本研究利用微波輔助可逆加成斷裂鏈轉移(Reversible Addition-Fragmentation Chain Transfer Polymerization, RAFT)活性自由基聚合製備環境敏感型聚(N-異丙基丙烯醯胺)-聚(甲基丙烯酸)-聚(甲基丙烯酸丁酯)嵌段共聚物(PNP-b-PMAA-b-PBMA)，進而將此共聚物與羧甲基幾丁聚醣(CMCS)自組裝形成奈米顆粒以此作為藥物載體，首先將幾丁聚醣進行化學修飾以形成CMCS，探討在不同反應溫度、反應時間、NaOH濃度對總取代度(DS)的影響，並且研究CMCS在不同pH 值水溶液下的溶解性，結果發現CMCS(DS = 2)在pH 4-6下不溶，其他pH 值則是澄清透明。同時比較傳統加熱與微波加熱對於取代度的差異，結果發現在相同取代度下，利用微波加熱可縮短反應時間至30分鐘(T = 40、45、60 oC)，藉由動態光散射測量其粒徑及表面電位，結果表明羧甲基幾丁聚醣pKa介於3-4之間與文獻相符，在pH值為4-6時粒徑遠大於其他pH值代表羧甲基幾丁聚醣鏈上的胺基及酸基自我相吸形成顆粒，pH 3以下則帶正電，pH 4以上則帶負電。
接著使用微波輔助RAFT活性自由基聚合PNP-b-PMAA-b-PBMA嵌段共聚物，反應中發現在混合溶劑系統中Dioxane及DMF的比例為28:2時，反應一小時後會產生均勻的顆粒，其原因為Dioxane會誘導嵌段共聚物形成自組裝顆粒，藉由UV及NMR確認在反應一小時後嵌段共聚物鏈長不會再增加。最後以同樣的方法合成出PNP-b-PMAA-b-PBMA三嵌段共聚物，探討三嵌段共聚物在純水與PBS緩衝液中LCST的變化，得知在PBS中會由於鹽類遮蔽效應而導致共聚物的LCST值與純聚(N-異丙基丙烯醯胺)一樣，而在純水中，嵌段共聚物則會因為pH 值改變而改變。在pH 值為3時，會因為低於聚(甲基丙烯酸)之pKa而造成嵌段共聚物所帶的負電不足以及分子間/分子內的氫鍵而沉澱，因此所合成出來的嵌段共聚物無法在pH 3的環境下與羧甲基幾丁聚醣形成複合顆粒。

In this study we uses microwave-assisted reversible addition fragmentation chain transfer living radical polymerization to prepare environmentally sensitive poly(N-isopropylacrylamide)-poly(methacrylic acid)-poly(butyl methacrylate) block copolymers, than the copolymer and carboxymethyl chitosan are self-assembled to prepare nanoparticle as a drug carrier.First,chitosan is chemically modified to form carboxymethyl chitosan (CMCS), discuss the influence of different reaction temperature, reaction time, NaOH concentration on the total degree of substitution, and study the solubility of CMCS at different pH values, result that CMCS (DS = 2) was incompatible at pH 4-6, and other pH values were clear and transparent. At the same time, comapare with difference between traditional heating and microwave heating for the degree of substitution was compared, and it was found that under the same degree of substitution, using the microwave heating can shorten the reaction time to 30 minutes (T = 40, 45, 60 oC), and the particle size and surface potential are measured by dynamic light scattering(DLS).. The results show that the pka of carboxymethyl chitosan is between 3-4 It is consistent with the literature. When the pH value is 4-6, the particle size is much larger than other pH values. It means that the amino groups and acid groups on the carboxymethyl chitosan chain self-attract to form particles. Below pH 3, it is positively charged. Above 4 is negatively charged.
Next, using microwave-assisted reversible addition fragmentation chain transfer living radical polymerization to synthesize poly(N-isopropylacrylamide)-poly(methacrylic acid) block copolymer, it was found that Dioxane and DMF in the mixed solvent system When the ratio is 28:2, uniform particles will be produced after one hour of reaction. The reason is that Dioxane will induce the block copolymer to form self-assembled particles. UV and NMR confirm that the chain length of the block copolymer will not increase after reaction 1 hr.Finally, the poly(N-isopropylacrylamide)-poly(methacrylic acid)-poly(butyl methacrylate) block copolymer was synthesized by the same method. Study LCST in the liquid, it is known that the copolymer LCST is the same as pure poly(N-isopropylacrylamide) when dissolved in PBS due to the salt shielding effect, while in pure water, the block copolymer will be The pH value changes and changes. When the pH value is 3, it is lower than the pKa of poly(methacrylic acid), which causes the block copolymer to have insufficient negative charge and precipitate. Therefore, the synthesized block copolymer cannot be combined with carboxymethyl under the environment of pH 3. Chitosan forms composite particles.

