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標題: | 藉由白藜蘆醇-硬脂酸合成物發展具標靶αvβ3組合蛋白能力之微脂體型藥物傳遞系統 Using resveratrol-modified stearate to develop a liposome-based drug delivery system by targeting integrin αvβ3 |
作者: | Jia-Ching Mao 毛嘉慶 |
指導教授: | 蕭寧馨(Ning-Sing Shaw) |
關鍵字: | 組合蛋白αvβ3,藥物傳遞,微脂體,白藜蘆醇-硬脂酸合成物,阿黴素, Integrin αvβ3,Drug delivery,Liposome,Resveratrol-modified stearate,Doxorubicin, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 以化學藥物進行癌症治療時,如何將藥物精確地送至病灶區域是醫療界全心追求的目標。近年來,可以用於運送藥物的奈米粒子陸續被開發出來,具有標靶功能的奈米傳遞系統不但可以有效毒殺腫瘤細胞,還可以降低對人體其他器官的副作用(如:心血管毒性、嘔吐及掉髮等)。標靶載體的設計通常是藉由修飾可辨認腫瘤細胞表面特定的受器(receptor)的配體(ligand)(例如:抗體、醣分子、小片段胺基酸序列或核酸序列等),因此能將載體內藥物專一地送到病灶。
過去的文獻指出,白藜蘆醇(resveratrol)可藉由乳癌細胞膜上的αvβ3組合蛋白(integrin)進入細胞,活化ERK1/2的訊息傳遞路徑並調控p53ser15的磷酸化,促使乳癌細胞進行凋亡。此外,其它文獻亦指出白藜蘆醇搭配臨床化療用藥阿黴素(doxorubicin)的使用可提高對乳癌細胞的毒殺能力。因此本篇研究擬利用白藜蘆醇(一種非黃酮類的酚類物質,存在於許多植物中,並具有抗氧化功能)作為標靶乳癌細胞的工具。利用白藜蘆醇-硬脂酸合成分子(由嘉義大學應用化學系鄭建中教授實驗室提供)搭配其他適當的磷脂質製備表面修飾有白藜蘆醇-硬脂酸合成分子之微脂體(resveratrol-modified stearate liposome),並裝載阿黴素,發展為可調控腫瘤細胞訊息傳遞、增強毒殺能力且具安全性之藥物傳遞系統。首先,我們利用流式細胞儀分析MCF7乳癌細胞上活化態的αvβ3組合蛋白的表現,結果發現在Mn2+處理的情況下活化態v3組合蛋白的表現量有提高。利用Mn2+處理活化細胞表面之αvβ3組合蛋白,觀察到MCF7乳癌細胞攝取不同比例RMS修飾之微脂體能力有差異,以7.5% RMS修飾之微脂體被攝取的程度較高且細胞毒殺能力提升。過去研究指出腫瘤微環境的弱酸性(pH~6.5)會促使αvβ3組合蛋白進行活化,我們模擬腫瘤微環境的條件觀察阿黴素與RMS微脂體的功效,發現弱酸性(pH~6.5)與Mn2+處理之組別一樣毒殺能力有提高,從毒性試驗結果發現裝載阿黴素之表面修飾有白藜蘆醇的微脂體(RMS-liposomal doxorubicin)與相等劑量之游離型阿黴素藥物(free doxorubicin)或裝載阿黴素藥物之微脂體(liposomal doxorubicin)更具有毒殺癌細胞的能力。本研究利用白藜蘆醇具有分子標靶在癌細胞會大量表現之活化態的αvβ3組合蛋白的特性,發展成更專一地的定位腫瘤且兼具功能性及安全性之微脂體藥物傳遞系統。 Chemotherapy is a category of medicine treatment that uses chemical substances and usually delivered via intravenous injection. To make sure that enough drug reaches a tumor, very large quantity of drug might have to be given. Precise delivery of drugs to tumor site thus becomes an important issue. Many studies have been done investigating the effects of nanoparticles in the application of drug delivery. Some of the pharmacological properties of free drugs can be manipulated through the utilization of specially designed nanocarriers. Nanocarriers has a number of advantages in drug delivery, including: (i) provide a shelter that prevent rapid metabolism of drugs in circulation; (ii) improve poor solubility of drugs and increase the bioavailability of drugs; (iii) lead to an intensive accumulation of drugs in tumor site (iv) reduce side-effect of free drugs by site-directing nanocarriers. In the light of the potential offered by nanoparticles, the development of a site-directing nanodrug is a promising approach to improve delivery efficiency and efficacy of drugs. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid and a phytoalexin, found naturally in several plants, which suppresses oxidative damage and is known to have anti-inflammatory, antioxidant, antitumor and immunomodulatory capabilities. Resveratrol was reported to exhibit αvβ3 integrin binding ability, and subsequently induce downstream pathway of extracellular regulated kinases 1 and 2 (ERK1/2) and serine-15-p53 dependent phosphorylation, and finally leading to apoptosis. In addition, several studies have been carried out to explore the synergistic effect of resveratrol and chemotherapy agent (e.g., doxorubicin). In this study, resveratrol-modified stearate (provided by Prof. Chien-Chung Cheng at Department of Applied Chemistry, National Chia-Yi University) was used to prepare resveratrol-modified liposomal doxorubicin (RML/Dox) that possessed capability of targeting αvβ3 integrin on the surface of tumor cells. Our results showed that, at the same drug dosage, resveratrol-modified liposomal doxorubicin demonstrated better efficacy when compare to conventional forms of free drug and liposomal drug. This might be due to the existence of resveratrol that concurrently upregulated downstream apoptosis pathway, resulting in the synergistic effect of doxorubicin chemotherapy and resveratrol treatment on killing breast cancer cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51199 |
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