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研究生：	楊惠嘉 Yang, Hui-Chia
論文名稱：	幾丁聚醣奈米微粒之製備及其生醫應用 Preparation and biomedical application of chitosan nanoparticles
指導教授：	洪敏雄 Hon, Min-Hsiung
學位類別：	博士 Doctor
系所名稱：	工學院 - 材料科學及工程學系 Department of Materials Science and Engineering
論文出版年：	2011
畢業學年度：	99
語文別：	中文
論文頁數：	103
中文關鍵詞：	幾丁聚醣、羧基甲基化幾丁聚醣、三聚磷酸鈉、5-氟尿嘧啶、14-羥柔紅黴素、去乙醯度、黏度分子量
外文關鍵詞：	chitosan, tripolyphosphate, viscosity of molecular weight, degree of deacetylation, carboxymethyl chitosan, fluorouracil, doxorubicin
相關次數：	點閱：120 下載：4
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奈米藥物遞送系統可藉由改變藥物在人體內的分布，達到高度靶向、控制釋放、提高難溶藥物的溶解率和吸收率，增加藥效及減少藥物毒性的目的。當奈米藥物載體被應用在局部給藥時，可使藥物的局部作用增加而進入全身血液循環的量減少。利用帶有異性電荷之分子並藉由其間之靜電吸引力來製作奈米載體的方式，製程簡便又不需使用有毒的化學交聯劑，頗受重視。
本研究以幾丁聚醣(CTS)為原料、三聚磷酸鈉(TPP)為交聯劑，製備奈米級載體，包覆5-氟尿嘧啶(5-Fluorouracil, 5-FU)，探討幾丁聚醣(CTS)去乙醯度(DD)及黏度分子量(Mv)對粒徑、包覆率及體外釋放速率的影響。由Zetasizer與TEM的結果顯示，藉由幾丁聚醣的NH3+與TPP中O-之靜電庫侖力可得到穩定的奈米複合顆粒。幾丁聚醣的去乙醯度及黏度分子量會影響奈米複合顆粒的粒徑。去乙醯度高、分子量小的幾丁聚醣，可以形成粒徑小且較緻密的結構。由FTIR和NMR圖譜，顯示5-FU確實可包覆於奈米複合顆粒上，包覆率和幾丁聚醣去乙醯度及黏度分子量有關，去乙醯度大、分子量小的幾丁聚醣包覆率大。90 %-DD，55-kDa-Mv之幾丁聚醣，可以製備70.6 nm的5-FU複合顆粒，並有66 %的包覆率。去乙醯度大、分子量大的幾丁聚醣，5-FU釋放速率慢。
本研究另選用同時含有去質子穩定的官能基(–OH)與質子化穩定的官能基(–NH2)的14-羥柔紅黴素(Doxorubicin, DOX)做為模擬藥劑，幾丁聚醣為載體，討論黏度分子量對粒徑、包覆率及體外釋放速率的影響，並和溶於水中帶負電荷的5-FU藥物比較。使用90 %-DD，55-kDa-Mv之幾丁聚醣，可製備113 nm的DOX複合顆粒，並有90 %的包覆率。分子量小的幾丁聚醣，DOX釋放速率慢。因為幾丁聚醣與DOX係以氫鍵鍵結，藥物釋放速率慢，但可以維持較長的藥效。
臨床上對於癌症病患施行化學治療時，最常面臨到的問題，就是所投與的藥物會幾乎均勻地分布到全身，因此藥物雖可有效殺死腫瘤細胞，但被輸送到患部以外的藥物，也同時摧毀組織與器官引起有害副作用。若將磁性奈米顆粒作為藥物的載體，經靜脈注射入體內，再於體外施加適當的磁場，以磁力控制體內的奈米磁性顆粒移向病變的部位，再釋放出療效的藥物，將可提高局部的藥物濃度進而達到治療效果。
本研究利用羧基甲基化幾丁聚醣被覆Fe3O4磁性奈米顆粒，將抗癌藥物5-氟尿嘧啶攜帶在磁性載體的表面，由XRD分析結果顯示，利用化學共沈澱法製備之磁性奈米顆粒為Fe3O4之尖晶時結構。由Zetasizer與TEM的結果顯示，羧甲基化幾丁聚醣被覆之磁性奈米顆粒平均粒徑為15.4 nm，5-FU包覆率為61%。

Nanoparticulate drug delivery systems offer several advantages over conventional forms of dosing, with polymer nanoparticles prepared from biomaterials being good candidates for use in drug delivery. Complexation between oppositely charged macromolecules has attracted much attention recently as a very simple and mild method for the preparation of chitosan bead formulations for the controlled release of drugs.
