含calebin-A之自微乳化藥物傳遞系統有效治療大腸直腸癌

Abstract

大腸直腸癌是全球人口最常患上的惡性腫瘤排名第三，同時也在全球十大癌症死因位居第三。近年來的研究發現從薑黃(Curcuma longa)根莖萃取的植物生化素calebin-A具有抗癌、抗發炎、抗氧化等保健功效。但calebin-A的疏水特性使其無法溶解在水溶液裡，導致其在動物實驗裡療效功能非常低。目前有不少研究利用各種藥物傳遞系統將疏水性物質傳遞到水裡。本研究的目的是使用自微乳化藥物傳遞系統(Self-microemulsifying drug delivery system, SMEDDS)改善calebin-A疏水性造成的低吸收率並進一步探討其在人類結直腸腺癌細胞株(HCT 116)異種移植裸鼠的抗癌功效。含calebin-A 的SMEDDS口服配方由polyoxyethylene (20) sorbitan momooleate (Tween 80)， polyethylene glycol 400 (PEG 400)和中鏈三酸甘油脂(MCT)製成，其粒徑大小為28.7 nm 而界面電位為 -9.7 mV。體外脂質消化實驗結果顯示含calebin-A 的SMEDDS 釋放水溶性calebin-A比calebin-A中鏈三酸甘油脂懸浮液高7.5倍。HCT 116異種移植裸鼠實驗結果顯示管餵含50 mg/kg calebin-A 的SMEDDS可以藉由上調細胞週期檢查點激酶、p53和p21的蛋白質表現量而減緩腫瘤生長； 降低cdc25A、cyclin B1、cdc2和cyclin A的蛋白質表現量使HCT 116異種移植鼠腫瘤停滯在S和G2/M期。綜合本研究的結果，自微乳化藥物傳遞系統(SMEDDS)可有效提高calebin-A對大腸直腸癌的治療功效。

Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death worldwide. Recent studies have shown that calebin-A, a phytochemical from the rhizomes of turmeric (Curcuma longa), has anti-cancer, anti-inflammation, and anti-oxidation potential. However due to its hydrophobic property, the therapeutic potentials of calebin-A is greatly limited in the in vivo models by its poor solubility. There are various drug delivery systems that have been reported to be successful in delivering hydrophobic agents into an aqueous environment. The aim of this study is to use self-microemulsifying drug delivery system (SMEDDS) to ameliorate the low bioavailability of calebin-A for further investigation of its anti-tumor potential in human colon carcinoma cell line (HCT 116) xenografts nude mice. In this study, SMEDDS containing polyoxyethylene (20) sorbitan monooleate (Tween 80), polyethylene glycol 400 (PEG 400), and medium-chain triglyceride (MCT) was fabricated for oral administration of calebin-A. The results showed that SMEDDS containing calebin-A had droplets size of 28.7 nm and zeta potential of -9.7 mV. Based on in vitro lipid digestion study, SMEDDS containing calebin-A produced 7.5-fold more solubilized calebin-A than calebin-A MCT suspension. The results from HCT 116 xenografts nude mice suggested that 50 mg/kg calebin-A SMEDDS could decrease tumor growth rate through upregulation of phosphorylated check point kinase, p53, p21 protein expressions; decreased cdc25A, cyclin B1, cdc2, cyclin A protein levels; resulting in S phase and G2/M phase arrest. According to the results from this study, SMEDDS could improve the efficacy of calebin-A for the treatment of colorectal cancer.