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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳進庭 | |
| dc.contributor.author | Hsiu-Wei Lee | en |
| dc.contributor.author | 李琇瑋 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:24:14Z | - |
| dc.date.copyright | 2013-07-26 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-16 | |
| dc.identifier.citation | 1. Miller, A.B., et al., Reporting results of cancer treatment. Cancer, 1981. 47(1): p. 207-214.
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Sadzuka, Y., et al., Effect of polyethyleneglycol (PEG) chain on cell uptake of PEG-modified liposomes. J Liposome Res, 2003. 13(2): p. 157-72. 59. Goto, S., et al., Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase pi. FASEB J, 2001. 15(14): p. 2702-14. 60. Raghavan, R., et al., Low-level (PPB) determination of cisplatin in cleaning validation (rinse water) samples. II. A high-performance liquid chromatographic method. Drug Dev Ind Pharm, 2000. 26(4): p. 429-40. 61. Augey, V., et al., High-performance liquid chromatographic determination of cis-dichlorodiammineplatinum(II) in plasma ultrafiltrate. J Pharm Biomed Anal, 1995. 13(9): p. 1173-8. 62. Hegedus, L., et al., Chemical reactivity of cisplatin bound to human plasma proteins. Cancer Chemother Pharmacol, 1987. 20(3): p. 211-2. 63. Chappuy, M., et al., Determination of platinum traces contamination by graphite furnace atomic absorption spectrometry after preconcentration by cloud point extraction. J Hazard Mater, 2010. 176(1-3): p. 207-12. 64. Hobbs, S.K., et al., Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A, 1998. 95(8): p. 4607-12. 65. Chang, D.K., et al., Antiangiogenic targeting liposomes increase therapeutic efficacy for solid tumors. J Biol Chem, 2009. 284(19): p. 12905-16. 66. Moghimi, S.M., A.C. Hunter, and J.C. Murray, Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev, 2001. 53(2): p. 283-318. 67. Lehtinen, J., et al., Analysis of cause of failure of new targeting peptide in PEGylated liposome: molecular modeling as rational design tool for nanomedicine. Eur J Pharm Sci, 2012. 46(3): p. 121-30. 68. Ishida, T., D.L. Iden, and T.M. Allen, A combinatorial approach to producing sterically stabilized (Stealth) immunoliposomal drugs. FEBS Lett, 1999. 460(1): p. 129-33. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17597 | - |