We selected fluorouracil (5FU) as a model drug because it has been suggested that chitosan might prevent the side effects induced by 5FU. In this study, we investigated the effects of the degree of deacetylation (DD) of chitosan on the resulting nanoparticles’ properties. The diameters of the nanoparticles, as determined by dynamic light scattering and TEM techniques, increased as the DD of chitosan decreased. We prepared fluorouracil-loaded chitosan nanoparticles and characterized them using FTIR and NMR spectroscopy. The encapsulation efficiency increased with the DD of chitosan. Particles produced using 90%-DD chitosan had a mean particle size of 113 nm and a 56.5% drug loading.
In addition, we examined the effect that the molecular weight of chitosan had on the resulting nanoparticles’ properties; the initial concentration of chitosan was held constant, but its molecular weight was decreased through the action of NaNO2. FTIR spectroscopy suggested that no structural change occurred during the depolymerization process. The diameters of the nanoparticles—determined using dynamic light scattering and TEM techniques—decreased as the value of the viscosity of molecular weight (Mv) of chitosan decreased. We prepared fluorouracil-loaded chitosan nanoparticles and characterized them using NMR spectroscopy. The encapsulation efficiency increased as the value of Mv of chitosan decreased. The particles produced using 55-kDa chitosan had a mean diameter of 70.6 nm and a 66% drug loading.
Doxorubicin (DOX) was a type of anti-cancer drug called an anthracycline glycoside, and has been widely used in the clinical field for several decades for the treatment of solid tumors. In water DOX was protonated and deprotonated, we want to know if it still works if the drug has both positive and negative charges. We prepared TPP-crosslinked chitosan beads and monitored the effects that the viscosity of molecular weight (Mv) of chitosan had on their physical properties and the encapsulation efficiency and in vitro release of DOX-loaded chitosan nanoparticles. The particles produced using 55-kDa chitosan had a mean diameter of 113 nm and a 91% drug loading.
Magnetic particles can be controlled by an external magnetic field gradient and hence could be suitable as the carrier of drug. We prepared the monodisperse carboxymethyl chitosan-conjugated Fe3O4 by co-precipitating Fe(II) and Fe(III) ions. The diameter of the nanoparticles—determined using dynamic light scattering and TEM techniques is 13.1 nm. The analyses of FTIR spectra confirm the binding of carboxymethyl chitosan to magnetic nanoparticles. The analyses of TEM and XRD patterns indicate that the size and structure of magnetic nanoparticles do not change after binding chitosan. In addition, we prepared fluorouracil-loaded magnetic chitosan nanoparticles and characterized them using FTIR. The particles produced using magnetic chitosan have a mean diameter of 15.4 nm and 61% drug loading indicating that these nanoparticles have a potential for use as drug delivery agents.

