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研究生:蔣伊婷
研究生(外文):Yi-Ting Chiang
論文名稱:研發具抗蛋白吸附及高穩定性之腫瘤標的高分子-微脂粒系統
論文名稱(外文):Development of Anti-protein Adsorptive Highly Stable Tumor Targeting Polymer-liposome System
指導教授:駱俊良
指導教授(外文):Chun-Liang Lo
學位類別:博士
校院名稱:國立陽明大學
系所名稱:醫學工程研究所
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:2014
畢業學年度:103
語文別:中文
論文頁數:176
中文關鍵詞:高分子微脂粒蛋白吸附抗癌治療奈米藥物
外文關鍵詞:polymerliposomeprotein adsorptionanticancer therapynanomedicine
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高分子-微脂粒在癌症治療上的發展目前面臨兩大挑戰:藥物釋放緩慢以及因血漿蛋白吸附導致大量累積於肝或脾臟。本研究提出兩種新型具抗蛋白吸附之具酸鹼應答高分子-微脂粒系統以解決這兩大問題。本研究第一部分導入物理交聯劑至酸鹼應答型高分子-微脂粒,首先本研究合成具酸鹼應答之高分子methoxy-poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-co-histidine)- cholesterol (mPEG-b-P(HPMA-co-His)-Chol),並與磷脂質製備成高分子-微脂粒,再利用含腫瘤標的物質之biotin2-PEG和高分子以氫鍵產生物理交聯,在生理環境下能夠穩定微脂粒的結構同時抵擋血漿蛋白之吸附,當高分子-微脂粒抵達腫瘤組織時,腫瘤組織的酸性環境(pH 6.5)導致高分子-微脂粒結構產生變形並將標的分子裸露出促進高分子-微脂粒進入癌症細胞,在細胞內隨著pH值下降高分子-微脂粒因正電相斥將包覆的抗癌藥物大量釋出,達到細胞毒殺的效果,實驗結果發現具物理交聯劑之高分子-微脂粒能有效抵抗蛋白質的吸附及其所造成的藥物洩漏,並且藉由穿透式電子顯微鏡和紫外-可見光光譜儀證明高分子-微脂粒在pH 6.5環境中中產生變形,將標的分子裸露出,由流式細胞儀分析和共軛焦顯微鏡的觀察可發現在腫瘤組織環境下高分子-微脂粒能增加進入腫瘤細胞的量,由非侵入活體螢光觀察發現具物理交聯劑之高分子-微脂粒會大量累積於腫瘤中,並由動物實驗發現含物理交聯劑的高分子-微脂粒具有良好的腫瘤抑制效果及較低的肝毒性。本研究第二部分則簡化高分子-微脂粒結構,導入具有抗蛋白吸附效果的丙烯酸甲氧基乙酯(MEA)合成出含丙烯酸甲氧基乙酯的高分子methoxy poly(ethylene glycol)-block- poly(hydroxyethyl methacrylate- co-methoxyethylacrylate)-cholesterol (mPEG-b-P(HEMA-co-MEA)- Chol),並將其製備成高分子-微脂粒根據實驗結果能有效防止纖維蛋白酶原的吸附,同時減少纖維蛋白酶原所造成的藥物洩漏情形和因吸附纖維蛋白酶原所導致的巨噬細胞吞噬作用,根據細胞毒性結果發現含丙烯酸甲氧基乙酯的高分子-微脂粒對老鼠纖維母細胞毒性低,因此在本研究第三部分本研究合成具有含丙烯酸甲氧基乙酯之酸鹼應答性高分子methoxy poly(ethylene glycol)-block- poly(hydroxypropylamide-co-methoxyethyl acrylate)-cholesterol(mPEG-b-P(HPMA -co-MEA-co-His)-Chol)並製備高分子-微脂粒作為奈米藥物載體,根據實驗結果發現含丙烯酸甲氧基乙酯高分子-微脂粒同樣具有抗蛋白吸附效果,經非侵入活體螢光觀察能大量減少微脂粒在肝臟的累積,在動物實驗結果也發現具有良好的腫瘤抑制效果。
Polymer-liposomes have been faced two main challenges in application of cancer therapy including slow drug release and large accumulations in liver or spleen, caused from the superficial protein adsorption. In order to overcome the hurdles, two novel anti-protein adsorptive and pH-sensitive polymer-liposomal systems in this study. At the first part of the study, the physical crosslinker was applied into the pH-sensitive polymer-liposomal systems. The pH-sensitive copolymer methoxy-poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-co-histidine)-cholesterol (mPEG-b-P(HPMA-co-His)-Chol) was first synthesized and fabricated with phospholipids into polymer-lipsomes. The hydrogen bonds would be generated between the polymer and crosslinkers comprising of targeting moieties biotin2-PEG, forming physical crosslinks. In physical environment, the physical crosslinker enabled to stabilize the liposomal structures and prevent from the plasma proteins adsorption onto the surfaces of the