目錄
中文摘要	I
英文摘要	III
目錄	V
圖目錄	VII
表目錄	XVI
第一章緒論	1
1.1 前言	1
1.2 研究動機與目的	1
第二章文獻回顧	3
2.1 幾丁質與幾丁聚醣之簡介	3
2.2 羧甲基幾丁聚醣之簡介	5
2.3 環境敏感型高分子	9
2.4 微波合成	19
2.5 可逆加成-斷裂鏈轉移聚合法(Reversible Addition-Fragmentation Chain Transfer, RAFT)	25
2.6 奈米顆粒藥物載體	32
第三章 實驗方法與實驗步驟	34
3.1實驗流程及架構	34
3.2 實驗藥品	34
3.3實驗儀器	39
3.3 實驗步驟	42
3.4材料之結構鑑定	52
3.5材料性質分析	53
第四章 結果與討論	54
4.1幾丁聚醣之結構鑑定	54
4.2 羧甲基幾丁聚醣之結構鑑定與性質分析	57
4.3 PNP-b-PMAA嵌段共聚物之合成與自組裝顆粒分析	78
4.4 PNP-b-PMAA-b-PBMA/CMCS複合載體與顆粒分析	123
第五章 結論	123
第六章 參考文獻	125
附錄	132

 
圖目錄
圖2-1 幾丁質去乙醯化反應2	4
圖2-2 纖維素、幾丁質和幾丁聚醣結構圖	4
圖2-3 羧甲基幾丁聚醣衍生物的製備方法	6
圖2-4 環境敏感型高分子示意圖	9
圖2-5 (A) PNP 化學結構圖 (B).鏈伸展(左)和鏈收縮(右)之相變示意圖	12
圖2-6 (A) 在LCST(32°C)以下水溶液中膨潤的PNP水凝膠 (B) 在LCST (32°C)以上收縮的PNP水凝膠	12
圖2-7 P(NIPAAm-co-AAc)在不同pH值下穿透度與溫度變化圖(a) pH 5.7 (b)	13
圖2-8 P(NIPAAm-co-MA)共聚物 在不同MA入料比例下吸收度與溫度變化圖50 (A) P1: P(NIPAAm-co-MA), NIPAAm : MA = 10: 1  (B) P2 :P(NIPAAm-co-	13
圖2-9 1989-2017年涉及有機和無機微波輔助合成的累積文獻	20
圖2-10 使用微波加熱DMF溶劑比較控制恆定瓦數或控制溫度之差異圖	20
圖2-11 試圖與振盪電場對準的偶極分子	22
圖2-12 不同溶劑於相同微波功率加熱下的升溫速率比較曲線圖67	22
圖2-13 微波功率150 W照射下，蒸餾水和自來水的溫度與時間關係圖。上面的曲線代表自來水，下面的曲線代表蒸餾水樣品。	23
圖2-14 溶液中的帶電粒子將跟隨施加的電場圖	23
圖2-15 RAFT聚合反應機制	27
圖2-16 RAFT聚合示意圖	28
圖2-17 在相似的實驗條件下，苯乙烯的常規聚合和RAFT聚合的典型分	28
圖2-18 常見的低活化單體	29
圖2-19 常見的高活性單體	30
圖2-20選擇用於各種聚合反應的Z類RAFT試劑	31
圖2-21選擇用於各種聚合反應的R類RAFT試劑	31
圖2-22 目前臨床中常用於癌症治療的奈米藥物種類圖88。	33
圖3-1 實驗流程及架構圖	34
圖3-2 微波合成反應裝置的瓶組配件圖	43
圖3-3 微波合成反應裝置的瓶組組裝	44
圖3-4 微波合成裝置內部圖	44
圖3-5 微波合成反應裝置的操作頁面-1	45
圖3-6 微波合成反應裝置的操作頁面-2	45
圖3-7 微波合成反應裝置的操作頁面-3	46
圖3-8 微波合成反應裝置的操作頁面-4	46
圖3-9幾丁聚醣的結構圖	47
圖3-10 利用微波加熱以合成反應羧甲基幾丁聚醣(CMCS)反應流程圖	48
圖3-11 微波輔助RAFT法合成PNP-CTA流程圖	49
圖3-12微波合成PNP-CTA及PNP共聚物的反應裝置圖	49
圖3-13 微波輔助RAFT合成 PNP-b-PMAA 流程圖	50
圖3-14微波輔助RAFT合成 PNP-b-PMAA-b-PBMA 流程圖	51
圖4-1 幾丁聚醣的傅里葉轉換紅外光譜圖	54
圖4-2 CS的1H-NMR光譜圖	56
圖4-3 (a)幾丁聚醣(b)羧甲基幾丁聚醣的傅里葉轉換紅外光譜圖	58
圖4-4 利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 0.5 mL，微波加熱功率= 200 W	64
圖4-5 利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq)= 1 mL，微波加熱功率= 200 W	65
圖4-6 利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 1.5 mL，微波加熱功率= 200 W	66
圖4-7 利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 2 mL，微波加熱功率= 200 W	67
圖4-8利用微波加熱於反應溫度為40 oC下反應時間 40 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 2 mL，微波加熱功率= 200 W	68
圖4-9 利用微波加熱於反應溫度為50 oC下反應時間 40 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 2 mL，微波加熱功率= 200 W	69
圖4-10 利用微波加熱於反應溫度為50 oC下反應時間 40 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 2 mL，微波加熱功率= 200 W	70
圖4-11 利用微波加熱於反應溫度為60 oC下反應時間 40 分鐘所測得的CMCS 1H-NMR光譜圖，10 N NaOH(aq) = 2 mL，微波加熱功率= 200 W	71
圖4-12 在不同反應溫度下，CMCS的羧甲基總取代度DStotal對反應時間的關係	72
圖4-13 利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘合成CMCS的反應曲線圖，10N NaOH(aq) = 0.5 mL，微波加熱功率 = 200 W	74
圖4-14利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘合成CMCS的反應曲線圖，10N NaOH(aq)= 1 mL，微波加熱功率 = 200 W	74
圖4-15利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘合成CMCS的反應曲線圖，10N NaOH(aq) = 1.5 mL，微波加熱功率 = 200 W 	75
圖4-16 利用微波加熱於反應溫度為30 oC下反應時間 10 分鐘的CMCS反應曲線圖，NaOH = 2 mL，微波加熱功率 = 200 W 	75
圖4-17利用微波加熱於反應溫度為40 oC下反應時間 40 分鐘合成CMCS的反應曲線圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	76
圖4-18利用微波加熱於反應溫度為60 oC下反應時間 40 分鐘合成CMCS的反應曲線圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	76
圖4-19 CMCS (DStotal = 2) 溶解在PBS緩衝溶液中在不同pH值下的粒徑及表面電位	77