總目錄
中文摘要	I
英文摘要	III
總目錄	VII
表目錄	XI
圖目錄	XII
英漢名詞與符號對照表	XVI
第一章  緒論	1
第二章  基礎理論與文獻回顧	4
2-1 幾丁質與幾丁聚醣	4
2-1-1 幾丁質與幾丁聚醣之特性	4
2-1-2 幾丁質及幾丁聚醣的製備	7
2-1-3 幾丁質與幾丁聚醣的應用	8
2-2 藥物傳輸技術	9
2-3 奈米藥物載體	11
第三章  實驗方法與步驟	17
3-1實驗流程	17
3-2實驗藥品	19
3-3實驗方法	20
3-3-1 不同分子量幾丁聚醣之製備	20
3-3-2 幾丁聚醣–三聚磷酸鈉奈米複合顆粒之製備	20
3-3-3 5-氟尿嘧啶/幾丁聚醣–三聚磷酸鈉奈米複合顆粒之製備	21
3-3-4 14-羥柔紅黴素/幾丁聚醣–三聚磷酸鈉奈米複合顆粒之製備	21
3-3-5 5-氟尿嘧啶/羧基甲基化幾丁聚醣–三聚磷酸鈉磁性奈米複合顆粒之製備	22
3-3-5-1磁性奈米顆粒之製備	22
3-3-5-2羧甲基化幾丁聚醣之製備	22
3-3-5-3羧甲基化幾丁聚醣被覆磁性奈米顆粒之製備	23
3-3-5-4 5-氟尿嘧啶/羧甲基化幾丁聚醣–三聚磷酸鈉磁性奈米複合顆粒之製備	23
3-4 材料分析	23
3-4-1尤伯洛德黏度計	23
3-4-2 粒徑與界面電位分析儀	24
3-4-3 穿透式電子顯微鏡	25
3-4-4 傅立葉轉換紅外線光譜儀	25
3-4-5 核磁共振光譜儀	25
3-4-6 X射線繞射儀	26
3-5 5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉奈米複合顆粒藥物釋放分析	26
3-5-1 5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉奈米複合顆粒包覆率計算	26
3-5-2 5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉奈米複合顆粒體外釋放實驗	26
3-6 14-羥柔紅黴素/幾丁聚醣-三聚磷酸鈉奈米複合顆粒藥物釋放分析	27
3-6-1 14-羥柔紅黴素/幾丁聚醣-三聚磷酸鈉奈米複合顆粒包覆率計算	27
3-6-2 14-羥柔紅黴素/幾丁聚醣-三聚磷酸鈉奈米複合顆粒體外釋放實驗	27
3-7 5-氟尿嘧啶/羧基甲基化幾丁聚醣-三聚磷酸鈉磁性奈米複合顆粒包覆率計算	27
第四章  幾丁聚醣奈米複合顆粒包覆5-氟尿嘧啶	29
4-1 前言	29
4-1-1 5-氟尿嘧啶簡介	29
4-1-2 載體包覆5-氟尿嘧啶給藥之發展.	32
4-2 幾丁聚醣黏度分子量分析	33
4-3  5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉奈米複合顆粒粒徑分析	36
4-3-1 幾丁聚醣去乙醯度對粒徑之影響	36
4-3-2 幾丁聚醣黏度分子量對粒徑之影響	36
4-4  5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉奈米複合顆粒分子結構分析	40
4-4-1 傅立葉轉換紅外線光譜儀分析	40
4-4-2核磁共振光譜儀分析	40
4-5  5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉包覆率分析	45
4-5-1 5-氟尿嘧啶包覆率分析	45
4-5-2 幾丁聚醣去乙醯度對包覆率之影響	45
4-5-3 幾丁聚醣黏度分子量對包覆率之影響	45
4-6  5-氟尿嘧啶/幾丁聚醣-三聚磷酸鈉藥物釋放分析	49
4-6-1 5-氟尿嘧啶檢量線製作	49
4-6-2 幾丁聚醣去乙醯度對體外釋放速率之影響	49
4-6-3 幾丁聚醣黏度分子量對體外釋放速率之影響	49
4-6-4 藥物釋放動力學之探討	53
4-7 小結	59
第五章  幾丁聚醣奈米複合顆粒包覆14-羥柔紅黴素	57
5-1前言	57
5-2 幾丁聚醣黏度分子量對粒徑的影響	60
5-3 14-羥柔紅黴素/幾丁聚醣-三聚磷酸鈉奈米複合顆粒分子結構分析	63
5-3-1傅立葉轉換紅外線光譜儀分析	63
5-3-2核磁共振光譜儀分析	63
5-4 14-羥柔紅黴素/幾丁聚醣-三聚磷酸鈉藥物釋放分析	67
5-4-1 14-羥柔紅黴素包覆率分析	67
5-4-2幾丁聚醣黏度分子量對包覆率的影響	67
5-4-3 幾丁聚醣黏度分子量對體外釋放速率的影響	71
5-4-4 藥物釋放動力學之探討	74
5-5 小結	79
第六章  羧甲基化幾丁聚醣磁性奈米複合顆粒包覆五氟尿嘧啶	80
6-1前言	80
6-2 羧甲基化幾丁聚醣分子結構分析	83
6-3 羧甲基化幾丁聚醣被覆磁性奈米顆粒分析	83
6-4 5-氟尿嘧啶/羧基基化幾丁聚醣-三聚磷酸鈉奈米複合顆粒分子結構分析	88
6-5 5-氟尿嘧啶/羧甲基化幾丁聚醣-三聚磷酸鈉磁性奈米複合顆粒包覆率分析	88
6-6 小結	91
第七章  總結論	92
參考文獻	94
自述	102
表目錄
Table 4-1 Effect of the degree of deacetylation on encapsulation efficiency (chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; stir time, 1 h; room temperature).	47
Table 4-2 Effect of the viscosity of molecular weight on encapsulation efficiency (90%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; stirring time, 1 h; room temperature).	48
Table 4-3 Release exponents (n) and determination coefficient (R2) following linear regression of release data from chitosan nanoparticles. (PBS solution pH 7.4, 37 °C).	55
Table 5-1 Effect of the viscosity of molecular weight on encapsulation efficiency (90%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; stirring time, 1 h; room temperature).	72