polymer-liposomes. As the polymer-liposomes arrived at the tumor sites, the mildly acidic tumor milieu (pH 6.5) could induce the deformations of the liposomes and the targeting moieties exposure owing to the positive charged repulsion of the copolymers. The exposed targeting moieties further enhance the entry of the polymer-liposomes into the tumor cells. The interior anticancer drugs of the polymer-liposomes would be rapidly liberated, leading to cytotoxicities for cancer cells. The experimental results have suggested that the physical crosslinker was capable of reducing the superficial protein adsorption as well as the drug leakage. The transmission electron microscopic images and the UV-Visible spectrum have identified respectively the deformation of the polymer-liposomes and the exposure of the targeting moieties at pH 6.5. According to the analysis of the flow cytometry and the confocal laser scanning microscopic images, the influxes of the polymer- liposomes toward tumor cells were lifted under the tumor tissue conditions. The polymer-liposomes with physical crosslinkers were in vivo observed preferential accumulation in tumors within 24 hours, also resulting in exceptional antitumor effects in the long term and less hepatic damages. At the second part in this study, the polymer-liposomal structures were simplified by introducing the antiprotein adsorptive 2-methoxyethylacrylate (MEA) for physical crosslonker substitution The copolymers methoxy poly(ethylene glycol)-block- poly(hydroxyethylmethacrylate- co-methoxyethylacrylate)-cholesterol (mPEG-b-P(HEMA-co-MEA)-Chol) were successfully synthesized for polymer-liposomal fabrication. The MEA-contained polymer-liposomes possessed ability to prevent fibrinogen adsorption and dru g leakage. Also, the MEA-contained polymer-liposomes decreased the uptakes by mouse macrophage cells RAW 264.7 after 24 hours incubation with fibrinogen. In addition, the MEA-contained polymer-liposomes exhibited very low cytotoxicities for mouse fibroblast. Therefore, at the third parts in the study, the MEA-contained pH-sensitive copolymers methoxy poly(ethylene glycol)-block-poly(hydroxypropyl- amide-co-methoxyethylacrylate)-cholesterol (mPEG-b-P(HPMA-co- MEA-co-His)-Chol)were synthesized and prepared for the polymer-liposomes as the nanomedical drug carriers. The experimental results indicated that MEA-contained pH-sensitive polymer-liposomes also showed impressive antiprotein adsorption. The in vivo results also elucidated that the MEA-contained polymer-liposomes could reduce significantly the deposition in the liver. The MEA-contained polymer-liposomes were also observed the excellent antitumor effects in vivo. The two novel polymer-liposomal systems were both potentials in application of anticancer therapy.