圖4-20微波加熱輔助RAFT聚合PNP-CTA 高分子鏈轉移劑，轉化率(Xwt)對反應時間(●)及偽一階反應動力(Psudo first-order kinetic)作圖(■)。反應條件:([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC)	80
圖4-21微波加熱輔助RAFT聚合PNP-CTA 高分子鏈轉移劑，轉化率(Xwt)對反應時間(●)及偽一階反應動力(Psudo first-order kinetic)作圖(■)。反應條件:([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC)	80
圖4-22 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC、反應時間20分鐘，n = 22)	81
圖4-23 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC、反應時間30分鐘，n = 30)	82
圖4-24 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC、反應時間40分鐘，n = 41)	83
圖4-25 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC、反應時間50分鐘，n = 47)	84
圖4-26 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC、反應時間60分鐘，n = 68)	85
圖4-27 微波加熱輔助RAFT聚合PNP-CTA聚合度與反應時間關係圖(反應溫度75 oC、微波功率600 W、Dioxane/DMF = 28 / 2)	86
圖4-28 利用微波加熱輔助RAFT聚合PNP-CTA的溫度反應曲線圖([NP]:[DMP]:[AIBN]=100:1:0.1、反應溫度75 oC、反應時間60分鐘，n = 68)	87
圖4-29 利用微波加熱輔助RAFT聚合PNP-CTA的溫度反應曲線圖 ([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC、反應時間60分鐘，n = 114)	88
圖4-30 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA0)，於反應時間0分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	91
圖4-31 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA0)，於反應時間10分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	92
圖4-32 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA0)，於反應時間20分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	93
圖4-33 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA3.6)，於反應時間30分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	94
圖4-34 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA7.5)，於反應時間40分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	95
圖4-35 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA7.7)，於反應時間50分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	96
圖4-36 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D28F2NP68MAA8)，於反應時間60分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL))	97
圖4-37 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D25F5NP68MAA8)，於反應時間60分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 25 / 5 (mL / mL))	98
圖4-38 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D20F10NP68MAA6)，於反應時間60分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 20 / 10 (mL / mL))	99
圖4-39 微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D15F15NP68MAA5)，於反應時間60分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 15 / 15 (mL / mL))	100
圖4-40微波加熱輔助RAFT合成PNP-b-PMAA嵌段共聚物(D0F30NP68MAA6)，於反應時間60分鐘下的1H-NMR圖譜。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 0 / 30 (mL / mL))	101
圖4-41 微波加熱輔助RAFT合成PNP-b-PMAA，在不同反應時間下溶液混濁變化，從左到右反應時間分別為0、10 、20 、30 、40 、50 及60 分鐘。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL)	102
圖4-42 微波加熱輔助RAFT合成PNP-b-PMAA，在不同反應時間下反應溶液光穿透率(λ=500 nm)與共聚物中MAA聚合度(m)的變化圖。反應條件:[MAA]:[PNP68-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W、反應溶劑Dioxane/DMF = 28 / 2 (mL / mL)	102
圖4-43微波加熱輔助RAFT合成PNP-b-PMAA-b-PBMA嵌段共聚物，於反應時間60分鐘下的1H-NMR圖譜。反應條件: [BMA]:[NP68MAA8-CTA]:[AIBN] = 100:1:0.1、反應溫度75 oC、微波功率 600 W 、反應溶劑Dioxane/DMF = 0 / 30 (mL / mL))	105
圖4-44 (a) PNP-CTA (b) PNP-b-PMAA (c) PNP-b-PMAA-b-PBMA 紅外線吸收光譜圖	108
圖4-45 PNP-CTA在超純水中(pH值為7.4)的穿透率(λ = 500 nm) 與溫度的關係圖(a)及穿透率對溫度的一次微分圖(b)，樣品濃度為1% (w/w)	110
