原文献：Synergistic Effect of Tangeretin and Atorvastatin for Colon Cancer Combination Therapy: Targeted Delivery of These Dual Drugs Using RGD Peptide Decorated Nanocarriers

作者：He Bao,Nanbo Zheng,Zhuanting Li，Yuan Zhi

文献链接：https://pubmed.ncbi.nlm.nih.gov/32801644/

摘要：Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the fourth leading cause of cancer death over the world. Nano-sized drug delivery systems are used for the treatment of cancers. The aim of this study was to develop a tangeretin (TAGE) and atorvastatin (ATST) combined nano-system decorated with RGD (RGD-ATST/TAGE CNPs) for colon cancer combination therapy.In this study, cyclized arginine-glycine-aspartic acid sequences(RGD) contained ligand was synthesized by conjugating cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) with D-α-tocopheryl succinate dichloromethane (TOSD) using polyethylene glycol (PEG) as a linker to obtain cRGDfK-PEG-TOSD. ATST and TAGE combined nanosystems: RGD-ATST/TAGE CNPs were prepared. The combination effects as well as antitumor effects of these two agents were evaluated on colon cancer cells and mice bearing cancer models.

cRGDfK 由多个氨基酸组成，其中关键的 RGD 序列能够特异性地与整合素（integrin）结合。整合素是一类存在于细胞表面的跨膜受体蛋白，在细胞黏附、迁移、增殖等生理过程中发挥着作用。cRGDfK 中的环状结构增加了其稳定性和对整合素的结合亲和力。研究采用聚乙二醇（Arg-Gly-Asp-Lys）（cRGDfK）合成环化精氨酸-甘氨酸-天冬氨酸序列（RGD）结合配体，获得cRGDfK-PEG-TOSD。过程如下：

含RGD的配体的合成

以cRGDfK与TOSD为连接体，合成PEG获得cRGDfK-TOSD（图1）。TOSD和PEG溶解在二氯甲烷，然后DCC添加滴在冰浴，搅拌过夜。然后将cRGDfK和DCC一起加入到混合物中。在反应后，混合物放入旋转蒸发器去除二氯甲烷，cRGDfK-PEG-TOSD被过滤分离，洗三次乙醚，通过真空干燥一夜。

图1：cRGDfK-PEG-TOSD、cRGDfK-PEG-TOSD的化学结构。

结论：通过1 H NMR确定了PEG-RGD参与制备的cRGDfK-PEG-TOSD的化学结构表征。1H核磁共振（CDCl3500MHz）δ：1.01（甲基TOSD），1.43（甲烯TOSD），2.12（氨基cRGDfK），2.41（甲基苯环TOSD），3.36（甲烯佩格），3.69（cRGDfK）的甲烯)，4.26（甲烯旁边酰胺链接），4.61（甲烯cRGDfK），6.33（NHcRGDfK），7.02（HcRGDfK苯环），7.46（NHcRGDfK），和8.02（酰胺链接的NH）。