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博碩士論文 etd-0701117-094143 詳細資訊
Title page for etd-0701117-094143
論文名稱
Title
熱敏性金奈米微粒-凝膠藥物載體調控脂肪生長
Light-triggered methylcellulose-gold nanoparticles hydrogel for leptin release to inhibit fat stores in adipocytes
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
78
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2017-07-20
繳交日期
Date of Submission
2017-08-01
關鍵字
Keywords
藥物遞送系統、瘦體素、熱敏性凝膠、光熱治療、金奈米微粒
gold nanoparticle, photothermal therapy, leptin, drug delivery, Methylcellulose
統計
Statistics
本論文已被瀏覽 5645 次,被下載 36
The thesis/dissertation has been browsed 5645 times, has been downloaded 36 times.
中文摘要
隨著時代變遷、工商業的發展,飲食也日趨走向精緻,間接造成許多肥胖等相關疾病,世界衛生組織指出在成年人口中約超過600萬人有肥胖超重的問題,也是許多慢性疾病的致病原因,截至目前為止治療肥胖的研究未曾間斷,特別是有關如何調控脂質生成問題。因此開發有效控制平台及為重要。在脂肪細胞中瘦體素主要是透過胰島素信號傳導使胰島素敏感而增加三酸甘油酯的水解及提升脂肪酸和葡萄糖氧化的現象,達到抑制脂肪生長、油滴堆積的效果,但是一般普遍的治療方式多以血液靜脈注射、口服腸胃吸收的方式給予瘦體素藥物,但釋藥率低、藥物代謝快、半衰期短、缺乏專一性,且藥物毒性高,為了避免傳統治療給藥所帶來的缺點,因此,此研究利用載體包覆藥物之方式,使藥物達到定點穩定釋放並維持較長的療效時程。其研究的目的是以甲基纖維素凝膠(MC- hydrogels)結合金屬奈米微粒(MC-gold NPs hydrogels)開發成具有光敏性的藥物載體系統並在組織中做持續遞送之局部治療。在所描述的方法中,當以980 nm雷射照射10分鐘後,金奈米微粒會有效吸收特定雷射波長之光源,使金屬間電子雲來回震盪,當震盪頻率與入射光頻率相同時,導致電子雲的集體震盪產生『共振效應』之現象,因而促使溫度提升並破壞凝膠的結構穩定性,使瘦體素從膠體逃脫進而影響脂肪細胞。另外,傳統的癌症治療是以放射或化療的方式治療,全身性給藥所帶來的藥物的副作用往往會引起像是心臟的傷害、血球降低、過敏、神經病變、肝腎功能下降並降低病人生活品質等,為了此項問題及提升載體應用性,因此我們運用MC-gold NPs hydrogels做靶向局部癌細胞治療。這種以聚合物包覆藥物的方式不僅能減少藥物對心臟肌肉、腎臟及周圍正常組織的毒性,並且作長時間的藥物釋放,有效地發揮Doxorubicin藥理和藥效作用,除此之外亦可提升患者之生活品質。
Abstract
Leptin released in response to increased trigyceride storage in adipocytes, leptin appears to significantly affect body weight but suffer from poor therapeutic effect and side effects after systemic administration. Leptin modifies adipocytes sensitivity to insulin to inhibit lipid accumulation. Additionally, glucose uptake by adipose tissue found no response to leptin when leptin was administered intravenously or directly to adipocytes. This prolonged exposure to leptin did, however, cause a substantial dose dependent inhibition of insulin-stimulated glucose uptake by the adipocytes. Loading in light-triggered degradable hydrogels can offer improvements in the accuracy and efficacy for sustained delivery at specific sites. In our approach, leptin were entrapped with methylcellulose (MC)-based hydrogels, with incorporation of gold nanoparticles (NPs). The incorporation of gold NPs into the MC hydrogels led to a tunable light-irradiation response that dictated hydrogel release rate of leptin. This manuscript demonstrates feasibility in designing tunable-thermo-sensitive hydrogels for loading multimodality therapeutic agents to enhance the bioactivity of leptin for obesity therapy. In comparison with the experiment controls with doxorubicin only, the MC-gold NPs hydrogels significantly enhanced the rate of cell death via apoptosis at the additional 72 hour when illuminated at 980 nm for 10 min. The aim of this study is to develop a light-sensitive MC-H incorporated with gold nanoparticles (MC-gold NPs hydrogels) for localized leptin delivery.
目次 Table of Contents
目錄
審定書 i
致謝 ii
中文摘要 iii
英文摘要 iv
目錄 v
圖目錄 viii
第一章 前言 1
1-1肥胖 2
1-1-1脂肪細胞與溫度與溫度響應 4
1-2 3T3-L1前脂肪細胞 4
1-2-1脂肪細胞生長過程 5
1-3脂肪細胞分化之轉錄因子 6
1-4瘦體素(Leptin) 9
1-4-1 瘦體素(Leptin)傳導機制 9
1-5癌症 11
1-5-1傳統癌症治療 11
1-5-2多柔比星誘導腫瘤細胞凋亡 13
1-6甲基纖維素(Methyl cellulose)溫敏性水凝膠 14
1-7光熱治療 15
1-8金奈米微粒(Gold Nanoparticles) 15
第二章 材料方法 17
2-1儀器與藥品 18
2-2甲基纖維素水凝膠製備 20
2-3試驗藥品製備 21
2-4金奈米微粒物理性測試 22
2-4-1金奈米微粒升溫測試 22
2-5高分子水膠-金奈米微粒之機械強度測試 23
2-6細胞培養 24
2-7細胞繼代培養 25
2-7-1細胞冷凍與保存 25
2-7-2 3T3-L1脂肪細胞分化 25
2-7-3 3T3-L1脂肪細胞之基因表達 26
2-8胰島素對細胞分化之影響 26
2-9紅油組織 Oil red O 染色法 28
2-10以Leptin ELISA Kit製至標準曲線 29
2-10-1以Leptin ELISA Kit測試藥物釋放 30
2-10-2 Leptin熱敏性金屬奈米微粒凝膠抑制3T3-L1 細胞測試………..30
2-11細胞相關轉錄因子表現測定 31
2-12 MTS細胞活性測試(MTS assay)原理 32
2-13多柔比星(Doxorubicin)體外藥物釋放測試 34
第三章 結果與討論 35
3-1實驗流程 35
3-2熱敏性水凝膠濃度測試 36
3-3金奈米物理特性 36
3-4材料對於細胞毒性影響 37
3-5皮膚測試 39
3-6雷射-細胞活性測試 40
3-7熱敏性金奈米凝膠升溫測試 41
3-8 3T3-L1脂肪細胞生長曲線的建立與細胞形態的觀察 42
3-9瘦體素-熱敏性金奈米微粒藥物釋放 44
3-10瘦體素-熱敏性金奈米載體調控脂肪細胞生長 45
3-11不同分化劑誘導下瘦體素-熱敏性金奈米載體調控脂肪細胞情形 47
3-12 3T3-L1脂肪細胞分化過程相關蛋白表達 50
3-13 DOX-熱敏性金奈米微粒藥物釋放 51
3-14 DOX-熱敏性金奈米微粒細胞攝取 52
第四章 結論與討論 53
參考文獻 54
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