圖4-46 PNP-CTA在PBS緩衝溶液中(pH值為7.4)的穿透率(λ = 500 nm) 與溫度的關係圖(a)及穿透率對溫度的一次微分圖(b)，樣品濃度為1%(w/w)	111
圖4-47 PNP-CTA在超純水(pH 7.4)及PBS中(pH 7.4) (sodium Chloride = 0.137 M/L )，鏈長與LCST關係圖，濃度為1% (w/w)。	112
圖4-48 NP68-CTA在PBS緩衝液中，(pH值為7.4)，不同濃度(0.1%-1.0%)下的穿透率(λ = 500 nm) 與溫度的關係圖(a)及穿透度對溫度的一次微分圖(b)	113
圖4-49 D28F2NP68MAA8在pH值為7.4及5.5下的穿透度(λ = 500 nm) 與溫度的關係圖，樣品溶解在超純水，濃度為1% (w/w)	114
圖4-50 PNP-b-PMAA在PBS緩衝液中，(pH值為 5.5)，不同MAA鏈長下的穿透率(λ= 500 nm) 與溫度的關係圖(a)及穿透度對溫度的一次微分圖(b)，樣品濃度為1.0% (w/w)。	115
圖4-51 PNP-b-PMAA在PBS緩衝液中，(pH值為 7.4)下的穿透率(λ = 500 nm) 與溫度的關係圖(a)及穿透度對溫度的一次微分圖(b)，樣品濃度為1.0% (w/w)。	116
圖4-52 PNP68-CTA溶解在PBS中 (pH 7.4)，25 oC下之粒徑分佈圖	118
圖4-53 PNP68-CTA溶解在PBS中 (pH 7.4)，37 oC下之粒徑分佈圖	118
圖4-54 PNP68-CTA溶解在超純水中 (pH 7.4)，25 oC下之粒徑分佈圖	118
圖4-55 PNP68-CTA溶解在超純水中 (pH 7.4)，37 oC下之粒徑分佈圖	119
圖4-56 NP68MAA8溶解在PBS中 (pH 7.4)，25 oC下之粒徑分佈圖	119
圖4-57 NP68MAA8溶解在PBS中 (pH 7.4)，37 oC下之粒徑分佈圖	119
圖4-58 NP68MAA8溶解在超純水中 (pH 7.4)，25 oC下之粒徑分佈圖	120
圖4-59 NP68MAA8溶解在超純水中 (pH 7.4)，37 oC下之粒徑分佈圖	120
圖4-60 NP68MAA8溶解在PBS中 (pH 5.5)，25 oC下之粒徑分佈圖	120
圖4-61 NP68MAA8溶解在PBS中 (pH 5.5)，37 oC下之粒徑分佈圖	121
圖4-62 NP68MAA8BMA4溶解在PBS中 (pH 7.4)，25 oC下之粒徑分佈圖	121
圖4-63 NP68MAA8BMA4溶解在PBS中 (pH 7.4)，37 oC下之粒徑分佈圖	121
圖A-1 利用微波加熱於反應溫度為40 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	132
圖A-2 利用微波加熱於反應溫度為40 oC下反應時間 20 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	133
圖A-3 利用微波加熱於反應溫度為40 oC下反應時間 30 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	134
圖A-4 利用微波加熱於反應溫度為45 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	135
圖A-5 利用微波加熱於反應溫度為45 oC下反應時間 20 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	136
圖A-6 利用微波加熱於反應溫度為45 oC下反應時間 30 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	137
圖A-7 利用微波加熱於反應溫度為45 oC下反應時間 40 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	138
圖A-8 利用微波加熱於反應溫度為50 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	139
圖A-9 利用微波加熱於反應溫度為50 oC下反應時間 20 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	140
圖A-10 利用微波加熱於反應溫度為50 oC下反應時間 30 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	141
圖A-11 利用微波加熱於反應溫度為60 oC下反應時間 10 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	142
圖A-12 利用微波加熱於反應溫度為60 oC下反應時間 20 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	143
圖A-13 利用微波加熱於反應溫度為60 oC下反應時間 30 分鐘所測得的CMCS 1H-NMR光譜圖，10N NaOH(aq) = 2 mL，微波加熱功率 = 200 W	144
圖B-1 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC、反應時間20分鐘，n = 35)145
圖B-2 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC、反應時間30分鐘，n = 62)	146
圖B-3 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC、反應時間40分鐘，n = 77)	147
圖B-4 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC、反應時間50分鐘，n = 90)	148
圖B-5 利用微波加熱輔助RAFT聚合PNP-CTA的 1H-NMR圖譜([NP]:[DMP]:[AIBN]=200:1:0.1、反應溫度75 oC、反應時間60分鐘，n = 114)	149

表目錄
表2-1 常見LCST型溫度敏感高分子的結構及臨界溶液溫度	14
表2-2 常見UCST型溫度敏感高分子的結構及臨界溶液溫度	15
表2-3 P(NIPAAm-co-AAc)共聚物的聚合條件、分子量和LCST	16
表2-4 P(NIPAAm-co-MA)共聚物的單體比例對LCST的影響	16
表2-5使用RAFT共聚合反應製備P(NIPAAm-co-AA)共聚物	16
表2-6 P(NIPAAm-co-AA)，P(NIPAAm-co-MAA) 和P(NIPAAm-co-AA)在不同的pHa下的LCST	16
表2-7 P(NIPAAm-co-PAA-co-BA)共聚物的聚合條件	17
表2-8 P(NIPAAm-co-PAA-co-BA)共聚物(P1-P6)在不同pH值下之LCST	17
表2-9 常見的酸鹼敏感型高分子	18
表2-10 溶劑和材料的損耗角正切(tanδ)	23
表3-1 合成PNP-CTA之進料莫爾比	50
表3-2 合成PNP-b-PMAA 之反應參數	51
表4-1 CS官能基紅外線光譜吸收峰的位置	55