| dc.description.abstract | 在癌症治療上目前有手術切除、化學治療、標靶治療，以及光動力治療等等，我們結合化學治療與光動力治療，將兩種化療藥物doxorubicin (Dox)或cisplatin (cDDP)結合光感物質Chlorin e6 (Ce6)，以微脂體 (Liposome)劑型同時包覆化療藥物以及光感物質，我們稱這種同時具有化療以及光動力療法的藥物為雙效微脂體，並依照包覆化療藥物的不同，命名為PL-Dox-Ce6以及PL-cDDP-Ce6，其中PL指的是修飾Polyethylene glycol (PEG)的微脂體。本篇研究目的在於建立最適化的雙效微脂體。研究論文的第一部分在於藉由調整雙效微脂體PL-cDDP-Ce6以及PL-Dox-Ce6脂質組成比例，以增進雙效微脂體在血清中的穩定性。為此，首先建立可以有效率分離及純化微脂體的方法。我們利用spin column來有效地自血清中分離微脂體，並降低血清蛋白在分析上面的干擾。在脂質組成調整部分，調整微脂體中膽固醇以及PEG的莫耳比例，發現在雙效微脂體PL-Dox-Ce6中提高膽固醇可以讓Dox與血清共混時穩定度上升，然而Ce6的穩定度卻會下降。而當降低PL-cDDP-Ce6的膽固醇含量，對微脂體的cisplatin滲漏影響不大，但是卻會讓Ce6的穩定度下降。在調整PEG的部分，發現提高微脂體PEG的含量可以同時降低PL-Dox-Ce6之Dox以及Ce6的滲漏情形。另外，同時提高PL-Dox-Ce6的膽固醇以及PEG含量，和原先配方比較可同時降低Ce6和Dox的滲漏。論文的第二部分，為將雙效微脂體 PL-cDDP-Ce6或PL-Dox-Ce6結合能專一辨認腫瘤血管新生接受器的胜肽IVO8和IVO24，並且探討其標靶特性。將胜肽修飾的雙效微脂體藥物，以C26以及H460這兩種小鼠腫瘤模式，測試藥物在各個組織、臟器的累積量。從實驗結果發現，修飾這兩種胜肽的雙效微脂體在腫瘤的藥物累積量並不能提升；然而，有胜肽修飾的微脂體反而更容易累積在肝臟以及脾臟。 | zh_TW |
| dc.description.abstract | The Liposomal drug delivery systems have been extensively studied in increasing the therapeutic index of chemotherapy. Photodynamic therapy (PDT), which is based on the administration of a photosensitizer followed by the irradiation of selective light, is a therapeutic modality for cancer treatment. Previously, we have developed a polyethylene glycol (PEG) modified liposome simultaneously encapsulated with a photosensitizer, Chlorin e6 (Ce6), in the lipid bilayer and a chemotherapeutic agent, doxorubicin (Dox) or cisplatin (cDDP), in the aqueous interior. Here we named as dual-effect liposome PL-Dox-Ce6 and PL-cDDP-Ce6. In the first part of this study, we tried to tune the molar ratio of lipid contents in liposomes, and then examine the serum stability of liposomes in the presesence of 80% FBS. A spin column method was developed to separate the liposome and serum proteins. The results showed that liposomes and serum proteins could be separated by spin column. By increasing the molar ratio of cholesterol in PL-Dox-Ce6, we found that the stability of Dox in liposome could be improved, but a dramatic loss of Ce6 was also found. However, when we increased the molar ratio of PEG in PL-Dox-Ce6, the serum stability of Ce6 and Dox could be improved. If we increased the molar ratio of cholesterol and PEG in liposomes, we found that the loss of Ce6 and Dox was lower than the formulation of DSPC: CHOL:DSPE-PEG= 100:50:2 (molar ratio). In the formulation of PL-cDDP-Ce6, the loss of cisplatin wasn’t significant when we lowered its cholesterol content. However, the loss of Ce6 in PL-cDDP-Ce6 was found in lowering the molar of cholesterol.
In the second part of this study, we tried to insert targeting peptides IVO24 and IVO8 which have been shown to target to the tumor vessels, into our dual-effect liposomes. In C26 tumor model, the drug accumulation in tumor sites was not significantly different between PL-cDDP-Ce6 and IVO24-PL-cDDP-Ce6. In H460 tumor model, the drug accumulation in tumor sites was not significantly different between PL-Dox-Ce6 and IVO24-PL-Dox-Ce6 or IVO8- PL-Dox-Ce6. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:24:14Z (GMT). No. of bitstreams: 1 ntu-102-R00b22019-1.pdf: 2085245 bytes, checksum: c9571b8639c74696cb26c455ea56bffc (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 中文摘要： I