圖目錄
Fig. 2-1 Chemical structure of chitin and chitosan. 	6
Fig. 2-2 The plasma concentration of a typical drug compound in different dosage forms.	10
Fig. 2-3 Ionic interaction of chitosan in pentasodium tripolyphosphate 
aqueous.	16
Fig. 3-1 Flow chart of the experiment (I).	17
Fig. 3-2 Flow chart of the experiment (II).	18
Fig. 3-3 The diagram of 5-FU and DOX in vitro release.	28
Fig. 4-1 Chemical structure of 5-fluorouracil.	31
Fig. 4-2 Molecular weight of 90%-DD chitosan measured by intrinsic method.(A) CTS to NaNO2 molar ratio, 0.02:1; reaction time, 3h; room temperature.(B) CTS to NaNO2 molar ratio, 0.01:1; reaction time, 3h; room temperature.	34
Fig. 4-3 FTIR spectra of (A) original and (B) depolymerized chitosan.	35
Fig. 4-4 Particle size distributions of (A) unloaded and (B) 5-FU-loaded TPP/chitosan nanoparticles. 90%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; cross-linking time, 1 h.	37
Fig. 4-5 Particle size distributions of (A) unloaded and (B) 5-FU-loaded TPP/chitosan nanoparticles. 75%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; chitosan cross-linking time, 1 h.	37
Fig. 4-6 TEM images of TPP/chitosan nanoparticles prepared using (A,B) 90%-DD and (C,D) 75%-DD chitosan. chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; cross-linking time, 1 h.	38
Fig. 4-7 Particle size distributions of 5-FU-loaded TPP/chitosan nanoparticles prepared at values of Mv of (A) 550, (B) 110, and (C) 55 kDa. 90%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; crosslinking time, 1 h. 	39
Fig. 4-8 TEM image of nanoparticles prepared using 55-kDa-Mv, 90%-DD chitosan.	39
Fig. 4-9 FTIR spectra of (A) unloaded and (B) 5-FU-loaded TPP/chitosan nanoparticles.	41
Fig. 4-10 1H NMR spectrum of chitosan 	42
Fig. 4-11 1H NMR spectrum of 5-FU	43
Fig. 4-12 1H NMR spectrum of 5-FU-loaded chitosan nanoparticles	44
Fig. 4-13 The calibration curve of 5-FU dissolved in methanol at 266 nm.	46
Fig. 4-14 The calibration curve of 5-FU dissolved in PBS at 266 nm.	51
Fig. 4-15 In vitro release profiles of 5-FU from chitosan nanoparticles in PBS solution (pH 7.4, 37 °C).	52
Fig. 4-16 In vitro release profiles of 5-FU from chitosan nanoparticles. in PBS solution (pH 7.4, 37 °C).	52
Fig. 5-1 Chemical structure of doxorubicin.	59
Fig. 5-2. Particle size distributions of DOX-loaded TPP/chitosan nanoparticles prepared at Mv values of (A) 550, (B) 200, (C) 110, and (D) 55 kDa. 90%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; crosslinking time, 1 h. 	61
Fig. 5-3 TEM images of  DOX-loaded TPP/chitosan nanoparticles prepared at Mv values of (A) 550, (B) 200, (C) 110, and (D) 55 kDa. 90%-DD chitosan concentration, 0.5 mg/mL; TPP concentration, 0.5 mg/mL; crosslinking time, 1 h.	62
Fig. 5-4 FTIR spectra of (A) chitosan, (B) DOX, and (C) DOX-loaded TPP/chitosan nanoparticles.	64
