DGLG-5FU. The cytotoxicity of the conjugates against the hepatoma cells was determined by an MTT assay, in which the cell specific targeting of the conjugated to hepatoma cells by covalently bonding to a galactosamine group was observed.
Three kinds of polymeric ADR conjugates of dextran was synthesized, including dextran-Gly-Leu-Gly-ADR (DGLGA) conjugate with lysosomally degradable tripeptide spacer group, dextran-Gly-Leu-Gly-ADR-galactosamine (DGLGA-Ga) conjugate with a targeting moiety of galactosamine on DGLGA, and dextran-C6H10-ADR (DC6A) conjugate with hexamethylene spacer group. The content of ADR moiety on the polymeric-drug conjugate was about 3mol%. The enzyme hydrolysis of DGLGA and DC6A was carried out by the incubation with papain. The total amount of ADR released after 48 hr was 43 mol% for DGLGA and less than 1 % for DC6A. For the in vitro cytotoxicity evaluation, DGLGA-Ga conjugate has higher cytotoxic efficacy than other conjugates for the incubation with Hep-3B cells, and the capability of targeting to hepatoma cell of galactosamine residue was observed consequently. In contrast, for the incubation with SiHa cells of these conjugates, there is no significant cytotoxicity observed. The in vivo cytotoxic efficacy of each conjugate (20 mg ADR-equiv./kg) against CT-26 mice colon cells implanted s.c. in Balb-C mice was studied. The DGLGA generated the best therapeutic effect with the presence of long term survival (LTS) at day 50 (2/6).

中文摘要 I
英文摘要 III
一、研究動機 1
二、研究目的 3
三、原理及文獻回顧 4
3.1 原理 4
3.1.1高分子藥物模型 8
3.1.2高分子載體 9
3.1.3寡間隔基 16
3.1.4標的作用 17
3.1.5胞飲作用 20
3.1.6酵素作用 28
3.1.7抗癌藥物 29
3.2文獻回顧 33
四、實驗 45
4.1實驗藥品 45
4.1.1高分子藥物合成 45
4.1.2水解實驗 46
4.1.3細胞實驗及動物實驗 46
4.2實驗儀器及測量方法 46
4.3高分子藥物之合成 47
4.3.1 Boc-Gly-Leu之合成 47
4.3.2 Boc-Gly-Leu-ONp 之合成 48
4.3.3 Boc-Gly-Leu-Gly之合成 48
4.3.4 Gly-Leu-Gly之製備 49
4.3.5 Boc-Gly-Leu-Gly-Ga之合成 49
4.3.6 Gly-Leu-Gly-Ga之製備 52
4.3.7 聚葡萄糖活化反應 52
4.3.8反應活化度的計算 52
4.3.9 Boc-Gly-Leu-Gly-5FU之合成 53
4.3.10 Gly-Leu-Gly-5FU之製備 53
4.3.11 dextran-Gly-Leu-Gly-5FU之合成 54
4.3.12 DGLG-5FU-Ga之合成 54
4.3.13 DGLG之合成 54
4.3.14 DGLGA之合成 60
4.3.15 DGLG-Ga之合成 60
4.3.16 Boc-Gly-Gly-Leu之合成 60
4.3.17 Gly-Gly-Leu之製備 64
4.3.18 DGGL之合成 64
4.3.19 DC6之合成 65
4.3.20 DGGLA之合成 65
4.3.21 DC6A之合成 65
4.4 5FU高分子藥物 72
4.4.1生物體外(in vitro)細胞毒性實驗 72
4.4.2酵素水解實驗 72
4.5 ADR高分子藥物 73
4.5.1生物體外(in vitro)細胞毒性實驗 73
4.5.2酵素水解實驗 73
4.5.3螢光實驗 73
4.5.4動物實驗 74
五、結果與討論 100
5.1高分子藥物合成 100
5.1.1 Boc-Gly-Leu之合成 100
5.1.2 Boc-Gly-Leu-ONp之合成 101
5.1.3 Boc-Gly-Leu-Gly之合成 102
5.1.4 Gly-Leu-Gly之合成 102
5.1.5聚葡萄糖活化反應 103
5.1.6活化度之計算 106
5.1.7活化度之影響因素 107
5.1.8 GLG-5FU之合成 117
5.1.9 DGLG-5FU 之合成 119
5.1.10 DGLG之合成 119
5.1.11 DGLGA之合成 121
5.2 5FU高分子藥物 124
5.2.1 5FU之含量 124
5.2.2水解實驗 127
5.2.3細胞毒性實驗 129
5.3 ADR高分子藥物 134
5.3.1 ADR之含量 134
5.3.2水解實驗 134
5.3.3細胞毒性實驗 140
5.3.4螢光實驗 144
5.3.5動物實驗 146
六、結論 156
七、參考文獻 158

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