目錄

誌謝...................................................... i
摘要........................................... iii
Abstract........................................ v
目錄.................................... ix
圖目錄........................... xv
表目錄................................ xxi
第一章、 研究動機 ............................... 1
第二章、 文獻探討 ................................... 3
2-1 癌症........................................ 3
2-2 EPR 效應.................................4
2-3 微脂粒於腫瘤組織釋藥之方式......................... 5
2-4 微脂粒的介紹......................... 6
2-5 微脂粒之種類........................ 9
2-5-1多層微泡(multilamellar vesicles; MLV)............. 10
2-5-2單層大微泡(large unilamellar vesicles; LUV) ....... 11
2-5-3單層小微泡(small unilamellar vesicles; SUV)....... 11
2-6 微脂粒在藥劑學上的發展................................ 12
2-6-1 傳統型微脂粒............ 13
2-6-2 遮蔽型微脂粒(stealth liposomes)............ 15
2-6-3 環境應答型高分子-微脂粒......................... 18
2-6-3-2 溫度應答型微脂粒..................... 20
2-6-3-3 多種環境應答型高分子-微脂粒........... 21
2-6-4 具腫瘤標的微脂粒................................... 22
2-6-4-1 免疫型微脂粒(immunoliposome)............ 22
2-6-4-2 具醣類標的之微脂粒........................... 23
2-6-4-3 小分子配體標的微脂粒.......................... 23
2-7微脂粒與血漿蛋白吸附...................... 24
2-7-1 血漿蛋白吸附對微脂粒之影響........................... 24
2-7-1-1 白蛋白的吸附對微脂粒之影響.................. 25
2-7-1-2 纖維蛋白酶原的吸附對微脂粒之影響纖........ 25
2-7-1-3 免疫球蛋白G的吸附對微脂粒之影響......... 25
2-8 水層與蛋白質吸附..................... 26
2-8-1 水層的分類............... 26
2-8-2 不同種類高分子的水層和蛋白吸附之關係........... 27
第三章、 含物理交聯劑抗蛋白吸附腫瘤外細胞間質標靶效果之酸鹼
應答高分子-微脂粒系統........................... 30
3-1 研究目的........................ 30
3-2 實驗方法與材料.................. 33
3-2-1 實驗藥品................... 33
3-2-2 實驗儀器................... 35
3-2-3 實驗方法.................... 36
3-2-3-1具酸鹼應答性之高分子的製備............. 36
3-2-3-2 物理交聯劑biotin2-PEG 的合成................ 41
3-2-3-3 微脂粒的製備與性質鑑定................. 41
3-2-3-4 物理交聯氫鍵鍵結之分析..................... 43
3-2-3-4 穩定性測試................................. 43
3-2-3-5 蛋白質吸附測試........................... 44
3-2-3-6 酸鹼應答性測試......................... 44
3-2-3-7 高分子-微脂粒藥物包覆抗癌藥物doxorubicin...... 45
3-2-3-8 高分子-微脂粒藥物包覆量分析............ 45