表4-2 CS的1H-NMR吸收峰位置	57
表4-3 CMCS官能基紅外線光譜吸收峰的位置	59
表4-4 CMCS的1H-NMR吸收峰的位置	62
表4-5 在不同反應條件下合成出的羧甲基幾丁聚醣的取代度(CS = 0.5 g , MCA = 1.5 g , IPA + NaOH = 12 mL)	63
表4-6 微波加熱輔助RAFT合成PNP-CTA高分子反應條件及轉化率、聚合度與分子量(反應溫度75 oC、微波功率600 W、Dioxane / DMF = 28 / 2)	87
表4-7在不同溶劑組成及不同反應溫度下以微波輔助RAFT合成PNP-b-PMAA嵌段共聚物組成([MAA]:[PNP68-CTA]:[AIBN]= 100:1:0.1、反應溫度75 oC，微波功率 600W。	103
表4-8 PNP-b-PMAA-b-PMBA 嵌段共聚物各基團的紅外線光譜吸收位置	107
表4-9 NP68及NP68MAA8溶解在超純水中 (pH = 7.4 & 5.5， 0.1%)下之粒徑及表面電位	122
表4-10 NP68及NP68MAA8及NP68MAA8BMA2溶解在PBS緩衝液 (pH = 7.4 ， 0.1%)下之粒徑及表面電位	122
表4-11 NP68MAA8溶解在PBS緩衝液(0.1%，pH = 5.5)下之粒徑及表面電位	122

1.	Vishu Kumar, A. B., et al., Characterization of chito-oligosaccharides prepared by chitosanolysis with the aid of papain and Pronase, and their bactericidal action against Bacillus cereus and Escherichia coli. Biochemical Journal 2005, 391 (2), 167-175.
2.	Kumar, M. et al., A review of chitin and chitosan applications. In Reactive and functional polymers, 2000; Vol. 46, pp 1-27.
3.	陳榮輝, 幾丁質,幾丁聚醣的生產製造,檢測與應用. 科學發展月刊 2001.
4.	Muzzarelli, R., Chitosan [in:] Muzzarelli R.(Ed.), Natural Chelating Polymers. Natural Chelating Polymers 1973.
5.	Kumar, M. et al., A review of chitin and chitosan applications. Reactive and functional polymers 2000, 46 (1), 1-27.
6.	Mi, F.-L., et al., pH-sensitive behavior of two-component hydrogels composed of N, O-carboxymethyl chitosan and alginate. Journal of Biomaterials Science, Polymer Edition 2005, 16 (11), 1333-1345.
7.	Chen, S.-C., et al., A novel pH-sensitive hydrogel composed of N, O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery. Journal of Controlled Release 2004, 96 (2), 285-300.
8.	Miao, J., et al., Preparation and characterization of N, O-carboxymethyl chitosan (NOCC)/polysulfone (PS) composite nanofiltration membranes. Journal of membrane science 2006, 280 (1-2), 478-484.
9.	Chen, L., et al., Effect of the degree of deacetylation and the substitution of carboxymethyl chitosan on its aggregation behavior. Journal of Polymer Science Part B: Polymer Physics 2005, 43 (3), 296-305.
10.	Zhang, L., et al., Blend membranes from carboxymethylated chitosan/alginate in aqueous solution. Journal of Applied Polymer Science 2000, 77 (3), 610-616.
11.	Liu, Z., et al., Calcium‐carboxymethyl chitosan hydrogel beads for protein drug delivery system. Journal of Applied Polymer Science 2007, 103 (5), 3164-3168.
12.	Muzzarelli, R. A., et al., Osteogenesis promoted by calcium phosphate N, N-dicarboxymethyl chitosan. Carbohydrate Polymers 1998, 36 (4), 267-276.
13.	van der Lubben, I. M., et al., Chitosan and its derivatives in mucosal drug and vaccine delivery. European Journal of Pharmaceutical Sciences 2001, 14 (3), 201-207.
14.	Tao, S., et al., Preparation of carboxymethyl chitosan sulfate for improved cell proliferation of skin fibroblasts. International journal of biological macromolecules 2013, 54, 160-165.
15.	Luo, P., et al., Preparation and characterization of carboxymethyl chitosan sulfate/oxidized konjac glucomannan hydrogels. International journal of biological macromolecules 2018, 113, 1024-1031.
16.	Upadhyaya, L., et al., Biomedical applications of carboxymethyl chitosans. Carbohydrate polymers 2013, 91 (1), 452-466.
