請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76666
標題: | 開發細胞胞器標靶奈米藥物技術為新型癌症治療策略 Development of subcellular-targeting nanodrug for cancer therapeutic strategy |
作者: | Chih-Wen Yang 楊智雯 |
指導教授: | 何佳安 |
關鍵字: | 癌症治療,粒線體標靶,奈米藥物傳遞系統, cancer therapy,mitochondrial targeting,nanodrug delivery system, |
出版年 : | 2016 |
學位: | 碩士 |
摘要: | 粒線體標靶藥物對癌症治療是個新興的策略;被稱為能量工廠的粒線體,除了供應細胞生長的能量,它在細胞凋亡機制中也扮演重要的角色。在粒線體內分佈許多訊息傳遞分子,調控細胞凋亡路徑,維持人體內環境的平衡。在癌化的細胞中,藉由特定分子的異常表現,使細胞凋亡機制失調,讓癌細胞能夠輕易逃脫細胞凋亡的途徑,不斷增生,也讓癌症治療效果不彰。因此藉著誘導粒線體凋亡訊息,重新啟動癌細胞凋亡機制的概念,有潛力成為癌症治療方法。過去研究指出,親脂性陽離子Triphenylphosphonium (TPP)因細胞膜電位為負電位(Δψ p)因素,容易進入細胞,細胞內的TPP分子可增加五到十倍,相較於細胞外。而細胞內粒線體胞器膜的負電位更高,理論上可使TPP分子更大量累積在粒線體中,若與細胞質之TPP含量相比,可增加到一百到五百倍。因此,在本論文研究中,運用TPP為靶向配體,開發具有粒線體標靶功能的新型奈米藥物傳遞系統並應用於癌症治療。在載體設計上,首先合成修飾TPP分子的磷脂質(Lipid-TPP),並將之使用於製備具有TPP靶向配體之金奈米粒子,在確定修飾有Lipid-TPP分子的金奈米粒子具有細線體標靶的能力後,我們接著將Lipid-TPP與生物可降解性的Poly(Lactide-co-Glycolide)高分子作結合,並包覆紫杉醇製備成為奈米藥物劑型,探討此奈米藥物對粒線體標靶性能與藥物傳遞的效率。從我們的實驗結果得知,奈米藥物系統與TPP分子結合可以選擇性累積在粒線體的位置,並將藥物更有效率傳送到粒線體胞器內,致使毒殺癌細胞效果增加。此外,本論文更深入探討癌細胞死亡機制,發現此奈米藥物系統,會影響細胞內粒線體的膜電位,改變粒線體的動態平衡調控。 Targeting mitochondria as a therapeutic objective for cancer treatment has become an emerging approach in recent years. Mitochondria are referred to the cells' powerhouses, and also the suicidal weapon stores. Dozens of lethal signal transduction pathways that converge on mitochondria, indicating that the mitochondria play pivotal roles in cell death and survival signaling. However, the tumor-specific alterations that protect themselves from apoptosis lead to cell death escape. Strategies on activating cell death machinery in cancer cells by regulating the mitochondrial biofunctions could therefore be promising therapeutic approaches. Herein we report triphenylphosphonium (TPP)-decorated nanosystems that selectively target the mitochondria. The lipophilic cation TPP enhanced cytosolic nanosystem accumulation by 5- to 10-fold from extracellular environment via negative membrane potential (Δψp), and further enhanced nanosystem in the mitochondrial matrix over 100- to 500-fold through negative potential (Δψm). The TPP-sensitized AuNP@lipid hybrid nanoparticles were first fabricated to examine their mitochondria-targeting capability. Next the mitochondria-targeting concept was demonstrated on the biodegradable PLGA@lipid hybrid nanosystems (PLGA = poly(D,L-lactide-co-glycolide)) encapsulating the drug paclitaxel (Taxol) to study their efficiency in targeting and intracellular drug delivery. Based on our preliminary results, TPP decoration onto nanosystems potentially improves their selective accumulation in mitochondria. Intracellular drug delivery performance also demonstrated that the cytotoxicity of the used anticancer drug increased due to the efficient drug delivery into mitochondria. In addition, our design of the nanosystem was found to cause the change in the mitochondrial dynamic and mitochondrial depolarization behaviors. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76666 |
DOI: | 10.6342/NTU201602987 |
全文授權: | 未授權 |
顯示於系所單位: | 生化科技學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-105-R02b22032-1.pdf 目前未授權公開取用 | 4.18 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。