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研究生:林庭毅
研究生(外文):Ting-Yi Lin
論文名稱:具還原/酸鹼應答之搭載DACHPt 玻尿酸奈米藥物載體應用於大腸癌標靶治療
論文名稱(外文):Redox/pH-Responsive DACHPt-Loaded Micelles Based on Hyaluronic Acid of Targeted Therapy for Colorectal Cancer
指導教授:駱俊良
指導教授(外文):Chun-Liang Lo
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物醫學工程學系
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:93
中文關鍵詞:玻尿酸還原應答酸鹼應答半胱胺酸組胺酸奧沙利鉑前驅物大腸癌
外文關鍵詞:Hyaluronic acidRedox-ResponsivepH-ResponsiveL-CysteineL-HistidineDACHPtColorectal Cancer
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本研究利用腫瘤組織的獨特生理特徵,開發ㄧ具還原與酸鹼應答之高分子奈米微胞,並以具備良好的生物相容性、低免疫反應性及標靶癌細胞表面標記物CD44的玻尿酸(Hyaluronic acid)當作奈米載體的主體,並修飾上天然的胺基酸使奈米載體具備選擇性釋放藥物及可在細胞內特定位置釋放藥物。第一種胺基酸為半胱胺酸(L-Cysteine),在氧化交聯後形成雙硫鍵促使奈米微胞的結構更加穩固,在血液循環及正常組織中不易釋放藥物,只可在高濃度穀胱甘肽(Glutathione)的腫瘤微環境中使雙硫鍵還原,使奈米微胞具有選擇性的釋放藥物之能力。此外,當奈米微胞被內吞形成核內體後,因第二種胺基酸為組胺酸(L-Histidine)的imidazole ring pka 值約在6.5,當pH 低於6.5 時會使其質子化,進而使奈米微胞產生膨潤的現象,加速藥物釋放效率,並其引發質子海綿效應 (proton sponge effect),導致核內體破裂讓藥物逃脫,達到有效釋放藥物進而誘導癌細胞凋亡。研究中成功合成出具還原與酸鹼應答之高分子Hyaluronic acid30k-Cysteine-Histidine (C2H2),以此高分子攜載奧沙利鉑前驅物DACHPt,並且成功製備出高分子奈米微胞 (C2H2-D4)。進一步,藉由體外試驗探討腫微環境中pH 與GSH對於奈米微胞變化的情形,由粒徑變化與藥物釋放的實驗數據得知奈米載體在腫瘤環境下具有選擇性的應答能力。除此之外,在細胞實驗中,C2H2-D4 奈米微胞具備標靶CD44 並有效毒殺大腸癌細胞,並對正常細胞小鼠纖維母細胞的毒性較小。因此,在此研究中,成功開發一具標靶與雙重應答之高分子奈米微胞可有效地應用於大腸癌治療。
Hyaluronic acid (HA) has some great ability such as biocompatible, biodegradable and non-immunogenic. Especially, HA can regulate cell proliferation and movement through CD44, a receptor specific to HA. This property makes HA an attractive material for hydrogel-based drug delivery. In this study, Hyaluronic acid30k-Cysteine-Histidine (C2H2) dual-sensitive polymers were conjugated with L-histidine and L-cysteine. The micelles were then prepared through dialysis to conjugate an anti-cancer drug dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt) which is the oxaliplatin parent complex. The properties of micelles exhibited targeting and controlled-release abilities. The particles size of the DACHPt-loaded C2H2 micelles was around 200 nm. The ICP-MS showed the successful conjugation of DACHPt to HA via a carboxylic group. The drug content of DACHPt in the micelles was approximately 38 w.t. %. The results of drug release demonstrated that the DACHPt-loaded C2H2 micelles exhibited the sensitivity of GSH and pH; the rate of drug release at the high concentration of GSH and pH 5.0 was faster than that at pH 7.4. In addition, the results of cytotoxicity indicated that the DACHPt-loaded C2H2 micelles had greater bioactivity in colon cancer cells than mouse fibroblast cells. The datas of flow cytometry assay confirmed that DACHPt-loaded C2H2 micelles were uptaken via CD44 receptors. Therefore, the Hyaluronic acid based Pt-loaded micelles have great potential for colon cancer therapy.
