臺灣博碩士論文加值系統

本論文透過兩種不同的新穎雙親性嵌段共聚高分子poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- 6-(methacrylamido)hexanoic acid] [PCL-b-P(TEGMA-co-AHA)]與poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- N-(2-(methacrylamido)ethyl) folatic amide] [PCL-b-P(TEGMA-co-FA)] 自組裝形成具多功能之複合高分子微胞，並針對其奈米結構、刺激應答性質(stimuli-responsive)與作為抗癌藥載體之應用進行研究。在本系統中以PCL作為可容納抗癌藥物的疏水鏈段，以具有溫度敏感性質的PTEGMA作為協助微胞分散於水中的親水鏈段，並在組成複合高分子微胞的兩種雙親性嵌段共聚高分子中分別於親水鏈段混摻微量具酸鹼值敏感性質的AHA與具癌症標靶功能的葉酸(Folic acid)。
在[PCL-b-P(TEGMA-co-AHA)]系列中，我們發現能夠透過改變AHA之混摻比例調整親水鏈段的親水性，進而將其最低臨界溶解溫度(lower critical solution temperature, LCST)調整至接近於人體體溫。當在不同酸鹼值環境時，高分子微胞由於AHA上的羧酸去質子化程度不同而改變微胞的親水性。因此在適當的AHA混摻比例下，我們可將微胞的LCST調整至在中性環境下高於37℃，而在酸性環境下低於37℃。如此一來，在接近中性的生理環境中藥物載體即可維持穩定的高分子微胞結構藉此在血液中達到較長的循環時間；並在接近酸性環境的癌細胞周圍由於LCST低於體溫而導致微胞崩解，達到快速藥物釋放的目的。
在[PCL-b-P(TEGMA-co-FA)]系列中，本研究將具有癌症標靶功能之葉酸以不同比例混摻於親水鏈段中以加速藥物在癌症細胞的累績。透過化學修飾於高分子側鏈的方式，我們能夠更準確的控制葉酸在高分子鏈中的含量，進而比較不同含量的葉酸對於癌細胞標靶功能之影響；並且利用TEGMA的保護避免其他酵素與葉酸非預期的作用與過早的內吞效應，藉以增加葉酸在癌症標靶功能之效率。此外，在複合高分子微胞系統中，透過調整兩種高分子的投料比例我們更能夠準確地控制微胞中葉酸含量與微胞的環境應答性質。

In this work, a new series of mixed polymeric micelles with multi-functionalities was investigated and their application as the carrier of anti-cancer drugs was explored. These micelles were self-assembled from two amphiphilic diblock copolymers, poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- 6-(methacrylamido)hexanoic acid] [PCL-b-P(TEGMA-co-AHA)] and poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- N-(2-(methacrylamido)ethyl) folatic amide] [PCL-b-P(TEGMA-co-FA)]. The hydrophobic core of micelles composed of the PCL block could act as the reservoir for hydrophobic drug, and the hydrophilic shell of micelles which facilities the dispersion of micelles in aqueous solution was functionalized with stimuli-responsive and actively targeting properties by tailoring the TEG, AHA and FA moieties as the pendants of the copolymers.
The stimuli-responsive properties of these micelles could be manipulated by adjusting the block ratio and the molar content of AHA, and the optimized lower critical solution temperature (LCST) was higher than 37℃ at physiological condition and lower than 37℃ in acidic environment so that the mixed micelles would have high stability in human body to get long circulation in blood and collapse around acidic cancer cell for rapidly drug delivery. Folic acid (FA) is known as a useful active-targeting ligand for the cancer cells overexpressed with folate receptors and widely used to improve micelles accumulation rate. We anchored folate within the corona layer PTEGMA because it has proved that the inert PTEGMA coronas are expected to protect FA moieties from undesirable enzymatic attack and premature endocytosis processes. By mixed micelles model, we could control the content of FA in nanoparticle more precisely.

摘要 I
Abstract III
誌謝 V
目錄 VII
流程目錄 (LIST OF SCHEMES) X
表目錄 (LIST OF TABLES) XI
圖目錄 (LIST OF FIGURES) XIII
第1章、 緒論 1
1.1研究背景與文獻回顧 1
1.1.1雙親性共聚高分子 1
1.1.2 功能性高分子材料 5
1.1.3藥物傳遞 13
1.2 研究動機與目的 26
第2章、 實驗 27
2.1實驗藥品 27
2.2實驗方法 29
2.2.1 單體合成 29
2.2.2 高分子聚合 31
2.2.3 微胞製備 36
2.2.4 Critical micelle concentration (CMC)檢測 36
2.2.5 Lower critical solution temperature (LCST)測試 38
2.2.6 藥物包覆與釋放 38
2.3儀器鑑定 41
2.3.1 Gel permeation chromatography (GPC) 41
2.3.2 Nuclear Magnetic Resonance (NMR) 41
2.3.3 Dynamic Light Scattering (DLS) 42
2.3.4 Ultraviolet-Visilbe Spectroscopy (UV-vis.) 42
2.3.5 Transmission Electron Microscopy (TEM) 43
2.3.6 Photoluminescence Spectroscopy (PL) 43
第3章、 結果與討論 44
3.1 聚合和鑑定 44
3.1.1 Hydroxyethyl 2-bromoisobutyrate (YQ initiator)合成 45
3.1.2 TEGMA單體合成 46
3.1.3 NSMA單體合成 47
3.1.4 Poly(ɛ-caprolactone)(PCL，P0)聚合 48
3.1.5 雙親性嵌段共聚高分子poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- N-hydroxysuccinimide methacrylate] [PCL-b-P(TEGMA-co-NSMA)，P1~P5]之合成 50
3.1.6 雙親性嵌段共聚高分子 [PCL-b-P(TEGMA-co-AHA)](P1-AHA、P2-AHA、P3-AHA)與[PCL-b-P(TEGMA-co-FA)] (P4-FA、P5-FA)之合成 52
3.2微胞的製備與性質鑑定 57
3.2.1溫度敏感性質 57
3.2.2 CMC性質測試 63
3.3混合微胞製備與性質鑑定 66
3.3.1 葉酸含量鑑定 67
3.3.2溫度敏感性質 69
3.3.3 CMC性質測試 75
3.4藥物包覆與釋放測試 77
3.4.1 藥物包覆 77
3.4.2 藥物釋放 81
第4章、 結論與未來工作 83
第5章、 文獻回顧 85

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