17.	Muzzarelli, R. A., et al., Removal of trace metal ions from industrial waters, nuclear effluents and drinking water, with the aid of cross-linked N-carboxymethyl chitosan. Carbohydrate polymers 1989, 11 (4), 293-306.
18.	Chen, L., et al., Relationships between the molecular structure and moisture-absorption and moisture-retention abilities of carboxymethyl chitosan: II. Effect of degree of deacetylation and carboxymethylation. Carbohydrate research 2003, 338 (4), 333-340.
19.	Wang, L., et al., Adsorption behaviors of Congo red on the N, O-carboxymethyl-chitosan/montmorillonite nanocomposite. Chemical Engineering Journal 2008, 143 (1-3), 43-50.
20.	Chen, Y., et al., Synthesis and characterization of a novel superabsorbent polymer of N, O-carboxymethyl chitosan graft copolymerized with vinyl monomers. Carbohydrate Polymers 2009, 75 (2), 287-292.
21.	Muzzarelli, R. A. J. C. p., Carboxymethylated chitins and chitosans. Carbohydrate polymers 1988, 8 (1), 1-21.
22.	Zhu, A., et al., The aggregation behavior of O-carboxymethylchitosan in dilute aqueous solution. Colloids and Surfaces B: Biointerfaces 2005, 43 (3-4), 143-149.
23.	Thanou, M., et al., Oral drug absorption enhancement by chitosan and its derivatives. Advanced drug delivery reviews 2001, 52 (2), 117-126.
24.	Xu, Q., et al., Immobilization of horseradish peroxidase on O-carboxymethylated chitosan/sol–gel matrix. Reactive and Functional Polymers 2006, 66 (8), 863-870.
25.	Joshi, J. M., et al., Ceric ammonium nitrate induced grafting of polyacrylamide onto carboxymethyl chitosan. Carbohydrate polymers 2007, 67 (3), 427-435.
26.	Sun, S., et al., Adsorption kinetics of Cu (II) ions using N, O-carboxymethyl-chitosan. Journal of hazardous materials 2006, 131 (1-3), 103-111.
27.	Delben, F., et al., Thermodynamic study of the interaction of N-carboxymethyl chitosan with divalent metal ions. Carbohydrate polymers 1989, 11 (3), 221-232.
28.	Wan Ngah, W., et al., Adsorption of gold (III) ions onto chitosan and N-carboxymethyl chitosan: equilibrium studies. Industrial & engineering chemistry research 1999, 38 (4), 1411-1414.
29.	Sun, S., et al., Adsorption properties and mechanism of cross-linked carboxymethyl-chitosan resin with Zn (II) as template ion. Reactive and functional polymers 2006, 66 (8), 819-826.
30.	Fei Liu, X., et al., Antibacterial action of chitosan and carboxymethylated chitosan. Journal of applied polymer science 2001, 79 (7), 1324-1335.
31.	Anitha, A., et al., Synthesis, characterization, cytotoxicity and antibacterial studies of chitosan, O-carboxymethyl and N, O-carboxymethyl chitosan nanoparticles. Carbohydrate polymers 2009, 78 (4), 672-677.
32.	Seyfarth, F., et al., Antifungal effect of high-and low-molecular-weight chitosan hydrochloride, carboxymethyl chitosan, chitosan oligosaccharide and N-acetyl-D-glucosamine against Candida albicans, Candida krusei and Candida glabrata. International Journal of Pharmaceutics 2008, 353 (1-2), 139-148.
33.	Zhao, D., et al., Biochemical activities of N, O-carboxymethyl chitosan from squid cartilage. Carbohydrate polymers 2011, 85 (4), 832-837.
34.	Feng, T., et al., Enhancement of antioxidant activity of chitosan by irradiation. Carbohydrate Polymers 2008, 73 (1), 126-132.
35.	Sun, T., et al., Superoxide anion scavenging activity of graft chitosan derivatives. Carbohydrate Polymers 2004, 58 (4), 379-382.
36.	Chen, X.-G., et al., The effect of carboxymethyl-chitosan on proliferation and collagen secretion of normal and keloid skin fibroblasts. Biomaterials 2002, 23 (23), 4609-4614.
37.	Chen, R.-N., et al., Development of N, O-(carboxymethyl) chitosan/collagen matrixes as a wound dressing. Biomacromolecules 2006, 7 (4), 1058-1064.
38.	Wongpanit, P., et al., Preparation and characterization of microwave‐treated carboxymethyl chitin and carboxymethyl chitosan films for potential use in wound care application. Macromolecular Bioscience 2005, 5 (10), 1001-1012.
39.	Xie, M., et al., CdSe/ZnS-labeled carboxymethyl chitosan as a bioprobe for live cell imaging. Chemical communications 2005,  (44), 5518-5520.
40.	Weng, L., et al., Non-cytotoxic, in situ gelable hydrogels composed of N-carboxyethyl chitosan and oxidized dextran. Biomaterials 2008, 29 (29), 3905-3913.
41.	Zhou, J., et al., Reduction in postoperative adhesion formation and re-formation after an abdominal operation with the use of N, O-carboxymethyl chitosan. Surgery 2004, 135 (3), 307-312.
