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系統識別號 U0026-1008201513584000
論文名稱(中文) 合成一種可穿透血腦屏障的新穎奈米製劑並用於腦腫瘤治療
論文名稱(英文) Synthesis of a novel blood-brain-barrier-penetrating nano-formulation for brain tumor therapeutics
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 張婉如
研究生(英文) Wan-Ru Chang
學號 T46024031
學位類別 碩士
語文別 英文
論文頁數 72頁
口試委員 指導教授-謝達斌
指導教授-鄭豐裕
口試委員-蘇五洲
中文關鍵字 腦腫瘤  血腦屏障  微胞  微脂體  協同作用 
英文關鍵字 brain tumor  blood-brain barrier  micelle  liposome  synergistic effect 
學科別分類
中文摘要 腦腫瘤為癒後最差的人類癌症之一,至今有效的臨床治療策略仍待開發,而多形性惡性膠質母細胞瘤(GBM)是最常見的原位神經惡性腫瘤,生長快速且具有周圍腦組織的侵略性,導致患者平均存活率約1年左右。目前傳統的療法成效仍極為有限,尤其化療藥物的治療遇到很大的困境,主要的原因是血腦屏障這個腦部特殊的構造,導致傳統藥物無法順利到達腦中的癌病灶區域。因此開發更有效滲入血腦屏障的媒介載體成為臨床很重要的未竟之需。先前的研究顯示紫杉醇類藥物可有效抑制微管聚合而在局部注射後顯著地抑制GBM腫瘤生長。然而,這類藥物投遞路徑在臨床上有其實際執行的挑戰與風險。
本研究根據藥物-藥物-共賦型的概念形成僅具有活性藥物成分而無賦型劑之奈米載體。一種雙性藥物在此擔任活性藥物成分與穿越血腦屏障的雙重角色。我們評估了三種候選雙性藥物,包含Fingolimod (FTY720)、Perifosine (KRX-0401)及Miltefosine (Impavido®)於藥物-藥物-共賦結構劑型中,並加入半合成紫杉醇衍生物Cabazitaxel (Jevtana®)。這樣的組合不僅具有內建的藥物加成性效果而能阻斷癌症訊息傳導路徑,且能提升穿越血腦屏障之效能。由穿透式電子顯微鏡觀察發現劑型為7~20 nm直徑之奈米球體與同步輻射小角度陰極射線散射(SAXS, beamline 23A1)分析結果一致。在細胞毒性試驗和以C6及U-87 MG癌細胞建立之動物模式研究顯示此種新穎的奈米藥物與單一藥物處理及其自由態之組合的組別比較起來具有更佳的癌細胞毒殺效果。我們期望此一新設計的藥物劑型在未來可以改善腦腫瘤未來臨床治療的整體預後。
英文摘要 Brain tumor is one of worst prognosis malignancy of human that effective clinical therapeutic strategies remained to be explored. Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. GBM displays aggressive growth and invasion to the surrounding brain tissues, leading to a median survival time only about 1 year. Current traditional therapeutics only showed limited efficacy, especially for chemotherapeutic drugs that blood-brain barrier (BBB) presented to be a major challenge for traditional medication to reach cancerous area in the brain tissues. Thus, development of vehicles that effectively penetrate BBB has become a critical clinical unmet need. Previous studies showed that paclitaxel-like drugs effectively inhibit microtubule depolymerization and could significantly suppress GBM growth through local injection. Such delivery route is, however, extremely challenging and risky in clinical practices.
In this study, we adopted drug-drug co-formulation concept for nano-vehicle that contains only active pharmaceutical ingredients (API) without excipients. An amphiphilic drug serves both the role of API and trans-BBB nano vehicle. We evaluated three candidate amphiphilic drugs including Fingolimod (FTY720)、Perifosine (KRX-0401), and Miltefosine (Impavido®) in a drug-drug co-formulation with semi-synthetic derivative of natural Taxoids (Jevtana®Cabazitaxel). Such combination not only harbor endogenous synergistics to overcome carcinogenesis signaling pathway, but may also augment trafficking through BBB. Transmission Electron Microscopy (TEM) and Dynamic light scattering (DLS) observation revealed round shape nanospheres of 7~20 nm in diameter consistent with Synchrotron Radiation Small-angle X-ray scattering (SAXS, beamline 23A1) analysis. MTT assay and animal study in cancer cells C6 and U-87 MG showed that such novel nanomedicine has excellent cytotoxicity to cancer cell lines much potent than single free form compounds or their combination in free drug format. We expect the newly designed drug could improve the overall outcome of brain tumor therapy in the future clinical therapy.
論文目次 中文摘要 I
Abstract III
Acknowledgement V
Figures Content I
Abbreviations II
Introduction 1
1.1 Brain tumor and glioblastoma multiforme (GBM) 1
1.2 Blood-brain barrier (BBB) 3
1.3 Invasive drug delivery strategies for brain tumors 5
1.3.1 Intra-arterial delivery 5
1.3.2 Convection-enhanced delivery 6
1.3.3 Implanted therapies 6
1.4 Nanoparticles as non-invasive delivery systems to brain tumors 8
1.4.1 Liposomes 8
1.4.2 Micelles 9
1.4.3 Dendrimers 10
1.5 Natural and synthetic compounds with API and excipient dual functions 11
1.5.1 Fingolimod (FTY720, Gilenya®) 11
1.5.2 Miltefosine (Impavido®) 12
1.5.3 Perifosine (KRX-0401) 13
1.6 Antimicrotubule agents for cancer 15
1.6.1 Antimicrotubule agents 15
1.6.2 Taxane compounds 15
1.6.3 Cabazitaxel (Jevtana®) 16
Material and Methods 18
2.1 Synthesis of a novel nano-formulation 18
2.2 Cell culture 19
2.2.1 Cell lines 19
2.2.2 Cell counting 19
2.2.3 Cell viability assay 20
2.3 Transmission electron microscope 21
2.4 Bioluminescence imaging analysis 22
2.5 Antitumor activity in tumor-bearing mice 22
Results 24
3.1 Characterization of nano-formulation 24
3.2 Cytotoxicity of the novel nanomedicine to cancer cell lines 25
3.3 In vivo nano-formulation bio-distribution in the brain 28
3.4 In vivo antitumor activity with subcutaneous tumors 29
Discussion 30
Conclusion 34
Figures and Legends 35
Reference 51
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