3-2-3-9 體外藥物釋放分析....................... 46
3-2-3-10 藥物洩漏分析............................ 46
3-2-3-11 腫瘤組織標的分析............................ 46
3-2-3-12 高分子-微脂粒之細胞存活率與細胞毒殺分析..... 49
3-2-3-13 競爭實驗............................ 51
3-2-3-14 含Dox之高分子-微脂粒於細胞內藥物釋放......... 52
3-2-3-15 高分子-微脂粒於動物體內之活體觀察................. 53
3-2-3-16 動物體腫瘤抑制作用以及毒性之評估........... 54
3-3 結果與討論..........................56
3-3-1 具酸鹼應答性之高分子的製備與鑑定..................56
3-3-1-1 共聚物mPEG-b-PHPMA-NH2 之製備與鑑定...... 56
3-3-1-2 Cholesterol 之改質............................. 59
3-3-1-3 共聚物mPEG-b-PHPMA-Chol 之製備與鑑定...... 62
3-3-1-4 具酸鹼應答性之高分子之製備與鑑定.................... 63
3-3-2具標靶分子之物理交聯劑biotin2-PEG 之製備與鑑定...... 65
3-3-3 高分子-微脂粒與腫瘤細胞間質標的高分子-微脂粒鑑定.66
3-3-4 物理交聯氫鍵鍵結之分析............................. 71
3-3-5穩定性測試和酸鹼應答度測試............................. 73
3-3-6 蛋白吸附測試.............. 76
3-3-7 抗癌藥物doxorubicin的包覆及含量測定.............. 78
3-3-8 體外藥物釋放模擬分析和藥物洩漏行為.............. 79
3-3-9、腫瘤組織標的分析................................. 81
3-3-10細胞毒性................ 86
3-3-11 動物實驗.................. 92
第四章、 含丙烯酸甲基乙酯高分子-微脂粒之基本性質探討...........109
4-1 研究目的.......................... 109
4-2 實驗方法與材料................. 110
4-2-1 實驗藥品 ............... 110
4-2-2 實驗儀器 ............... 112
4-2-3 實驗方法.................. 113
4-2-3-1 不同重複單元組成共聚物
mPEG-b-P(HEMA-co-MEA)-Chol之合成........... 113
4-2-3-2 高分子-微脂粒之製備及基本性質鑑定................ 114
4-2-3-3 高分子-微脂粒之穩定性測試................ 114
4-2-3-4高分子-微脂粒之抗癌藥物doxorubicin HCl藥物含量及包覆效率... 114
4-2-3-5包覆抗癌藥物doxorubicin之高分子-微脂粒在蛋白
質溶液中之洩漏情形..................... 115
4-2-3-6 高分子-微脂粒對正常細胞株之細胞毒性測試..... 116
4-2-3-7 巨噬細胞吞噬實驗................... 116
4-2-3-8 高分子-微脂粒對癌症細胞吞噬之影響及吞噬路徑之探討...... 116
4-3 結果與討論......................... 118
4-3-1 合成與鑑定不同比例組成之共聚物mPEG-b-P(HEMA-co-MEA)-Chol .... 118
4-3-2 高分子-微脂粒之製備與鑑定.............. 121
4-3-3 高分子-微脂粒穩定性以及蛋白質吸附測試.......... 123
4-3-4 藥物包覆及藥物洩漏測試............................. 127
4-3-5 細胞毒性之測試................... 129
4-3-6 巨噬細胞吞噬作用................ 130
第五章、含丙烯酸甲氧基乙酯之抗蛋白吸附酸鹼應答
高分子-微脂粒系統.........135
5-1 研究目的............................ 135
5-2 實驗方法與材料................. 136
5-2-1 實驗藥品 ............... 136
5-2-2 實驗儀器 ............... 138
5-2-3 實驗方法.................. 139