42.	Moad, G. J. P. C., RAFT polymerization to form stimuli-responsive polymers. Polymer Chemistry 2017, 8 (1), 177-219.
43.	Schmaljohann, D. J. A. d. d. r., Thermo-and pH-responsive polymers in drug delivery. Advanced drug delivery reviews 2006, 58 (15), 1655-1670.
44.	Lanzalaco, S., et al., Poly (n-isopropylacrylamide) and copolymers: A review on recent progresses in biomedical applications. Gels 2017, 3 (4), 36.
45.	Lin, S.-Y., et al., Drying methods affecting the particle sizes, phase transition, deswelling/reswelling processes and morphology of poly (N-isopropylacrylamide) microgel beads. Polymer 1999, 40 (23), 6307-6312.
46.	Katsumoto, Y., et al., Conformational change of poly (N-isopropylacrylamide) during the Coil− Globule transition investigated by attenuated total reflection/infrared spectroscopy and density functional theory calculation. The Journal of Physical Chemistry A 2002, 106 (14), 3429-3435.
47.	Boutris, C., et al., Characterization of the LCST behaviour of aqueous poly (N-isopropylacrylamide) solutions by thermal and cloud point techniques. Polymer 1997, 38 (10), 2567-2570.
48.	Li, J., et al., Aqueous-based electrospun P (NIPAAm-co-AAc)/RSF medicated fibrous mats for dual temperature-and pH-responsive drug controlled release. RSC Advances 2020, 10 (1), 323-331.
49.	Garbern, J. C., et al., Injectable pH-and temperature-responsive poly (N-isopropylacrylamide-co-propylacrylic acid) copolymers for delivery of angiogenic growth factors. Biomacromolecules 2010, 11 (7), 1833-1839.
50.	Constantin, M., et al., Poly (N-isopropylacrylamide-co-methacrylic acid) pH/thermo-responsive porous hydrogels as self-regulated drug delivery system. European Journal of Pharmaceutical Sciences 2014, 62, 86-95.
51.	Yin, X., et al., Poly (N-isopropylacrylamide-co-propylacrylic acid) copolymers that respond sharply to temperature and pH. Biomacromolecules 2006, 7 (5), 1381-1385.
52.	Joshi, R. V., et al., Dual pH-and temperature-responsive microparticles for protein delivery to ischemic tissues. Acta biomaterialia 2013, 9 (5), 6526-6534.
53.	Roy, D., et al., New directions in thermoresponsive polymers. Chemical Society Reviews 2013, 42 (17), 7214-7243.
54.	Kocak, G., et al., pH-Responsive polymers. Polymer Chemistry 2017, 8 (1), 144-176.
55.	Gao, Y.-J., et al., Polymers with tertiary amine groups for drug delivery and bioimaging. Science China Chemistry 2016, 59 (8), 991-1002.
56.	Hoffman, A. Hydrogels for biomedical applications. Advanced drug delivery reviews 2012, 64, 18-23.
57.	Dai, S., et al., pH-Responsive polymers: synthesis, properties and applications. Soft Matter 2008, 4 (3), 435-449.
58.	Gedye, R., et al., The use of microwave ovens for rapid organic synthesis. Tetrahedron letters 1986, 27 (3), 279-282.
59.	Giguere, R. J., et al., Application of commercial microwave ovens to organic synthesis. Tetrahedron letters 1986, 27 (41), 4945-4948.
60.	Lidström, P., et al., Microwave assisted organic synthesisÐa review. Tetrahedron Letters 2001, 57, 9225-9283.
61.	Danks, T. Microwave assisted synthesis of pyrroles. Tetrahedron Letters 1999, 40 (20), 3957-3960.
62.	Deshayes, S., et al., Microwave activation in phase transfer catalysis. Tetrahedron Letters 1999, 55 (36), 10851-10870.
63.	Strauss, C. A strategic,‘green’approach to organic chemistry with microwave assistance and predictive yield optimization as core, enabling technologies. Australian journal of chemistry 2009, 62 (1), 3-15.
64.	Dhongade, S., A brief Review of MW Assisted Condensation Reactions: A Green Approach.
65.	Cablewski, T., et al., Development and application of a continuous microwave reactor for organic synthesis. The Journal of organic chemistry 1994, 59 (12), 3408-3412.
66.	Díaz‐Ortiz, Á., et al., A critical overview on the effect of microwave irradiation in organic synthesis. The Chemical Record 2019, 19 (1), 85-97.
67.	科安知識庫, 微波加熱於分析聚合物的分子量分布情形之應用. 2006.
68.	Kappe, C. O., High-speed combinatorial synthesis utilizing microwave irradiation. Current opinion in chemical biology 2002, 6 (3), 314-320.
69.	Liu, B., et al., Microwave–assisted synthesis of quaternized carboxymethyl chitosan in aqueous solution and its thermal behavior. Journal of Macromolecular Science, Part A 2012, 49 (3), 227-234.
70.	Wang, L.-Y., et al., Microwave-assisted solvent-free synthesis of some hemicyanine dyes. Dyes and pigments 2004, 62 (1), 21-25.
71.	Varma, R., Solvent-free organic syntheses. using supported reagents and microwave irradiation. Green Chemistry 1999, 1 (1), 43-55.