目錄
致謝-----i
摘要-----ii
Abstract-----iv
目錄-----v
圖目錄-----x
表目錄-----xiv
第一章 研究動機與目的-----1
第二章 文獻探討-----3
2.1 奈米藥物載體的發展與應用-----3
2.2 腫瘤微環境-----8
2.3 GSH應答材料-----13
2.4 酸鹼應答材料-----14
2.5 CD44於癌症的表現-----16
2.6 玻尿酸與CD44-----19
2.7 玻尿酸藥物載體於癌症治療應用 -----20
2.8 鉑類藥物的發展-----23
2.9 鉑類藥物機制與限制-----25
2.10 抗癌藥物:奧沙利鉑前驅物DACHPT-----28
第三章 材料與方法-----31
3.1 實驗藥品-----31
3.2 實驗儀器與裝置-----34
3.3 具還原與酸鹼應答高分子之製備-----36
3.3.1 Hyaluronic acid30k-L-Cys ( HA30k-C )之合成與鑑定-----36
3.3.2 Hyaluronic acid30k-L-His ( HA30k-H ) 之合成與鑑定-----37
3.3.3 Hyaluronic acid30k-L-Cys, L-His ( HA30k-CH ) 之合成與鑑定-----37
3.3.4 Hyaluronic acid30k-L-Cys-L-His ( HA30k-C-H ) 之合成與鑑定-----38
3.3.5 奧沙利鉑前驅物DACHPt 之改質-----39
3.3.6 高分子之界面電位分析-----40
3.3.7 HA30k-C2H2高分子(C2H2)之氧化量測試-----40
3.4 高分子奈米微胞之製備-----41
3.5 高分子奈米微胞之基本性質分析-----41
3.5.1 奈米微胞之粒徑分析-----41
3.5.2 奈米微胞之微觀型態分析-----42
3.5.3 DACHPt 之載藥率與有效包覆效率分析-----42
3.5.4 奈米微胞之穩定度測試-----42
3.5.5 奈米微胞之界面電位分析-----43
3.6 高分子奈米微胞之GSH與酸鹼應答測試-----43
3.6.1 奈米微胞之粒徑變化分析-----43
3.6.2 奈米微胞之形態變化分析-----43
3.6.3 奈米微胞之藥物釋放分析-----44
3.6.4 應答後C2H2之紅血球溶血測定-----44
3.7 高分子奈米微胞之生物體外試驗-----45
3.7.1 細胞與培養液製備-----45
3.7.2 細胞培養與繼代-----46
3.7.3 細胞計數-----46
3.7.4 高分子奈米微胞細胞毒性測試-----47
3.8 高分子奈米微胞細胞吞噬情形-----48
3.8.1 攜帶FITC之高分子奈米微胞製備-----48
3.8.2 細胞攝取觀察-----49
3.8.3 高分子奈米微胞對細胞週期影響-----49
3.8.4 高分子奈米微胞逃脫核內體( endosome )情形與ROS之影響-----50
第四章 結果與討論-----52
4.1 具還原與酸鹼應答高分子-----52
4.1.1 Hyaluronic acid30k-L-Cys (C2) 之合成與鑑定-----53
4.1.2 Hyaluronic acid30k-L-His (H2) 之合成與鑑定-----55
4.1.3 Hyaluronic acid30k-L-Cys-L-His (C2-H2) 之合成與鑑定-----56
4.1.4 Hyaluronic acid30k-L-Cys 1, L-His 1 (C1H1) 之合成與鑑定-----58
4.1.5 Hyaluronic acid30k-L-Cys 2, L-His 2 (C2H2) 之合成與鑑定-----60
4.1.6 Hyaluronic acid30k-L-Cys 3, L-His 3 (C3H3) 之合成與鑑定-----62
4.1.7 高分子之界面電位與酸鹼應答行為-----64
4.1.8 HA30k-C2H2高分子(C2H2)之氧化量測試-----65
4.2 高分子奈米微胞之基本性質分析-----66
4.2.1 高分子奈米微胞之粒徑、界面電位、有效包覆率與載藥率-----66
4.2.2 奈米微胞之穩定性、GSH與酸鹼應答測試-----68
4.2.3 奈米微胞之型態分析-----72
4.2.4 奈米微胞之藥物釋放分析-----74
4.3 高分子奈米微胞之生物體外試驗-----76
4.3.1 不同高分子奈米微胞細胞毒性測試-----76
4.3.2 高分子奈米微胞細胞吞噬情形-----79
4.3.3 高分子奈米微胞對細胞週期影響-----80
4.3.4 高分子奈米微胞逃脫核內體(Endosome)情形-----81
4.3.5 應答後C2H2之溶血測試-----83
4.3.6 高分子奈米微胞之ROS影響-----84
第五章 結論-----86
第六章 參考文獻-----87

圖目錄
圖 2 1、用於靶向癌症的奈米載體實例。-----4
圖 2 2、生物大分子載體的性質和應用以及代表性蛋白質和多醣的結構。-----6
圖 2 3、內源刺激:通過氧化還原電位、活性氧、酶和pH值等使藥物釋放。-----7
圖 2 4、外源觸發:通過熱、超聲波、磁能和光的刺激使藥物釋放。-----7
圖 2 5、奈米載體以不同形式將藥物遞送至腫瘤示意圖。-----9
圖 2 6、細胞氧化還原平衡示意圖。-----11