ABSTRACT: II 目錄 IV 第一章 緒論 1 1.1 癌症及其治療方式 1 1.2 癌症的光動力治療 2 1.3 微脂體與癌症治療 3 1.3.1 微脂體的介紹 3 1.3.2 以微脂體作為藥物載體 6 1.3.3 微脂體藥物與癌症的標靶治療 (Targeting therapy) 6 1.4 微脂體藥物的分離技術 7 1.5 CHLORIN E6、DOXORUBICIN、CISPLATIN (CDDP) 微脂體藥物性質與分析 9 1.5.1 Chlorin e6 (Ce6) 9 1.5.2 Doxorubicin 10 1.5.3 cisplatin (cDDP) 11 1.6 研究動機與目的 12 1.7 研究架構 13 第二章 材料與方法 14 2.1 藥品與儀器 14 2.1.1 藥品 14 2.1.2 儀器 16 2.2 細胞株 16 2.2.1 細胞培養液 17 2.2.2 繼代培養方法 17 2.2.3 細胞計數 17 2.3 微脂體製備與性質分析 18 2.3.1 雙效微脂體PL-Dox-Ce6 的製備 18 2.3.2 雙效微脂體PL-cDDP-Ce6 的製備 18 2.3.3 藥物的定量 19 2.3.4 微脂體的脂質定量 20 2.4 微脂體於血清中的穩定性分析 20 2.4.1 分離微脂體、free drug以及血清蛋白 20 2.4.2 Chlorin-e6以及Doxorubicin的分析 21 2.5 於微脂體表面修飾胜肽作為標靶治療 21 2.6 活體動物實驗 22 2.6.1 動物與腫瘤模式 22 2.6.2 藥物於活體組織分布 22 2.7 統計分析 23 第三章 結果 24 3.1 最適化分離微脂體、血清蛋白以及FREE FORM藥物之分離方法 24 3.1.1 以Gel filtration分離微脂體 24 3.1.2 以spin column分離微脂體 24 3.2 調整雙效微脂體PL-DOX-CE6之脂質比例 25 3.2.1 調整雙效微脂體 PL-Dox-Ce6之膽固醇 (cholesterol)比例 25 3.2.2 調整雙效微脂體 PL-Dox-Ce6之Polyethylene glycol (PEG)比例 26 3.2.3 同時調整雙效微脂體 PL-Dox-Ce6之膽固醇以及Polyethylene glycol (PEG)之比例 27 3.3 調整雙效微脂體PL-CDDP-CE6之膽固醇比例 27 3.4 以石墨式原子吸收光譜儀偵測CISPLATIN與HPLC方法之比較 28 3.5 雙效微脂體PL-CDDP-CE6 結合標靶血管新生的胜肽IVO24並測試該微脂體在BALB/C 小鼠體內的藥物分布 29 3.6 雙效微脂體PL-DOX-CE6 結合標靶血管新生的胜肽IVO24以及IVO8並測試該微脂體在BALB/C 小鼠體內的藥物分布 29 3.7 雙效微脂體PL-DOX-CE6 結合標靶血管新生的胜肽IVO24以及IVO8並測試該微脂體在SCID MICE體內的藥物分布 30 第四章 討論 31 4.1 膠體過濾法 (GEL FILTRATION)分離血清中微脂體的可能問題 31 4.2 透過SPIN COLUMN可以分離純化血清中的雙效微脂體 31 4.3 膽固醇(CHOLESTEROL)對雙效微脂體PL-DOX-CE6或者PL-CDDP-CE6的穩定性影響 33 4.4 POLYETHYLENE GLYCOL (PEG)對雙效微脂體PL-DOX-CE6的重要性 34 4.5 雙效微脂體PL-DOX-CE6於配方調整後血清穩定性之探討 35 4.6 以石墨式原子吸收光譜儀偵測CISPLATIN與HPLC方法之比較 36 4.7 雙效微脂體PL-CDDP-CE6 以及 PL-DOX-CE6結合標靶血管新生的胜肽IVO24或IVO8在腫瘤模式無法提升藥物累積量原因之探討 37 第五章 結論 41 第六章 參考資料 54 第七章 附錄 59 | |
| dc.language.iso | zh-TW | |
| dc.title | Ce6 結合化療藥物 cisplatin或 doxorubicin之
雙效微脂體最適化探討 | zh_TW |
| dc.title | The optimization of dual-effect liposome encapsulated Ce6 and chemotherapeutic drugs, cisplatin or doxorubicin | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃慶璨,許瑞祥,蔡翠敏 | |
| dc.subject.keyword | Chlorin e6 (Ce6),Doxorubicin(Dox),Cisplatin (cDDP),膽固醇,Polyethylene glycol (PEG), | zh_TW |
| dc.subject.keyword | Chlorin e6,Doxorubicin,Cisplatin,Photodynamic therapy,Dual-effect liposome, | en |
| dc.relation.page | 62 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-07-16 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| 顯示於系所單位： | 生化科技學系 | |
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