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研究生:李昀儒
研究生(外文):Yun-Ru Li
論文名稱:開發以聚己內酯薄膜為基礎之長效型藥物釋放系統
論文名稱(外文):Sustained Release of Cisplatin from Drug Delivery System Based on PCL Membrane
指導教授:楊台鴻
指導教授(外文):Tai-Horng Young
口試委員:邱文英陳晉興劉澤英
口試委員(外文):Wen-Ying ChiuJin-Shing ChenTse-Ying Liu
口試日期:2016-07-14
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:70
中文關鍵詞:長效藥物釋放聚己內酯薄膜惡性肋膜積水奈米粒子順鉑沾黏混參腫瘤抑制雙重藥物釋放
外文關鍵詞:sustained drug deliveryPCL membranemalignant pleural effusioncisplatinPLGA nanoparticlestumor-suppressing abilitydual drug delivery
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為了建立能夠治療惡性肋膜積水且以聚己內酯薄膜為基礎的長效藥物釋放系統,因此在膜中混參由溶劑置換法所形成的奈米粒子來發展出此系統達到長時間穩定釋放抗癌藥物:順鉑。在體外實驗中發現奈米粒子釋放藥物時間遠比含藥膜的釋放天期長,且在細胞毒殺實驗也發現奈米粒子的毒性較小,推測結果是因為藥物釋放相較於含藥膜較為緩慢。另外,在抑制腫瘤生長的動物實驗也發現同時含藥和奈米粒子的薄膜在十八天後可以看到比含藥水溶液和一般含藥膜有較好的抑制生長情形。本研究也利用大鼠腹腔沾黏實驗觀察用氯化鈉作為致孔劑的多孔膜和有混參奈米粒子的膜的沾黏情況,結果發現兩者的沾黏情形沒有顯著差異,也都比表面較為緻密的膜的沾黏效果好,而根據掃描電子顯微鏡發現其原因可能是奈米粒子會造成膜的表面結構多孔化,促進沾黏反應。與預期相同,混參有奈米粒子的聚己內酯膜可以被用作兩階段藥物釋放系統。實驗結果顯示,此系統可以控制粒子內的藥物接在膜內藥物之後釋放,這說明了此系統有機會取代目前臨床治療惡性肋膜積水的給藥方式成為新的可以同時進行肋膜沾黏和體內釋放藥物的產品。

To develop a sustained drug delivery system based on PCL membrane, promoting pleural adhesion, for the treatment of malignant pleural effusion (MPE), cisplatin (CDDP)-encapsulated PLGA nanoparticles (PLGA/CDDP NPs) were fabricated via solvent displacement method for the purpose of prolonging drug delivery. The PCL membrane incorporating CDDP and PLGA/CDDP NPs (PLGA/CDDP NP-PCL/CDDP membrane) was investigated under the in vitro and in vivo conditions with the comparison of PCL membrane incorporating CDDP (PCL/CDDP membrane) and free CDDP in solution form. As nanoscale drug carriers, the PLGA/CDDP NPs released the drug in a long-term manner for a longer period than PCL/CDDP membrane and were also less cytotoxic than free CDDP and PCL/CDDP membrane which probably due to the slower release of CDDP from NPs. The tumor-suppressing ability was observed that PLGA/CDDP NP-PCL/CDDP membrane could successfully inhibit the tumor growth after 17days because of the sustained release of CDDP in tumor-bearing mice, as shown by changes in tumor volumes, body weights, and survival trends. Histological analysis of tumor sections on Day 21 also showed that PLGA/CDDP NP-PCL/CDDP membrane had an obvious anti-tumor effect than other treatments. In addition, there was no significant difference of abdominal adhesion effect between the PLGA NP-PCL membrane and the porous PCL membrane probably because PCL membrane blended with PLGA NPs also had the porous surface structure facilitating the adhesion response without influencing the living conditions of rats. As expected, PLGA NP-PCL membrane system can also be used as two-step drug delivery system serving as a promising new treatment for MPE.

致謝 1
中文摘要 2
Abstract 3
Content 5
List of Tables 7
List of Figures 8
Chapter 1 Introduction 9
1.1 Malignant Pleural effusion 9
1.2 PCL Membrane 10
1.3 Cisplatin 11
1.4 Drug Delivery System 13
1.5 Objective 14
Chapter 2 Materials and Methods 16
2.1 Biological and Chemical Reagents 16
2.2 Instruments 17
2.3 Animals 18
2.4 Tumor Cells 18
2.5 Cell Culture 19
2.6 Preparation of CDDP-PCL Membrane 20
2.7 Fabrication of PLGA Nanoparticles incorporating CDDP 20
2.8 Preparation of CDDP-PCL Membrane Dispersed with CDDP-PLGA Nanoparticles 20
2.9 Characterization of PCL Membrane and PLGA Nanoparticles 21
2.10 Two-Step Drug Release Profile of PCL Membrane 22
2.11 In Vitro Drug Release Profile 22
2.12 In Vitro Anti-tumor effect 23
2.13 In Vivo Abdominal Adhesion Studies 23
2.14 In Vivo Anti-tumor Efficacy 25
2.15 Immunohistological Examination 25
2.16 Statistical Analysis 26
Chapter 3 Results 27
3.1 Characteristics of PCL Membrane and Nanoparticles 27
3.2 The Release Profile of CDDP-Membrane and Nanoparticles 29
3.3 Two-Step Drug Release Profile of PCL Membrane 31
3.4 In Vitro Cytotoxicity of CDDP-Membrane and Nanoparticles 32
3.5 In Vivo Study of Abdominal Adhesion 33
3.6 In Vivo Study of Anti-tumor Efficacy 34
3.7 Immunohistological Examination 36
Chapter 4 Discussion 37
4.1 Effective Therapy for Malignant Pleural Effusion 37
4.2 Sustained Drug Release System 39
4.3 In Vivo Anti-tumor Efficacy 42
4.4 Effective PCL Membrane Adhesion 44
4.5 Development of Two-Step Drug Release System 45
Chapter 5 Conclusion and Perspective 46
Figures 47
Tables 64
References 66



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