Fig. 5-5. 1H NMR spectra of (A)DOX, and (B)DOX-loaded TPP/chitosan nanoparticles.	65
Fig. 5-6. 1H NMR spectra of (A) DOX, and (B) DOX-loaded TPP/chitosan nanoparticles.	66
Fig. 5-7 The calibration curve of DOX dissolved in methanol at 478 nm.	68
Fig. 5-8 1H NMR spectrum of DOX-loaded TPP/chitosan. 	70
Fig. 5-9 The calibration curve of DOX dissolved in PBS at 480 nm.	72
Fig. 5-10 In vitro release profiles of DOX from chitosan nanoparticles in PBS solution (pH 7.4, 37 °C).	73
Fig. 5-11 Matrix-release plot for DOX release behavior of chitosan (550-kDa-Mv) nanoparticles at pH 7.4.	75
Fig. 5-12 Matrix-release plot for DOX release behavior of chitosan (200-kDa-Mv) nanoparticles at pH 7.4.	76
Fig. 5-13 Matrix-release plot for DOX release behavior of chitosan (110-kDa-Mv) nanoparticles at pH 7.4.	77
Fig. 5-14 Matrix-release plot for DOX release behavior of chitosan (55-kDa-Mv) nanoparticles at pH 7.4. 	78
Fig. 6–1 An illustration for the carboxymethylation and binding onto Fe3O4 nanoparticles of chitosan.	82
Fig. 6-2 FTIR spectra of (A) chitosan and (B) carboxymethyl chitosan.	84
Fig. 6-3 Particle size distributions of (A) Fe3O4 nanoparticles and (B) carboxymethyl chitosan-bound Fe3O4 nanoparticles 	85
Fig. 6-4 TEM images of (A) Fe3O4 nanoparticles and (B) carboxymethyl chitosan-bound Fe3O4 nanoparticles. 	85
Fig. 6-5 FTIR spectra of (A) carboxymethyl chitosan and (B) carboxymethyl chitosan-bound Fe3O4 nanoparticles	86
Fig. 6-6 XRD patterns for (A) Fe3O4 nanoparticles and (B) carboxymethyl chitosan-bound Fe3O4 nanoparticles.   	87
Fig. 6-7 FTIR spectra of (A) carboxymethyl chitosan-bound Fe3O4, (B) 5-FU, and (C) 5-FU-loaded magnetic nanoparticles.	89
                                    

[1] http://www.itri.org.tw工研院-研發-生物科技網頁
[2] R. K. Soong, G. D. Bachand, H. P. Neves, A. G. Olkhovets, H. G. Craighead, C. D. Montemagno, Powering an Inorganic Nanodevice with a Biomolecular Motor. Science 290, 1555–1558 (2000)
[3] 江晃榮，生體高分子(幾丁質•膠原蛋白)產業現況與展望，財團法人生物技術開發中心 (1998)
[4] R. Fernández-Urrusuno, P. Calvo, C. Remuñán-López, J. L.Villa-Jato, M.J. Alonso, Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm. Res. 16, 1576–1581 (1999).
[5] T. M. Jackanicz, H. A. Nash, D. L. Wise, J. B. Gregory, Polylactic acid as a biodegradable carrier for contraceptive steroids. Contraception, 8, 227–234 (1973).
[6] D. L. Wise, T. D. Fellman, J. E. Sanderson, R. L. Wentworth, Lactide/glycolide acid polymers in: G. Geregoriadis (Ed.). Drug Carriers in Biology and Medicine. Academic Press. London, 237–270 (1979).
[7] Y. Hu, X. Jianga, Y. Dinga, H. Gea, Y. Yuanb, C. Yang, Synthesis and characterization of chitosan–poly(acrylic acid) nanoparticles. Biomaterials, 23, 3193–3201(2002).
[8] R. A. A.Muzzarelli, Chitin. Pergramon Press, Oxford UK (1977).
[9] 張耀中，葡萄糖胺衍生物萃取與生醫材料改質應用，大同大學生物工程研究所，碩士論文(2008).