圖 2 7、哺乳動物細胞中葡萄糖代謝示意圖。-----12
圖 2 8、二硫鍵的合成方法示意圖。-----14
圖 2 9、氧化還原應答載體示意圖。-----14
圖 2 10、Histidine imidazolium質子化與pH值依賴關係及自組裝HA-PHIS微胞在細胞內pH值應答釋放藥物示意圖。-----15
圖 2 11、奈米載體利用質子海綿效應逃脫胞內體示意圖。-----16
圖 2 12、CD44蛋白和基因結構示意圖。-----17
圖 2 13、HA 的結構和功能。-----20
圖 2 14、HA修飾的奈米粒子或微胞標靶過表達CD44的癌細胞示意圖。-----22
圖 2 15、鉑類藥物結構圖。-----24
圖 2 16、奧沙利鉑的作用機制於DNA中Pt-GG錯合物的形成。-----26
圖 2 17、GSH對於順鉑抗藥性示意圖。-----27
圖 2 18、奧沙利鉑相關抗藥機制概述。-----27
圖 2 19、順鉑、DACHPt和奧沙利鉑的化學結構。-----28
圖 2 20、通過PAM-PGlu-b-PEG和DACHPt中的羧基之間的錯合形成搭載DACHPt單分子微胞(UM/DACHPt)示意圖。-----29
圖 2 21、奧沙利鉑的結構和搭載DACHPt微胞(DACHPt/m)示意圖。-----29
圖 3 1、Hyaluronic acid30k-L-Cys (HA30k-C) 之合成機制。-----36
圖 3 2、Hyaluronic acid30k-L-His ( HA30k-H ) 之合成機制。 -----37
圖 3 3、Hyaluronic acid30k-L-Cys, L-His ( HA30k-CH )合成之機制。-----38
圖 3 4、Hyaluronic acid30k-L-Cys-L-His ( HA30k-C-H ) 之合成機制。-----39
圖 3 5、DACHPt 改質示意圖。-----40
圖 4 1、高分子Hyaluronic acid30k-L-Cys之1H-NMR光譜圖。-----54
圖 4 2、高分子Hyaluronic acid30k-L-Cys之ATR圖譜。-----54
圖 4 3、高分子Hyaluronic acid30k-L-His之1H-NMR光譜圖。-----56
圖 4 4、高分子Hyaluronic acid30k-L-His之ATR圖譜。-----56
圖 4 5、高分子Hyaluronic acid30k-L-Cys-L-His之1H-NMR光譜圖。-----57
圖 4 6、高分子Hyaluronic acid30k-L-Cys-L-His之ATR圖譜。-----58
圖 4 7、高分子Hyaluronic acid30k-L-Cys 1, L-His 1之1H-NMR光譜圖。-----59
圖 4 8、高分子Hyaluronic acid30k-L-Cys 1, L-His 1之ATR圖譜。-----60
圖 4 9、高分子Hyaluronic acid30k-L-Cys 2, L-His 2之1H-NMR光譜圖。-----61
圖 4 10、高分子Hyaluronic acid30k-L-Cys 2, L-His 2之ATR圖譜。-----62
圖 4 11、高分子Hyaluronic acid30k-L-Cys 3, L-His 3之1H-NMR光譜圖。-----63
圖 4 12、高分子Hyaluronic acid30k-L-Cys 3, L-His 3之ATR圖譜。-----64
圖 4 13、Hyaluronic acid30k-L-Cys 2, L-His 2 (C2H2)不同pH 值之界面電位。-----65
圖 4 14、利用Ellman's reagent測其L-Cystein檢量線。-----66
圖 4 15、不同奈米微胞於4 ℃時穩定度粒徑分析圖。-----69
圖 4 16、不同奈米微胞之GSH與酸鹼應答粒徑變化。-----71
圖 4 17、不同奈米微胞之GSH與酸鹼應答粒徑分布。-----72
圖 4 18、不同奈米微胞在不同GSH與pH值環境下反應48小時後TEM型態圖。-----74
圖 4-19、C2H2-D4奈米微胞在不同GSH與酸鹼環境中藥物釋放情形。-----75
圖 4 20、不同高分子奈米微胞之HCT116胞毒性測試。-----78
圖 4 21、不同高分子奈米微胞之L929胞毒性測試。-----79
圖 4 22、C2H2-D4細胞吞噬情況。-----80
圖 4 23、DACHPt水錯合物與搭載DACHPt之高分子奈米微胞對於細胞週期之影響。-----81
圖 4 24、標定FITC之C2H2-D4奈米微胞在高GSH與低pH環境的人類大腸癌細胞株(HCT116)之共軛焦顯微鏡影像。-----83
圖 4 25、C2H2在低pH 值下於不同時間點與紅血球共培養6和12小時之溶血情形。-----84
圖 4 26、標定FITC之C2H2-D4奈米微胞在高GSH與低pH環境的人類大腸癌細胞株(HCT116)之共軛焦顯微鏡影像。-----85

表目錄
表 2 1、利用HA作為靶向治療研究的實例。-----21
表 4 1、HA之高分子合成進料莫爾比與組成比例。-----53
表 4 2、不同比例DACHPt之奈米微胞基本性質。-----66
表 4 3、不同奈米微胞基本性質。-----67
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