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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張富雄 | |
dc.contributor.author | Kuan-Chi Huang | en |
dc.contributor.author | 黃冠綺 | zh_TW |
dc.date.accessioned | 2021-06-08T02:23:47Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-18 | |
dc.identifier.citation | Arpicco, S., G. De Rosa, and E. Fattal, Lipid-Based Nanovectors for Targeting of CD44-Overexpressing Tumor Cells. J Drug Deliv, 2013. 2013: p. 860780.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19863 | - |
dc.description.abstract | 以抗癌藥物治療腫瘤一段時間後,往往會有多重抗藥性(multidrug resistance; MDR)的產生,以至於抗癌藥物無法有效地對腫瘤進行治療。而最常導致MDR的產生即是腫瘤細胞之細胞膜上大量表現藥物運輸蛋白(drug transporter),其中又以p-glycoprotein (P-gp)最常見。P-gp位於細胞膜表面,可以將其受質排出細胞外,避免受質停留於細胞內,對細胞造成毒殺效果。而P-gp有廣泛的受質專一性,許多抗癌藥物亦是其受質,例如:Doxorubicin、Etoposide等。 以脂微粒作為藥物的載體,用於治療抗藥性腫瘤被認為是一個具有潛力的治療方法,因其可以透過內吞作用 (endocytosis),有效的將藥物運輸至細胞中,避免P-gp之作用,並有利於增加藥物在細胞中的含量以達到毒殺效果。此外,以玻尿酸 (hyaluronic acid)修飾脂微粒可以減少非專一性之結合、增加循環效果,且玻尿酸為CD44 受體之配位體,可用於做為標靶治療。因此,本研究利用玻尿酸修飾正價脂微粒並包覆抗癌藥物,分析其對腫瘤之治療效果。 本實驗利用膽固醇為基礎的正價脂質 (GEC-Chol),與膽固醇 (Chol)以不同比例混和,製備膽固醇基礎之脂微粒 (GCC)。接著脂微粒以不同濃度之玻尿酸進行修飾。實驗結果發現,GEC-Chol : Chol之molar ratio為1 : 3,且脂微粒與玻尿酸之濃度比為22.5 : 1時,是脂微粒與玻尿酸混和之最佳比例。而利用流式細胞儀分析細胞對脂微粒及玻尿酸脂微粒之吞噬效果,其結果顯示,細胞對玻尿酸脂微粒吞噬效果較差,表示玻尿酸脂微粒有助於減少非專一性之結合。另一方面,玻尿酸脂微粒包覆抗癌藥物組與未被包覆之藥物組相比,不論在活體外或活體內,皆顯著的增加治療抗藥性腫瘤之效果。 本研究探討玻尿酸包覆脂微粒及其對抗藥性腫瘤治療效果之分析,期望未來可以應用於活體治療,且作為往後用於活體抗藥性腫瘤治療之參考,並改善正價奈米材料應用上的不足,運用在更廣泛之用途。 | zh_TW |
dc.description.abstract | Chemotherapy is one of the major cancer treatments, but this treatment could be impeded by cellular mechanisms such as multidrug resistance (MDR). The most common attribute to drug resistance is the overexpression of P-glycoprotein (P-gp), which is the plasma membrane protein encode by mdr1 gene and acts as an energy-dependent efflux transporter. P-gp has the wide range of substrate specificity, for example, Doxorubicin, Etoposide; it can pump out the antitumor drug to reduce intracellular drug accumulation and compromise drug efficacy. Previous study indicates that nanoparticles, with the endocytosis mechanism of cell uptake, have potential to overcome drug resistance and prevent P-gp from pumping out. On the other hand, micelles modified with hyaluronic acid could reduce non-specific binding and improve half life in blood circulation. Furthermore, hyaluronic acid as ligand of CD44 receptor on general tumor cells surface also could be strategy of targeting therapy for cancers. Consequently, we used hyaluronic acid modified micellar etoposide to study the drug resistance tumor. In this study, the major lipid, GEC-Chol which is a kind of cationic cholesterol-based lipid was fabricated, and mixed with different ratio of cholesterol to prepare cholesterol-based nanoparticles (GCC). Then, modified with hyaluronic acid in different concentration. The results indicate that, GEC-Chol : Chol as 1 : 3, and micelles : hyaluronic