[10] G. A. F. Roberts, Chitin Chemistry. 65–83, The Macmillan Press LTD., London UK (1992).
[11]F. Lee, Chitin and chitosan: Speciality biopolymers for foods, medicine and industry (1989).
[12]曾念國，奈米科技應用於藥物傳輸的技術發展趨勢，工研院產經資訊中心， (2003).
[13]范國烜，幾丁聚醣奈米粒之製備及其應用於紅黴素控制釋放之探討，海洋大學食品科學系碩士論文，p.45(2003).
[14]劉正雄譯(L. Shargel, and A. B. C. Yu, Applied Biopharmaceutics and Pharmacokinetics. 1993.)，應用生物藥劑學與藥物動力學，合記圖書出版社翻譯出版，chap.7，台灣台北(1994).
[15] 蔣浩恩，抗發炎高分子前驅藥之酵素催化水解及動力學之探討，高雄醫學大學藥學研究所碩士論文(2001).
[16] J.E. Kipp, The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs. Int. J. Pharm. 284, 109–122, (2004).
[17] R. Gref, Y. Minamitake, M.T. Peracchia, V. Trubetskoy, V. Torchilin, R. Langer, Biodegradable long-circulating polymeric nanospheres. Science 263, 1600–1603 (1994).
[18] G.M. Barratt, Therapeutic applications of colloidal drug carriers. Pharm. Sci. Technol. Today. 3, 163–171 (2000).
[19] M. F. Zambaux, F. Bonneaux, R. Gref, P. Maincent, E. Dellacherie, M. J. Alonso, P. Labrude, C. Vigneron, Influence of experimental parameters on the characteristics of poly(lactic acid) nanoparticles prepared by double emulsion method. J. Control. Rel. 50, 31–40 (1998).
[20] T. Niwa, H. Takeuchi, T. Hino, N. Kunou, Y. Kawashima, Preparations of biodegradable nanospheres of water-soluble and insoluble drugs with D, L- lactide/ glycolide copolymer by a novel spontaneous emulsification solvent diffusion method and the drug release behavior. J. Control. Rel. 25, 89–98 (1993)
[21] T. D. Birnbaum, J. D. Kosmala, D. B. Henthorn, L. B. Peppas, Controlled release of β-estradiol from PLAGA microparticles: The effect of organic phase solvent on encapsulation and release. J. Control. Rel. 65, 375–387 (2000).
[22] R. Bodmeier, J. W. McGinity, Solvent selection in the preparation of poly(D,L-lactide) microsphere prepared by the solvent evaporation method. Int. J. Pharm. 43, 179–186 (1988)
[23] E. Allemann, J. C. Leroux, R. Gurnay, E. Doelker, In vitro extended-release properties of drug-loaded poly( D, L lactide acid) nanoparticles produced by a salting-out procedure. Pharm. Res. 10, 1732–1737 (1993).
[24] G. D. Quintanar, Q. A. Ganem, E. Alleman, H. Fessi, E. Doelker, Influence of stabilizer coating layer on the purification and freeze drying of poly(D, L- lactide acid) nanoparticles prepared by emulsification-diffusion technique. J. Microencap. 15, 107–119 ( 1998).
[25] T. Jung, A. Breitenbach, T. Kissel, Sulfobutylated poly(vinyl alcohol) -graft-poly(lactide-co-glyclide) facilitate the preparation of small negative charged biodegradable nanospheres for protein delivery. J. Control. Rel. 67, 157–169 (2000).
[26] D. L. Wise, T. D. Fellman, J. E. Sanderson, R. L. Wentworth, Lactide/glycolide acid polymers in: G. Geregoriadis (Ed.). Drug Carriers in Biology and Medicine. Academic Press. London, 237–270 (1979).
[27] T. M. Jackanicz, H. A. Nash, D. L. Wise, J. B. Gregory,Polylactic acid as a biodegradable carrier for contraceptive steroids. Contraception, 8, 227–234 (1973).
[28] L. C. Anderson, D. L. Wise, J. F. Howes,An injectable sustained release fertility control system. Contraception, 13, 375–384 (1976).
[29] C. G. Pitt, M. M. Gratzi, A. R. Jeffcot, R. Zweidinger, A. Schindler, Sustained release drug delivery systemsⅡ: factors affects release rate for poly(ε-caprolactone) and related biodegradable polyesters. J. Pharm. Sci. 68, 1534–1538 (1979).