5-2-3-1具酸鹼應答性高分子 mPEG-b-P(HPMA-co-MEA-co-His)-Chol .... 139
5-2-3-2高分子-微脂粒之製備及性質、型態鑑定................ 140
5-2-3-3 高分子-微脂粒之穩定性測試.............. 140
5-2-3-4高分子-微脂包覆抗癌藥物之製備與含量與
包覆效率分析........................... 141
5-2-3-5 包覆抗癌藥物doxorubicin高分子-微脂粒之穩定性及酸鹼應答性........... 142
5-2-3-6 細胞毒性測試.................... 142
5-2-3-7 細胞吞噬作用及細胞內釋藥觀測.......... 143
5-2-3-8包覆抗癌藥物高分子-微脂粒之生體分布性.......... 144
5-2-3-9包覆抗癌藥物高分子-微脂粒對腫瘤抑制效果
以及動物體內毒性評估............... 144
5-2-3-10 長期使用包覆抗癌藥物doxorubicin
高分子-微脂粒對肝和腎功能影響........... 145
5-3 結果與討論.........................146
5-3-1 高分子mPEG-b-P(HPMA-co-MEA-co-His)-Chol合成.... 146
5-3-2高分子-微脂粒之製備與基本性質分析............ 149
5-3-3 高分子-微脂粒抗蛋白吸附測試............... 150
5-3-4 高分子-微脂粒藥物包覆量及藥物包覆效率............ 151
5-3-5 含抗癌藥物doxorubicin高分子-微脂粒之藥物洩漏率及
酸鹼應答性測試........ 153
5-3-5-1 含抗癌藥物高分子-微脂粒藥物洩漏測試............ 153
5-3-6 含抗癌藥物高分子-微脂粒之酸鹼應答性測試................ 154
5-3-7 細胞內噬作用及釋藥行為之探討................ 155
5-3-7-1 細胞內噬作用...................... 155
5-3-7-2 細胞內釋藥行為之觀察............. 156
5-3-8 細胞毒性測試.......... 158
5-3-8-1 材料對正常細胞株之毒性測試.......... 158
5-3-8-2 含抗癌藥物doxorubicin高分子-微脂粒對
癌症細胞株之毒性測試................ 159
5-3-9 生體分布性............ 161
5-3-10 抗腫瘤效果及動物體內毒性評估........... 163
5-3-11 動物體給藥後對肝和腎功能指數之評估......... 165
第六章、 結論 ............................... 166
第七章、 參考文獻 ..........................168

圖目錄

圖2-1、腫瘤形成和血管新生的過程示意圖…………………………………3
圖2-2、EPR效應:在腫瘤細胞的血管通透性佳,高分子易通過 ………...4
圖2-3、微脂粒進入腫瘤細胞並將藥物釋出之方式示意圖…………………5
圖2-4、微脂粒內噬作用之過程示意圖………………………………………6
圖2-5、磷脂質之化學結構式……………………………………………….6
圖2-6、依照脂雙層膜數和粒徑大小不同所分類之微脂粒……………….9
圖2-7、微射流均質乳化機之示意圖………………………………………10
圖2-8、微脂粒之進化史…………………………………………….………13
圖2-9、常見之磷脂質組成與結構………………………………………….14
圖2-10、遮蔽型微脂粒和傳統型微脂粒清除率之示意圖…………………16
圖2-11、DSPE和PEG-DSPE之化學結構式………………………………16
圖2-12、微脂粒表面不同PEG密度會影響PEG在膜上之型態…………17
圖2-13、具酸鹼應答性之高分子succinylated poly(glycidol)s所製備之高分 子-微脂粒示意圖……………………………………………19
圖2-14、高分子圍籠微脂粒示意圖…………………………………….20
圖2-15、溫度應答性高分子-微脂粒在高於或低於LCST時之變化…….21
圖2-16、含Brij78之溫度應答型高分子-微脂粒………………………….21
圖2-17、主動標的微脂粒之示意圖………………………………….……..22
圖2-18、葉酸結合至PEG-DSPE化學結構式……………………………24
圖2-19、葉酸標的遮蔽型微脂粒在體內分布之情形…………………….24
圖2-20、水層結構圖………………………………………………………26
圖2-21、凍解水層對吸附蛋白影響之示意圖……………………………27
圖2-22、PEG和PMEA之示差掃描量熱儀實驗的比較……………….27
