臺灣博碩士論文加值系統

維生素E衍生物，生育酚琥珀酸酯 α-tocopheryl succinate (α-TOS)，對於癌症細胞的特異性與優異抗癌效果，使其近年來被廣泛討論與應用於癌症治療。然而，α-TOS在高分子微胞之應用，除了α-tocopheryl polyethylene glycol succinate (TPGS)外較為少見。本研究以α-TOS為主軸，接枝上不同功能之高分子，自組裝形成奈米微胞，針對人類大腸癌細胞(HCT116)進行in vitro 與 in vivo之抑癌效果評估，實驗將分為三部分進行。在研究的第一個部分，結合含維生素E接枝型高分子與mPEG-b-PLA團聯高分子製備出複合型奈米微胞，對於其組成與特性進行探討。在第二部分的實驗，則是將含維生素E之高分子包載小分子抗癌藥物Dox，組裝成奈米微胞，藉以降低正常細胞毒性與提升化療效果。最後一個部分的實驗，將酸鹼敏感型分子Histidine與高分子鍵結，製備出柱狀微胞，並深入探討柱狀微胞與傳統球狀微胞於蛋白質吸附、細胞吞噬與癌症治療之差異。
第一部分的研究係利用兩條高分子鏈段，包含團聯高分子methoxy poly (ethylene glycol)-b-poly(D,L-lactide)，mPEG-b-PLA，與接枝型高分子poly(hydroxypropyl methacrylamide)-g-α-tocopheryl succinate，PHPMA-g-α-TOS，自組裝形成複合型微胞並包覆抗癌藥物doxorubicin，Dox，針對複合型微胞之高分子組成與性質鑑定進行了詳細的研究。經由實驗證實，以16個α-TOS重複單位之接枝型高分子與48個lactide重複單位之團聯高分子可組裝出最佳粒徑大小之複合型微胞，約為45nm。並利用接枝型高分子組裝而成的接枝型微胞當成對照組進行後續實驗。當藥物濃度為1mg/ml時，自組裝之複合型微胞可得最佳粒徑約110nm，其載藥率為1.4wt%。mPEG-b-PLA團聯高分子也在本研究中證實了其存在於複合型微胞之重要性，由於外層覆蓋著PEG親水殼層，使得複合型微胞擁有優異的抗蛋白質吸附表面，可避免被巨噬細胞吞噬，在血清環境中較為穩定。在酸性環境下複合型微胞可以有效的釋放Dox，且mPEG-b-PLA易於水解的特性也加速了微胞結構瓦解與α-TOS釋放。由細胞毒性的測試可以證實，複合型奈米微胞在不包覆藥物的狀態下對正常細胞無毒性，而載藥微胞則顯示了其對於癌細胞的優異毒殺效果。
第二部分的研究，則是將第一部分中的兩條高分子，聚集其優點，利用脂鍵聚合成一條雙親性高分子methoxy polyethylene glycol-block- poly(2-hydroxyethyl methacrylate-graft-a-TOS)，mPEG-b-P (HEMA-g-a-TOS)，利用溶劑交換的方式可成功製備出粒徑大小約為50nm之高分子微胞，並對於癌症治療進行了體內與體外的實驗。富含a-TOS之高分子微胞在中性環境中粒徑均一且性質穩定，在酸性胞器的環境下可因部分脂鍵水解導致結構變型，進而釋放a-TOS與抗癌藥物Dox，Dox在酸性環境下96小時之累積釋放量可達80%，而a-TOS在酸性環境下也可被偵測到具有較顯著的釋放行為，進一步證實了微胞結構的瓦解。而包覆Dox之奈米微胞在研究中被證實對癌細胞有明顯毒殺效果，卻可以有效降低Dox對正常細胞的傷害。在動物實驗方面，mPEG-b-P (HEMA-g-a-TOS)高分子微胞除了可以有效的經由EPR效應提升在腫瘤組織的累積，對於長期腫瘤抑制也有顯著的效果，且不會造成肝腎負擔。
第三個部分，為了提升微胞系統之酸鹼應答性質，將第二部分的mPEG-b-P (HEMA-g-a-TOS)高分子做延伸，另外接枝上酸鹼敏感型分子，Histidine。本實驗利用Histidine側鏈之pKa值為6，在酸性環境下可被質子化之特性，使微胞結構不穩定，加速微胞瓦解並促進藥物釋放。另一方面，為了提升a-TOS與Dox對於癌細胞的共治療效應，也將微胞同時裝載小分子Dox與小分子a-TOS兩種藥物。研究發現，包覆藥物之mPEG-b-P (HEMA-g-a-TOS-g-His)高分子微胞會成柱狀外型，由於球狀與柱狀高分子微胞在高分子結構、表面電荷與粒徑大小上都沒有明顯的差異，故本實驗針對了高分子微胞之型態差異進行了在生物體環境中的比較。在結構上，由於柱狀微胞分子結構排列較緊密，使其載藥量超過球狀的兩倍，且因接枝Histidine，使微胞在酸性環境下的藥物釋放更顯著，在24小時內，Dox之藥物釋放率接近90%，a-TOS之釋放率更是接近100%。進一步導致柱狀微胞在細胞毒性的測試有優異的表現。與球狀微胞相比，柱狀細胞毒殺癌細胞的效果較好，且對於正常細胞毒性較低。然而，由於型態的差異，表面曲度較低柱狀微胞會吸引部分血清蛋白質吸附，導致粒徑變化劇烈，使其被癌細胞吞噬的效果與球狀微胞相比略遜一籌。在動物實驗部分，雖然兩種型態之微胞都在腫瘤有明顯累積，但由於柱狀微胞有蛋白質吸附的狀況，吸引巨噬細胞的吞噬，增加了肝臟中的累積。總而言之，兩種型態之奈米微胞各有其優缺點，希望可以提供未來於高分子奈米微胞在型態上之研究提供些許助益。
本研究以α-TOS為基礎，將其接枝上具有不同功能之高分子，組裝出四種高分子微胞系統，包覆抗癌藥物Dox，進行癌症治療之相關實驗。實驗結果可證實，本研究所開發之四種高分子微胞系統皆具備酸鹼應答性質，酸性環境下脂鍵鍵結加速水解，可將微胞結構瓦解並觸發藥物釋放。微胞系統所釋放之α-TOS與Dox也存在了共治療的效應，可有效提升癌症治療效果並降低對正常細胞之毒性。研究結果亦證實，具備PEG殼層之高分子微胞系統具備良好的抗蛋白質吸附效果。在最後一個部分的實驗，針對不同的微胞型態進行了深入的探討，證實微胞型態之差異有可能提升蛋白質吸附的機率，導致被體內網狀內皮系統所捕捉並造成肝臟累積。本研究深入探討了α-TOS在癌症藥物載體應用上的各種可能性，實驗結果亦證實了此類高分子微胞使用於癌症治療之潛力。