[30] P. Calvo, J. L. Vila-Jato, M. J. Alonso, Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules and nanoemulsions as ocular drug carriers. J. Pharm. Sci. 85, 530–536 (1996).
[31]陳慶源，幾丁聚醣在藥物運送系統上之應用，食品工業，32(4)，18–28 ( 2000).
[32] K. Roy, H. Q. Mao, S. K. Huang, K. W. Leong, Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nature Med. 5, 387–391 (1999).
[33] X. Z. Shu, K.J. Zhu, A novel approach to prepare tripolyphosphate:chitosan complex beads for controlled release drug delivery. Int. J. Pharm. 201, 51–58 (2000).
[34] Y. Pan, Y. J. Li, H. Y. Zhao, J. M. Zheng, H. Xu, G. Wei, J. S. Hao, F. D. Cui, Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int. J. Pharm. 249, 139–147 (2002).
[35] Y. Xu, Y. Du, Effect of molecular structure of chitosan: protein delivery properties of chitosan nanoparticles. Int. J. Pharm. 250, 215–226 (2003).
[36] F. L. Mi, S. S. Shyu, C. Y. Kuan, S.T. Lee, S. F. Jang, Chitosan-Polyelectrolyte complexation for the preparation of gel beads and controlled release of anticancer drug: 1. Effect of phosphorous polyelectrolyte complex and enzymic hydrolysis of polymer. J.of Applied Polymer Sci. 74, 1868–1879 (1999).
[37] S. Mao, X. Shuai, F. Unger, M. Simon, D. Bi, T. Kissel, The depolymerization of chitosan: effects on physicochemical and biological properties. Int. J. Pharm. 281, 45–54 (2004).
[38] G. G. Maghami, G. A. F. Robert, Evaluation of the viscometric constants for chitosan. Makromol. Chem. 189, 195–200 (1988).
[39]簡啟恆，純化蒙脫石做為5-FU藥物載體於大腸癌治療之研究，台灣大學大材料所碩士論文，p.10 (1999).
[40]莊博仁，合成五氟尿嘧啶衍生物的MCRs及其機構的研究，成功大學化學所碩士論文，p.4 (2005).
[41] M. Gokce, T. F. Akada, M. kiremitci-Gumusderelioglu, 5-FU loaded pHEMA drainage implants for glaucoma-filtering surgery: device design and in vitro release kinetics. Biomaterials, 17, 941–949 (1996).
[42] M. D. Blanco, O. Garcia, R. M. Trigo, J. M. Teijon, 5-Fluorouracil release from copolymeric hydrogels of itaconic acid monoester: I. Acrylamide-co-monomethyl itaconate. Biomaterials, 17, 1061–1067 (1996).
[43] Y. E. Fang, Q. Cheng, X. B. Lu, Kinetics of in vitro drug release from chitosan/gelatin hybrid membranes. J. Appl. Polym. Sci., 68, 1751–1758 (1998).
[44] Y. Kimura, H. Okuda, Prevention by chitosan of myelotoxicity, gastrointestinal toxicity and immunocompetent organic toxicity induced by 5-fluorouracil without loss of antitumor activity in mice. Jpn. J. Cancer Res. 90, 765–774 (1999).
[45]劉正雄編譯，應用生物藥劑學與藥物動力學，合記圖書出版社，台灣，chap4 (2002).
[46] T. Yoshizawa, S.Y. Yoshitsune, K.J. Hong, T. Kajiuchi, pH-and temperature-sensitive release behaviors from polyelectrolyte complex films composed of chitosan and PAOMA copolymer. Eur. J. Pharm. Biopharm. 59, 307–313 (2005).
[47] L. A. Zwelling, Protein-associated DNA strand breaks in L1210 cells treated with the DNA intercalating agents 4’-(9-acridiny-lamino)-methanesulfon-
m-anisidide and adeiamycin. Biochemistry 20, 6553–6563 (1981).
[48] E. M. Nelson, K. M. Tewey, L. F. Liu, Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide. Proc. Natl. Acad .Sci. USA 81, 1361–1365 (1984).
[49] D. A. Gewirtz, A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem. Pharmacol. 57, 727–741 (1999).