圖2-23、和PMEA結構相似poly(meth)acrylate類高分子……………….28
圖2-24、纖維蛋白酶原吸附至PMEA表面和PHEMA之情形…………28
圖2-25、PEG和PMEA表面改質後心血管體外循環導管蛋白吸附情形29
圖3-1、腫瘤細胞間質標的高分子-微脂粒之構造示意圖 ………………...31
圖3-2、腫瘤細胞間質標的高分子-微脂粒之運送、主動標的和藥物釋放過程之示意圖…………………………………………………………32
圖3-3、Cholesterol-COOH 合成示意圖…………………….………………36
圖3-4、Cholesterol-NHS ester 合成示意圖…………………..……………37
圖3-5、巨起始劑mPEG2-ABCPA之合成示意圖…………………………38
圖3-6、mPEG-b-PHPMA-NH2的合成示意圖…………………….……….39
圖3-7、mPEG-b-PHPMA-Chol的合成示意圖……………………….…….39
圖3-8、mPEG-b-P(HPMA-co-His)-Chol的合成示意圖…………….…….40
圖3-9、Biotin2-PEG 合成示意圖…………………………………………41
圖3-10、mPEG2-ABCPA之1H-NMR圖譜………………………………57
圖3-11、mPEG2-ABCPA之FT-IR圖譜………………………………….57
圖3-12、超過濾後mPEG2-ABCPA之GPC圖…………………………….58
圖3-13、mPEG-b-PHPMA-NH2之1H-NMR圖譜……………………….59
圖3-14、mPEG-b-PHPMA-NH2之FT-IR圖譜……………………………..59
圖3-15、cholesterol-COOH之1H-NMR圖譜………………………………60
圖3-16、cholesterol-COOH之FT-IR圖譜………………………………….60
圖3-17、cholesterol-NHS ester 1H-NMR圖譜………………………………61
圖3-18、cholesterol-NHS ester之FT-IR圖譜……………………………….61
圖3-19、mPEG-b-PHPMA-Chol之1H-NMR圖譜……………………….62
圖3-20、mPEG-b-PHPMA-Chol之FT-IR圖譜…………………………..63
圖3-21、mPEG-b-P(HPMA-co-His)-Chol之1H-NMR圖譜………………64
圖3-22、mPEG-b-P(HPMA-co-His)-Chol之FT-IR譜圖………………….64
圖3-23、mPEG-b-P(HPMA-co-His)-Chol之GPC分子量測定圖….…….64
圖3-24、Biotin2-PEG之1H-NMR圖譜…………………………….…….66
圖3-25、Biotin2-PEG之FT-IR圖譜………………………………………66
圖3-26、微脂粒之TEM圖……………………………………………….68
圖3-27、SAXS圖譜……………………………………………………….70
圖3-28、加入物理交聯劑後紫外-可見光光譜之變化……………………71
圖3-29、團聯共聚物加入物理交聯劑後紅外光光譜圖………………….72
圖3-30、穩定性測試:粒徑變化、PDI值……………………………….73
圖3-31、酸鹼應答性測試:粒徑變化、PDI值……………………………..74
圖3-32、不同酸鹼值下高分子-微脂粒之表面電荷變化…….……………74
圖3-33、高分子-微脂粒在不同pH值下4小時的型態變化………………75
圖3-34、蛋白質吸附之情形……………………………………………….77
圖3-35、高分子-微脂粒藥物包覆率及包覆效率…………………………..78
圖3-36、不同pH值下藥物釋放之情形…………………………………..79
圖3-37、蛋白質溶液藥物洩漏之情形……………………………………80
圖3-38、不同pH值下藥物釋放下氫鍵於紫外-可見光光譜之變化…….82
圖3-39、流式細胞儀螢光強度……………………………………………84
圖3-40、流式細胞儀螢光強度統計………………………………………85
圖3-41、高分子-微脂粒累積於腫瘤細胞之共軛焦顯微鏡圖………….. 86
圖3-42、材料對老鼠纖維母細胞L929之細胞毒性結果………….….. 87
圖3-43、高分子-微脂粒對大腸癌細胞HCT116細胞毒殺效果……….88
圖3-44、含Dox之高分子-微脂粒在細胞內釋藥共軛焦顯微鏡圖………89
圖3-45、腫瘤主動標的效果之細胞毒殺測試……………………………90
圖3-46、競爭實驗對細胞毒性之影響……………………………………91
圖3-47、動物體注射高分子-微脂粒後6小時和24小時全身累積情形…94
圖3-48、注射高分子-微脂粒6小時和24小時器官累積情形………….94
圖3-49、注射高分子-微脂粒24小時後器官螢光強度情形……………..95