α-Tocopheryl Succinate (a-TOS) has been widely studied because of their anti-tumor properties. It has been demonstrated that a-TOS molecules could selectively kill cells with a malignant or transformed phenotype. Additionally, a-TOS and Dox could exhibit cooperated effect to increase the anti-cancer efficacy via enhancing cellular uptake level of Dox.In this study, three different micelle drug delivery systems were developed. a-TOS containing polymers were applied to self-assemble into micelles and deeply evaluated the anti-tumor therapeutic efficacy.
The first part of this study, mixed micelles formed from the biocompatible diblock copolymer methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PLA) and the vitamin E containing graft copolymer poly(hydroxypropyl methacrylamide)-g-a-tocopheryl succinate (PHPMA-g-a-TOS) were investigated to encapsulate anticancer drug doxorubicin (Dox) for evaluating anticancer capacity. Various graft and diblock copolymers were synthesized and characterized. According to our experimental results, mixed micelles composited of mPEF-b-PLA diblock copolymer which contained 48 repeating units of lactide and P(HPMA-g-α-TOS) grafted copolymer which contained 16α-TOS repeating units showed optimal size and size distribution. The size of mixed micelles was around 45nm. When the Dox concentration of 1mg / ml, mixed micelles could get optimum particle size of about 110nm and drug loading rate was 1.4wt%. The mPEG-b-PLA diblock copolymers were showed the importance in mixed micelle system. These copolymers not only exhibited excellent anti-protein adsorption abilities, but also accelerated a-TOS cleaved from graft copolymers and released from mixed micelles. From the cytotoxicity test, mixed micelles presented a low risk to L929 normal cells but high toxicity to HCT116 colon cancer cells. An internalization study indicated that mixed micelles were accumulated more in HCT116 cells than micelles prepared from graft copolymers alone because mixed micelles had better stability in a serum medium. An ex vivo study also showed that mixed micelles could largely accumulate in the tumor.
To simplify the chemical structure of vitamin E containing polymers. An a-tocopheryl succinate (a-TOS) containing diblock copolymer was further synthesized by conjugation of a-TOS molecules and a mPEG-b-PHEMA hydrophilic diblock copolymer by ester bonds. The polymeric micelles were then obtained by solvent exchange process and the size of polymeric micelle was around 50nm. In acidic surroundings such as endosomes or secondary lysosomes, the structures of the Dox-loaded polymeric micelles deformed and released the drug loads. After 96h observation, the accumulative release of Dox was upto 80%. Additionally, Dox-loaded polymeric micelles enhanced the cytotoxicity of Dox and a-TOS to cancer cells in vitro. Dox-loaded polymeric micelles also showed an exceptional tumor inhibiting effect in vivo. Micelles could accumulate in tumor tussue sucsessfully by EPR effect and showed hypotoxic to the liver and kidney
In order to enhance the pH-sensitivity of micelle system, we introduced pH-responsive molecular, histidine, into polymer structure. The imidazole ring of histidince has a pKa around pH 6 and would be protonated in acidic surrounding. Micelle structure became unstable due to the repulsive force caused by positive charge. After durg encapsulation, the morphology of micelles became cylindroid. To understand the influence of different-shaped micelles on biologic system and therapeutic efficacy, the third part of this study prepared spherical and cylindrical micelles that composed of mPEG-b-P(HPMA-g-α-TOS) based copolymers for encapsulating anticancer drugs, doxorubicin, and α-TOS. Experimental results map the relationship between micellar shape with protein adsorption, size changes of micelles, macrophages uptake, normal/cancer cell internalization, normal organ/tumor accumulation and cancer therapeutic efficacy. As compared to cylindrical micelles, the adsorption of protein and the changes of size on spherical micelles are limited, the therapeutic efficacy of spherical micelles is better. According to these results, we demonstrate that the shape of micelles deeply affects the micellar properties in many ways, which provides some reference basis for future design of micelles in cancer therapy.
In this study, α-TOS based polymeric micelle systems were developed in four different ways and encapsulated with Dox as drug carriers. The cooperation effect of α-TOS and Dox was showed significantly in vitro and in vivo in four micelle systems. α-TOS could efficiently enhance the cellular level of Dox and influence the cell cycle in cancer cell. At the same time, α-TOS containing micelles could reduce the cytotoxicity of Dox to normal cells. Polymeric micelles which covered by PEG shell has been demonstrated the anti protein adsorption ability and blood circulation time prolongation in this study. The relationship between micelle morphology and physiological environment was also investigated. It has been proved that cylindrical morphology of micelles could increase protein adsorption probability and capture by RES system. Above all, α-TOS containing polymeric micelle systems were showed highly potential in chemo-drug co-treatment cancer therapeutic applications.