72.	Lidström, P., et al., Microwave assisted organic synthesisÐa review. Tetrahedron 2001, 57, 9225-9283.
73.	Kumar, S., et al., Preparation, characterization and optical property of chitosan-phenothiazine derivative by microwave assisted synthesis. Journal of Macromolecular Science®, Part A: Pure and Applied Chemistry 2009, 46 (11), 1095-1102.
74.	Huacai, G., et al., Graft copolymerization of chitosan with acrylic acid under microwave irradiation and its water absorbency. Carbohydrate polymers 2006, 66 (3), 372-378.
75.	Singh, V., et al., Microwave enhanced synthesis of chitosan-graft-polyacrylamide. Polymer 2006, 47 (1), 254-260.
76.	Luo, J., et al., Preparation and characterization of quaternized chitosan under microwave irradiation. Journal of Macromolecular Science, Part A: Pure and Applied Chemistry 2010, 47 (9), 952-956.
77.	Ge, H.-C., et al., Preparation of carboxymethyl chitosan in aqueous solution under microwave irradiation. Carbohydrate research 2005, 340 (7), 1351-1356.
78.	Barner-Kowollik, C., Handbook of RAFT polymerization. John Wiley & Sons: 2008.
79.	McLeary, J. B., et al., Beyond inhibition: a 1H NMR investigation of the early kinetics of RAFT-mediated polymerization with the same initiating and leaving groups. Macromolecules 2004, 37 (7), 2383-2394.
80.	Moad, G., et al., Living free radical polymerization with reversible addition–fragmentation chain transfer (the life of RAFT). Polymer International 2000, 49 (9), 993-1001.
81.	Moad, G., RAFT polymerization to form stimuli-responsive polymers. Polymer Chemistry 2017, 8 (1), 177-219.
82.	Zhu, J., et al., Reversible addition–fragmentation chain transfer polymerization of styrene under microwave irradiation. Journal of Polymer Science Part A: Polymer Chemistry 2006, 44 (23), 6810-6816.
83.	Tran, J. D., et al., Microwave‐Assisted Reversible Addition–Fragmentation Chain Transfer Polymerization of Cationic Monomers in Mixed Aqueous Solvents. Macromolecular Chemistry and Physics 2020, 221 (3), 1900397.
84.	Castagnet, T., et al., Microwave-Assisted Ultrafast RAFT Miniemulsion Polymerization of Biobased Terpenoid Acrylates. Biomacromolecules 2020.
85.	Wang, Y. M., et al., Microwave-assisted synthesis of thermo-and pH-responsive antitumor drug carrier through reversible addition-fragmentation chain transfer polymerization. Express Polymer Letters 2017, 11 (4), 293.
86.	Brooks, W. L. A., et al., Microwave‐Assisted RAFT Polymerization. Israel Journal of Chemistry 2012, 52 (3‐4), 256-263.
87.	Moad, G., et al., Toward living radical polymerization. Accounts of chemical research 2008, 41 (9), 1133-1142.
88.	Wicki, A., et al., Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. Journal of controlled release 2015, 200, 138-157.
89.	Albanese, A., et al., The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annual review of biomedical engineering 2012, 14, 1-16.
90.	Bregoli, L., et al., Nanomedicine applied to translational oncology: a future perspective on cancer treatment. Nanomedicine: Nanotechnology, Biology and Medicine 2016, 12 (1), 81-103.
91.	Huang, X., et al., Influence of radiation crosslinked carboxymethyl-chitosan/gelatin hydrogel on cutaneous wound healing. Materials Science and Engineering: C 2013, 33 (8), 4816-4824.
92.	Schilli, C. M., et al., A new double-responsive block copolymer synthesized via RAFT polymerization: poly (N-isopropylacrylamide)-b lock-poly (acrylic acid). Macromolecules 2004, 37 (21), 7861-7866.
93.	Lavertu, M., et al., A validated 1H NMR method for the determination of the degree of deacetylation of chitosan. Journal of pharmaceutical and biomedical analysis 2003, 32 (6), 1149-1158.
94.	Ge, H.-C., et al., Preparation of carboxymethyl chitosan in aqueous solution under microwave irradiation. Carbohydrate research 2005, 340 (7), 1351-1356.
95.	李佳恬, 溫感型複合水凝膠系統作為傷口敷料之研究. 淡江大學 化學工程與材料工程學系 2017.
96.	Wang, L., et al., Adsorption properties of Congo Red from aqueous solution onto surfactant-modified montmorillonite. Journal of hazardous materials 2008, 160 (1), 173-180.
97.	Kappe, C. O., How to measure reaction temperature in microwave-heated transformations. Chemical Society Reviews 2013, 42 (12), 4977-4990.
98.	Feng, C., et al., Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery: in vitro and in vivo evaluation. International journal of pharmaceutics 2013, 457 (1), 158-167.
99.	Radzevicius, P., et al., Synthesis by one-pot RAFT polymerization and properties of amphiphilic pentablock copolymers with repeating blocks of poly (2-hydroxyethyl methacrylate) and poly (butyl methacrylate). European Polymer Journal 2017, 87, 69-