圖3-50、Biotin在動物體內的競爭實驗…………………………………..95
圖3-51、腫瘤抑制效果及毒性評估…………………………………………96
圖3-52、注射free Dox和Cy 5.5標定含Dox高分子-微脂粒後第1天腫
組織、肝、脾等器官累積情形……………………………………98
圖3-53、注射free Dox和Cy 5.5標定含Dox高分子-微脂粒後第3天腫瘤組織、肝、脾等器官累積情形…………………………………..101
圖3-54、注射free Dox和Cy 5.5標定高分子-微脂粒後第7天腫瘤組織、肝、脾等器官累積情形…………………………………………104
圖3-55、肝功能指數GOT、GPT………………………………..…………108
圖3-56、腎功能指數BUN、creatinine…………………………………….108
圖4-1、mPEG-b-P(HEMA-co-MEA)-Chol之合成反應式………………113
圖4-2、團聯共聚物mPEG-b-P(HEMA-co-MEA)-Chol之1H-NMR圖119
圖4-3、團聯共聚物mPEG-b-P(HEMA-co-MEA)-Chol之FT-IR圖譜….120
圖4-4、高分子-微脂粒之穿透式電子顯微鏡型態觀測…………………..122
圖4-5、高分子-微脂粒於pH 7.4磷酸根水溶液中24小時後之變化……123
圖4-6、高分子-微脂粒在不同蛋白質溶液中6小時及24小時的粒徑變化
…………………………………………………………….………125
圖4-7、高分子-微脂粒於磷酸緩衝水溶液以及蛋白質溶液中6小時和24小時之藥物洩漏率……………………………………………….128
圖4-8、高分子-微脂粒在高濃度下對老鼠纖維母細胞L929之細胞
毒性測試………………………………………………………….129
圖4-9、高分子-微脂粒與血清蛋白成分混合24小時後巨噬細胞吞噬之情形
……………………………………………………………………….130
圖4-10、不同高分子-微脂粒癌症細胞吞噬路徑之分析………………….133
圖5-1、mPEG-b-P(HEMA-co-MEA-co-His)-Chol之合成反應式………139
圖5-2、高分子mPEG-b-P(HPMA-co-MEA-co-His)-Chol之1H-NMR圖譜
…………………………………………………………………….147
圖5-3、高分子mPEG-b-P(HPMA-co-MEA-co-His)-Chol之FT-IR圖譜147
圖5-4、高分子-微脂粒之穿透式電子顯微鏡之影像……………………150
圖5-5、高分子-微脂粒分別在蛋白質溶液中24小時後之粒徑變化…..151
圖5-6、包含抗癌藥物之高分子-微脂粒分別在蛋白質溶液中6小時和
24小時藥物洩漏情形…………………………….………….…153
圖5-7、高分子-微脂粒不同酸鹼環境下藥物釋放行為圖 ………………154
圖5-8、大腸癌細胞HCT116在1和3小時對高分子-微脂粒吞噬……155
圖5-9、高分子-微脂粒在人類大腸癌細胞內之共軛焦顯微鏡圖………..157
圖5-10、高分子-微脂粒對小鼠纖維母細胞L929之細胞毒性……...…..159
圖5-11、包覆抗癌藥物高分子-微脂粒以及小分子抗癌藥物對大腸癌細胞HCT116之細胞毒性……………………………………………...160
圖5-12、裸鼠體給藥後6小時以及24小時之生體分布情形以及給藥24小時後高分子-微脂粒於全身器官與腫瘤之累積情情形…………162
圖5-13、高分子-微脂粒腫瘤抑制效果、體重變化以及生存曲線………..164
























表目錄

表2-1、正在進行臨床試驗或已上市之微脂粒產品………………………….8
表2-2、不同疏水碳鏈之命名………………………………………………..15
表3-1、共聚物mPEG-b-P(HPMA-co-His)-Chol之組成比………………..65
表3-2、不同高分子-微脂粒、傳統型微脂粒之組成和粒徑大小、
分布結果…………………………………………….………………67
表3-3、腫瘤標的高分子微脂粒之交聯程度………………………….……72
表3-4、不同pH 值下物理交聯程度………………………………….……83
表4-1、高分子mPEG-b-P(HEMA-co-MEA)-Chol之鑑定………….……121
表4-2、高分子-微脂粒之組成和粒徑大小與分布………………….….…122
表4-3、微脂粒之藥物含量及藥物包覆效率………………….………….127
表5-1、不同高分子共聚物之組成…………………………………………148
表5-2、高分子-微脂粒之粒徑大小與分布………………………………..149
表5-3、高分子-微脂粒之藥物含量及藥物包覆效率……………………..152
表5-4、小鼠給藥30天後肝功能及腎功能評估指標………………………165
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