章節目錄
誌謝 i
中文摘要 ii
Abstract v
章節目錄 viii
圖目錄 xii
表目錄 xvii
第一章、 研究動機 1
第二章、 文獻探討 3
2-1 癌症與腫瘤微環境 3
2-2 高分子微胞在癌症治療之應用 6
2-2.1高分子微胞之製備與作用機制 8
2-2.2被動標靶 10
2-2.3主動標靶 11
2-2.4 環境應答型高分子微胞 12
2-3 維生素E與其衍生物 15
2-3.1 維生素E治療癌症之作用機轉 18
2-3.2 維生素E與其他藥物之合併治療 22
2-3.3具維生素E之高分子在癌症治療之應用 24
第三章、 含維生素E接枝型高分子與mPEG-b-PLA團聯高分子之載藥複合型微胞之製備與鑑定 25
3-1、研究目的 25
3-2、實驗方法與材料 27
3-2.1、實驗藥品 27
3-2.2、儀器與裝置 28
3-2.3、高分子之合成與鑑定 29
3-2.4、複合型微胞的製備與分析 32
3-2.5、複合型微胞之酸鹼應答性 33
3-2.6、複合型微胞之藥物釋放行為 34
3-2.7、複合型微胞之蛋白質吸附測試 34
3-2.8、複合型微胞之細胞毒性測試 34
3-2.9、複合型微胞之細胞吞噬效果 35
3-2.10、複合型微胞之動物體內分布測試 36
3-2.11、統計分析方法 36
3-3.1、雙團聯共聚物 mPEG-b-PLA 之合成鑑定 37
3-3.2、接枝型高分子 PHPMA-g-α-TOS 之合成鑑定 39
3-3.3、複合型奈米微胞之鑑定 43
3-3.4、複合型奈米微胞之穩定性與酸鹼應答性分析 45
3-3.5、複合型微胞之Dox包覆率 48
3-3.6、奈米微胞之藥物釋放行為 49
3-3.7、奈米微胞於血清蛋白中之穩定度 51
3-3.8、載藥奈米微胞之細胞毒性測試 53
3-3.9、載藥奈米微胞之細胞吞噬行為 57
3-3.10、載藥奈米微胞之動物器官分布 59
第四章、 含維生素E之高分子微胞應用於降低正常細胞毒性與提升化療效果 .61
4-1、研究目的 61
4-2、實驗方法與材料 63
4-2.1、實驗藥品 63
4-2.2、儀器與裝置 63
4-2.3、名詞對照 64
4-2.4、雙團連共聚物mPEG-b-PHEMA之合成 65
4-2.5、mPEG-b-P(HEMA-g-a-TOS) 之合成 66
4-2.6、高分子微胞與載藥高分子微胞之製備 67
4-2.7、高分子微胞之藥物釋放行為 68
4-2.8、細胞毒性測試 69
4-2.9、癌細胞對高分子微胞之吞噬行為 69
4-2.10、細胞週期分析 69
4-2.11、動物體內之生物分佈探討 70
4-2.12、腫瘤抑制與生化指數分析 70
4-2.13、統計分析方法 71
4-3、結果與討論 71
4-3.1、高分子合成與鑑定 71
4-3.2、高分子微胞之製備與鑑定 76
4-3.3、藥物釋放行為 78
4-3.4、細胞吞噬行為分析 82
4-3.5、細胞毒性測試 84
4-3.6、細胞週期探討 88
4-3.7、動物體內生物分佈分析 90
4-3.8、高分子微胞於動物體內抗癌效益 92
第五章、球狀與柱狀微胞在蛋白質吸附、細胞吞噬與癌症治療之比較 96
5-1、研究目的 96
5-2、實驗方法與材料 98
5-2.1、實驗藥品 98
5-2.2、儀器與裝置 99
5-2.3、名詞對照 100
5-2.4、高分子合成 100
5-2.5、微胞製備 103
5-2.6、藥物包覆率與藥物釋放行為 103
5-2.7、蛋白質吸附 104
5-2.8、細胞吞噬行為 104
5-2.9、生物分佈性分析 105
5-2.10、細胞毒性測試 105
5-2.11、細胞內釋藥觀測 105
5-2-12、細胞週期分析 106
5-2.13、動物體內之抗腫瘤效果與肝腎毒性分析 106
5-2.14、統計分析方法 107
5-3、結果與討論 108
5-3.1、高分子材料鑑定 108
5-3.2、微胞之製備與鑑定 112
5-3.3、微胞之酸鹼應答性質與藥物釋放行為 114
5-3.4、微胞形態與蛋白質吸附之關係 116
5-3.5、動物分佈分析 120
5-3.6、微胞形態對於細胞吞噬行為之影響 122
5-3.7、微胞形態對於細胞毒性之影響 125
5-3.8、微胞形態對於細胞週期之影響 127
第六章、結論 133
第七章、參考文獻 135