[50] L.J. Goldstein, H. Galski, A. Fojo, M. Willingham, S.L. Lai, A. Gazdar, R. Pirker, A. Green, W. Crist, G.M. Brodeur, M. Lieber, J. Cossman, M.M. Gottesman, I. Pastan, Expression of multidrug resistance gene in human cancers, J. Natl. Cancer Inst. 81, 116–124 (1989)
[51] D.Von Hoff, M. Rozencweig, M. Piccart, The cardiotoxicity of anticancer agents, Semin. Oncol. 9, 23–33 (1982).
[52] W.A.R.Van Heeswijk, Synthesis, characterization and anti-tumor activity of acromolecular prodrugs of adriamycin, in: J.M. Anderson, S.W. Kim (Eds.), Recent Advances in Drug Delivery Systems, Plenum, New York, pp.77–100 (1984).
[53] D.J. Kerr, Microparticulate drug delivery systems as an adjunct to cancer treatment, Cancer Drug Deliv. 4, 55–61 (1987).
[54] G.S. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, K. Kataoka, Physical entrapment of adriamycin in AB block copolymer micelles, Pharm. Res. 12, 192–195 (1995).
[55] D. Missirlis, R. Kawamura, N. Tirelli, A. Hubbell, Doxorubicin encapsulation and diffusional release from stable, polymeric, hydrogel nanoparticles, Eur. J. Pharm. Sci. 29, 120–129 (2006).
[56] A. Gabizon, R. Shiota, D. Papahadjopoulos, Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times, J.of the National Cancer Institute 81, 1484–1488 (1989).
[57] K. Akiyoshi, I. Taniguchi, H. Fukui, J. Sunamoto, Hydrogel nanoparticle fromed by self-assembly of hydrophobized polysaccharide. Stabilization of adriamycin by complexation. Eur. J. Pharm. Biopharm. 42, 286–290 (1996).
[58] K. A. Janes, M. P. Fresneau, A. Marazuela and A. Fabra, Chitosan nanoparticles as delivery systems for doxorubicine. J. Control Release 73, 255–267 (2001).
[59] 鄭豐裕，四氧化三鐵磁性奈米粒子之製備及其在生物醫學上的應用，成功大學化學所博士論文，p22 (2006).
[60] S. Si, A. Kotal, T. K. Mandal, S. Giri, H. Nakamura, T. Kohara, Size-controlled synthesis of magnetite nanoparticles in the presence of polyelectrolytes. Chem. Mater. 16, 3489–3496 (2004).
[61] Y. Ding, Y. Hu, X. D. Jiang, L. Y. Zhang, C. Z. Yang, Polymer-monomer pairs as a reaction system for the synthesis of magnetic Fe3O4-polymer hybrid hollow nanospheres. Angew. Chem. Int. Ed. 43, 6369–6372 (2004).
[62] X. D. Tong, Y. Sun, Application of magnetic agarose support in liquid magnetically stabilized fluidized bed for protein adsorption. Biotechnol. Progr. 19, 1721–1727 (2003).
[63] X. Hong, W. Guo, H. Yuang, J. Li, Y. M. Liu, L. Ma, Y. B. Bai, T. J. Li, Periodate oxidation of nanoscaled magnetic dextran composites. J. Magn. Magn. Mater. 269, 95–100 (2004).
[64] W. Q. Jiang, H. C. Yang, S. Y. Yang, H. E. Horng, J. C. Huang, Y. C. Chen, C. Y. Hong, Preparation and properties of superparamagnetic nanoparticles with narrow size distribution and biocompatible. J. Magn. Magn. Mater. 283, 210–214 (2004).
[65] H. Honda, A. Kawabe, M. Shinkai, T. Kobayashi, Development of chitosan-conjugated magnetite for magnetic cell separation. J. Ferment. Bioeng. 86, 191–196 (1998).
[66] Y.C. Chang, D.H. Chen, Adsorption kinetics and thermodynamics of acid dyes on a carboxymethylated chitosan-conjugated magnetic nano-adsorbent. Macromol. Biosci. 5 254–261 (2005).
[67] 張揚狀，表面被覆幾丁聚醣之多功能磁性奈米載體的製備與應用，成功大學化工所博士論文，p97 (2005).

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