acid as 22.5 : 1, is the most perfect ratio to study. To reveal the cellular uptake of hyaluronic acid modified micelles, flow cytometry was used to analyze the changes in amount of fluorescence in cells and analysis statistical results. The results shows that, hyaluronic acid modified micelles have less affinity with tumor cells than GCC, so it is a potential strategy to bring down the non-specific binding. Moreover, the cytotoxicity of hyaluronic acid modified micellar etoposide has more efficiency compared to free drug whatever in vivo or in vitro. The findings of this study have important implications for understanding effectiveness of hyaluronic acid modified micelles targeting to drug resistant tumor cells. It is expected that the hyaluronic acid modified micelles will be used widely in the future, and can improve the inadequate in nanomaterial applications for cancer therapy. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:23:47Z (GMT). No. of bitstreams: 1 ntu-104-R02442028-1.pdf: 1982620 bytes, checksum: 1f59f9dbe6a3e0866add1264a261ff09 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 口試委員審定書 Ⅰ 致謝 Ⅱ 中文摘要 Ⅲ 英文摘要 Ⅳ 第一章 緒論 1.1 抗藥性腫瘤 1 1.1.1 多重藥物抗藥性 1 1.1.2 P-glycoprotein 2 1.1.3 常用之抗藥性細胞株 3 1.1.4 抗藥性腫瘤之治療方法 4 1.2 奈米粒子 5 1.2.1 奈米粒子特性 5 1.2.2 奈米藥物遞送系統 7 1.3 玻尿酸 9 1.3.1 玻尿酸與CD44受體間關係 10 1.3.2 玻尿酸於奈米粒子之應用 11 1.4 研究動機與目的 13 第二章 實驗材料與方法 2.1 實驗材料 14 2.1.1 細胞株 14 2.1.2 實驗動物 14 2.1.3 脂質 14 2.1.4 化學藥品 14 2.1.5 儀器 15 2.2 實驗方法 16 2.2.1 脂微粒包覆藥物之製備 16 2.2.2玻尿酸修飾脂微粒之製備 17 2.2.3 脂微粒粒徑大小、均質度以及表面電荷之分析 17 2.2.4 脂微粒於不同溶液中之穩定性測試 18 2.2.5 脂微粒包覆藥物之效率測試 18 2.2.6 細胞株繼代培養 19 2.2.7 利用流式細胞儀分析細胞株中CD44受體之表現量 19 2.2.8 利用流式細胞儀分析細胞吞噬脂微粒之效率 20 2.2.9 藥物及玻尿酸脂微粒包裹依託泊苷對細胞毒性之分析 21 2.2.10 玻尿酸脂微粒包裹依託泊苷對腫瘤治療之分析 21 第三章 實驗結果 3.1 玻尿酸脂微粒粒徑大小、均質度以及表面電荷之分析 23 3.2 脂微粒穩定性之分析 24 3.3 脂微粒包覆藥物之效率分析 24 3.4 細胞中CD44受體表現量之分析 25 3.5 玻尿酸修飾脂微粒被細胞吞噬之情形 25 3.6 藥物及玻尿酸脂微粒包裹依託泊苷對細胞毒性之影響 26 3.7活體內測試玻尿酸脂微粒包覆依託泊苷抗腫瘤之療效 26 3.8腫瘤組織H E染色之分析 27 第四章 討論 4.1玻尿酸脂微粒粒徑大小、均質度以及表面電荷之分析 29 4.2 脂微粒穩定性之分析 30 4.3 脂微粒包覆藥物之效率分析 31 4.4 細胞中CD44受體表現量之分析 32 4.5 玻尿酸修飾脂微粒被細胞吞噬之情形 32 4.6 藥物及玻尿酸脂微粒包裹依託泊苷對細胞毒性之影響 34 4.7活體內測試玻尿酸脂微粒包覆依託泊苷抗腫瘤之療效 34 第五章 圖表與說明 表一 不同組成比例之玻尿酸脂微粒之物性分析 37 表二 於不同溶液中脂微粒的穩定性 38 表三 脂微粒對於依託泊苷之包覆率 39 圖一 玻尿酸脂微粒之製備 40 圖二 利用流式細胞儀分析細胞中CD44受體之表現量 41 圖三 利用流式細胞儀分析細胞吞噬脂微粒之效率 42 圖四 不同抗癌藥物對細胞之毒性影響 43 圖五 脂微粒包覆依託泊苷對細胞毒性之影響 44 圖六 活體治療流程及小鼠體重 45 圖七 玻尿酸脂微粒包覆依託泊苷對小鼠活體腫瘤之治療效果 46 圖八 腫瘤組織H E染色 47 第六章 參考文獻 48 | |
dc.language.iso | zh-TW | |
dc.title | 玻尿酸修飾包覆依託泊苷之脂微粒及其對抗藥性腫瘤治療之分析研究 | zh_TW |
dc.title | Hyaluronic acid modified micellar etoposide for drug resistance tumor therapy | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張明富,林文澧,詹東榮 | |
dc.subject.keyword | 腫瘤抗藥性,奈米粒子,玻尿酸, | zh_TW |
dc.subject.keyword | MDR,micelle,Hyaluronic acid, | en |
dc.relation.page | 51 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-08-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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