 
圖目錄
第二章、文獻探討
圖2-1、angiogenic switch[2] 3
圖2-2、Enhanced Permeability and Retention (EPR) effect[4] 4
圖2-3、腫瘤細胞因缺氧環境行糖解作用示意圖[10] 5
圖2-4、常見的奈米粒子載體[11] 6
圖2-5、高分子微胞 (A)雙親性高分子於水中自聚合成高分子微胞 (B)雙親性高分子以物理滯留方式包覆疏水性藥物。[15] 7
圖2-6、高分子微胞之製備方式 (A) 溶劑置換法 (B)溶劑揮發法[16] 9
圖2-7、General concept of endocytosis[18](A)胞吞作用之路徑 (B)受質被細胞吞噬之機制 10
圖2-8、(A)被動標靶 (B) 上:小分子的簡單擴散；下：被動標靶之高分子微胞在腫瘤內的累積效應[23] 11
圖2-9、General concept of active targeting. (A)針對癌細胞的主動標靶 (B)針對腫瘤血管內皮細胞的主動標靶。[23] 12
圖2-10、細胞內不同胞器的pH值變化[26] 13
圖2-11、(A) 典型之高分子溶液與溫度之間的相變化行為 (B)溫感型高分子微胞的作用示意圖。[36] 14
圖2-12、氧化還原型高分子微胞在癌細胞作用示意圖。[37] 15
圖2 -13、維生素E之八種異構物。[40] 16
圖2-14、維生素E之三大功能性區域[43] 18
圖2-15、細胞週期與調控蛋白[46] 20
圖2-16、細胞凋亡途徑：extrinsic pathway和intrinsic pathway 21
圖2-17、TPGS之化學結構[69] 22

