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標題: | 開發以粒線體為標靶之奈米藥物載體 Development of nano drug carriers targeting mitochondria |
作者: | Song-Ling Wong 翁松翎 |
指導教授: | 何佳安(Ja-an Ho) |
關鍵字: | 奈米藥物載體,粒線體,藥物傳遞,金奈米粒子, nano drug carrier,mitochondria,drug delivery,gold nanoparticles, |
出版年 : | 2014 |
學位: | 碩士 |
摘要: | 近年來,以粒線體為標的開發抗癌藥物成為新一代癌症治療的重要研究方向。粒線體是細胞的能量以及死亡的調控中心,且腫瘤細胞粒線體的功能普遍異常,因此針對腫瘤細胞和正常細胞在代謝以及死亡調控上的顯著差異尋找標的,是重要的新藥發展策略。目前已經有多種以粒線體為標靶的藥物進入到臨床試驗階段。
以奈米藥物載體攜帶抗癌藥物有下列優點:1)奈米藥物載體可以透過enhanced permeability and retention effect (EPR effect)使抗癌藥物累積在腫瘤,降低對正常組織及器官的副作用;2)可以使疏水性藥物均勻的分散在生物系統中,避免因使用助溶劑造成的副作用;3)可以在載體上做各種修飾增加不同功能(ex: targeting, imaging),而不用改變藥物的分子結構。基於上述奈米藥物載體的優點,及以癌細胞粒線體為標靶之化學治療策略的發展,開發能有效運送藥物至粒線體之藥物載體有其必要性。 在本研究中,我們利用修飾有triphenylphosphonium (TPP)分子之磷脂質來包覆金奈米粒子(phospholipid capped gold nanoparticles, PLGNP)表面,使其成為以粒線體為標靶之奈米粒子;並利用金奈米粒子可以透過感應耦合質譜儀(ICP-MS)準確量化的特點,來評估我們的修飾方法是否可以使奈米粒子有效地進入到粒線體。通過合成方法的最佳化,目前已經合成出適合用來做細胞實驗的PLGNP-TPP。下一步將會使癌細胞與PLGNP-TPP共培養後,分離出粒線體並用ICP-MS評估其進入到粒線體的效率。若ICP-MS測得的數據證明PLGNP-TPP可以有效地進入到粒線體,則此修飾策略將可應用到其他不同種類的奈米藥物載體上,並且PLGNP-TPP也有機會成為研究奈米粒子與粒線體功能等基本研究的重要工具。 本研究也嘗試利用有無粒線體標靶分子修飾之PLGNP來闡明金奈米粒子對粒線體功能的影響。在細胞存活率試驗(MTT assay)發現PLGNP-TPP會影響A549肺癌細胞的存活率,進一步測試和粒線體活性有關的指標,發現細胞中的ATP level下降,並有粒線體膜電位失常等現象。細胞中針對粒線體受損有一套處理的機制,受損的粒線體會被細胞自噬清除以維持細胞內整體粒線體的正常功能。觀察細胞自噬的marker ,即microtubule-associated protein 1light chain 3的表現後我們發現,與PLGNP-TPP共培養後的細胞有活化細胞自噬的現象。初步的結果顯示PLGNP-TPP會造成細胞中粒線體的受損,並開啟細胞中修復粒線體受損的機制。詳細的過程還需要更進一步研究,以判斷PLGNP-TPP或是其他以粒線體為標靶的奈米藥物載體在使用上需注意的事項或是所需要的改良。 In recent years, targeting mitochondria as a therapeutic target has become an emerging strategy in cancer treatment. Mitochondria are often referred to as a central hub for responses to cellular stress and cell injury; in addition, the well-established functions of mitochondria in energy supply/storage and apoptosis provide novel targets for tumor cell suicide. Therefore the alterations in cancer cells that protect cell from apoptosis can be utilized to inhibit proliferation of cancer cell. Furthermore, strategies of re-programming in cancer cells with metabolic differences from their normal counterparts may lead to alternative therapeutic approaches. Currently there are several drug candidates that are attempted to use in targeting mitochondria are in cancer clinical trials. Nanodrugs are known to offer several key features, including: (i) site-directing nanodrug can be found to accumulate intensively in tumor site by enhanced permeability and retention effect (EPR effect), avoiding or minimizing side effects to the normal tissue; (ii) improved pharmacokinetic profile for drugs with poor solubility; (iii) versatility of nanodrugs (can be designed to obtain mutli-functions, including imaging, hyperthermia, stimuli-controlled release). Considering the great potential offered by mitochondrially-targeted nanodrugs, the development of a reliable mitochondria-targeted nanocarrier is desirable. In this study, the unique characteristics of triphenylphosphonium (TPP) was exploited to design a mitochondrial targeting nanodrug. It was achieved by developing a facile synthetic strategy to conjugate this mitochondria-targeted moiety onto the phospholipid layer of the gold nanoparticles functionalized with phospholipids |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4936 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 生化科技學系 |
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