第三章、含維生素E接枝型高分子與mPEG-b-PLA團聯高分子之載藥複合型微胞之製備與鑑定
圖3-1、含維生素E接枝型高分子與mPEG-b-PLA團聯高分子之載藥複合型微胞卡通示意圖。 26
圖3-2、mPEG-b-PLA之合成步驟 29
圖3-3、脂化反應催化劑DPTS之合成 30
圖3-4、P(HPMA)之合成 30
圖3-5、接枝型高分子PHPMA-g-a-TOS之合成。 32
圖3-6、mPEG-b-PLA 之 1H-NMR 光譜圖(A) ，FT-IR光譜圖 (B)　與GPC鑑定圖(C)。 38
圖3-7、P(HPMA) 之 1H-NMR 光譜圖(A) ，FT-IR光譜圖 (B)　與GPC鑑定圖(C)。 41
圖3-8、P(HPMA)-g-α-TOS 之 1H-NMR 光譜圖(A) ，FT-IR光譜圖 (B)　與GPC鑑定圖(C)。 43
圖3-9、(A)三種不同 α-TOS 比例之 P(HPMA)-g-α-TOS 與 L35 之粒徑及分布。(B) E16 與三種不同組成比之 mPEG-b-PLA 之粒徑及分布 45
圖3-10、奈米微胞於 pH7.4 及 pH4.5 環境下之粒徑變化(*:p<0.05) 46
圖3-11、奈米微胞於 pH7.4 與 pH4.5 不同時間點之 TEM 圖 47
圖3-12、利用GPC進行mPEG-b-PLA水解測試 47
圖3-13、複合型與接枝型奈米微胞在不同酸鹼值下之Dox (A) 與α-TOS (B) 藥物釋放行為 50
圖3-14、奈米微胞於 BSA 蛋白質溶液之粒徑變化量(**:p<0.01, ***:p<0.001) 52
圖3-15、HCT116細胞對於微胞在有無血清蛋白環境下之吞噬情形。SF: serum free medium 52
圖3-16、α-TOS 及奈米微胞與小鼠纖維母細胞株 L929 共培養之細胞毒性(a)24h(b)96h 54
圖3-17、α-TOS 及奈米微胞與人類結腸癌細胞株HCT116共培養之細胞毒性(a)24h(b)96h 55
圖3-18、Dox及奈米微胞與人類結腸癌細胞株HCT116共培養之細胞毒性 56
圖3-19、藥物及含藥奈米微胞與人類大腸癌細胞共培養 1及24 小時之分布情況 58
圖3-20、奈米微胞於裸鼠體內重要器官與腫瘤在24小時的累積情形。 60

第四章、 含維生素E之高分子微胞應用於降低正常細胞毒性與提升化療效果
圖4-1、含維生素E之團鏈高分子之 (A)化學結構與(B)作用示意圖 62
圖4-2、雙團連共聚物mPEG-b-PHEMA之合成 66
圖4-3、高分子mPEG-b-P(HEMA-g-a-TOS)之合成 67
圖4-4、高分子mPEG-b-P(HEMA)之化學結構鑑定(A)1H-NMR (B)FT-IR (C)GPC 73
圖4-5、高分子mPEG-b-P(HEMA-g-α-TOS)之化學結構鑑定(A)1H-NMR (B)FT-IR 75
圖4-6、PHE40(A)與PHE64(B)在DMF中之水合半徑 76
圖4-7、高分子微胞在不同pH環境下之α-TOS藥物釋放行為(A)以及粒徑變化(B) 79
圖4-8、Dox在不同pH值之緩衝溶液下的釋放行為 80
圖4-9、載藥微胞於pH7.4與pH5.0環境中1、12、48、96小時之TEM影像。 81
圖4-10、藥物Dox及載藥微胞與人類大腸癌細胞 HCT116 共同培養0.5、1以及3小時之細胞吞噬情況 83
圖4-11、癌細胞HCT116與載藥微胞共培養2小時之細胞吞噬量化分析。 84
圖4-12、α-TOS與未載藥微胞對於HCT116(A)與L929(B)之細胞毒性測試 86
圖4-13、Dox與載藥微胞對於HCT116(A)與L929(B)之細胞毒性測試 87
圖4-14、α-TOS、Dox、載藥微胞與HCT116及L929培養48小時後之IC50 87
圖4-15、Dox、未載藥微胞以及載藥微胞與HCT116共培養24小時後，對於細胞週期之影響 89
圖4-16、(A)微胞於動物體內分佈之活體影像分析 (B)微胞於動物各主要器官與腫瘤組織內之累積情形。 91
圖4-17、腫瘤抑制效果 (A)腫瘤相對體積變化 (B)裸鼠體重變化 93
圖4-18、動物之肝腎功能指數分析 (A)肝功能指數:GOT與GPT (B)腎功能指數:BUN與CRE 95

第五章、球狀與柱狀微胞在蛋白質吸附、細胞吞噬與癌症治療之比較
圖5-1、實驗示意圖 97
圖5-2、 小分子α-TOS-MA合成示意圖 101
圖5-3、高分子 mPEG-b-P(HPMA-g-α-TOS) (product 1) 與 mPEG-b-P(HPMA-g-α-TOS-g-His)(product 2)合成示意圖 102
圖5-4、mPEG-b-P(HPMA-g-α-TOS) 之結構鑑定(A) 1H-NMR光譜圖 (B)FT-IR光譜圖 109
圖5-5、mPEG-b-P(HPMA-g-α-TOS-g-His) 之結構鑑定(A) 1H-NMR光譜圖 (B)FT-IR光譜圖 111
圖5-6、PT與PTH高分子載藥前後之微胞形態TEM影像。(A)載藥前 (B)載藥後 112
圖5-7、球狀與柱狀微胞在中性與酸性環境下之Dox釋放行為(A) 、α-TOS釋放行為(B) 與形態變化(C) 116
圖5-8、球狀與柱狀微胞於不同蛋白質共培養24小時後之吸附現象分析 (A) BSA (B)fibrinogen (C)IgG。Ctrl:control，Sph:spherical，Cyl:cylindrical 118
圖5-9、微胞與血清蛋白共培養24小時之粒徑變化 119
圖5-10、巨噬細胞RAW264.7對於球狀與柱狀微胞之吞噬行為分析 120
圖5-11、微胞在裸鼠體內之生物分佈性分析 (A)全身性分佈 (B)內臟累積 (C)內臟累積量化圖 121
圖5-12、針對L929與HCT116細胞株之微胞攝取行為探討 123
圖5-13、微胞於HCT116細胞內之分佈情形與藥物釋放 124
圖5-14、微胞的細胞毒性測試 (A)48小時內，未載藥之球狀微胞與柱狀微胞對L929以及HCT116之毒殺效果 (B) 48小時內，載藥之球狀微胞與柱狀微胞對L929以及HCT116之毒殺效果 126
圖5-15、載藥微胞對於L929與HCT116細胞週期之影響 (A) 載藥微胞週期與L929細胞共培養24小時後之細胞週期量化圖 (B) 載藥微胞週期與HCT116細胞共培養24小時後之細胞週期量化圖 (C) L929之FL2-A histogram (D) HCT116之 FL2-A histogram 128
圖5-16、載藥微胞之長期治療效果。(A)腫瘤抑制效果 (B)動物體重變化 (C)肝指數 (D)腎指數 131
圖5-17、球狀與柱狀微胞之特異性卡通示意圖 132
 
表目錄
第二章、文獻探討
表2-1、α-TOS對於多種細胞株具有誘導細胞凋亡的能力[42] 17

第三章、含維生素E接枝型高分子與mPEG-b-PLA團聯高分子之載藥複合型微胞之製備與鑑定
表3-1、mPEG-b-PLA 之組成比例 39
表3-2、P(HPMA)-g-α-TOS之組成比例 43
表3-3、奈米微胞以不同 Dox 濃度進行包覆之性質分析 48

第四章、 含維生素E之高分子微胞應用於降低正常細胞毒性與提升化療效果
表4-1、高分子mPEG-b-P(HEMA-g-α-TOS)之組成比例 74
表4-2、不同組成比例mPEG-b-P(HEMA-g-α-TOS)所組裝成之高分子微胞粒徑分佈 77

第五章、球狀與柱狀微胞在蛋白質吸附、細胞吞噬與癌症治療之比較
表5-1、PT與PTH高分子之組成與數量平均分子量 110
表5-2、微胞載藥前後之粒徑分佈、PDI與表面電位以及藥物包覆含量與藥物包覆效率 113

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