Ge Yunfei, Kwon Mi-Hye, Kou Fang, Uthamapriya Rajavel Arumugam, Zhang Peng, Lee Dong-Jin, Yang Ruijuan, Bao Honghui, Palanisamy Subramanian, You SangGuan
College of Food Science and Technology, Yunnan Agricultural University, Kunming, Yunnan 650 201, China; Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120, Gangneung, Gangwon 210-702, Republic of Korea.
Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120, Gangneung, Gangwon 210-702, Republic of Korea; East Coast Life Sciences Institute, Gangneung-Wonju National University, 120, Gangneung, Gangwon 210-702, Republic of Korea.
Int J Biol Macromol. 2024 Dec;283(Pt 3):137653. doi: 10.1016/j.ijbiomac.2024.137653. Epub 2024 Nov 17.
The study focuses on the development of folate-targeted conjugates utilizing Angelica gigas polysaccharide (F2) as a drug carrier for colorectal cancer therapy. We synthesized F2-C-5-FU conjugates by linking carboxymethyl-5-fluorouracil (C-5-FU) with folic acid (FA) through ester bonding. The drug release behavior of F2-C-5-FU-FA was pH-dependent, favoring release under alkaline conditions. After 96 h in phosphate buffer (pH 7.4), the conjugate exhibited a cumulative release of 54.7%, which was higher compared to other pH environments. In vitro, F2-C-5-FU-FA showed enhanced cytotoxicity and increased cellular uptake in folate receptor-positive HCT-116 cells compared to A549 cells. The conjugate also induced G2/M cell cycle arrest and modulated the BAX/BCL-2 mRNA expression ratio through the MAPK and NF-κB signaling pathways. In vivo, F2-C-5-FU-FA increased tumor fluorescence intensity, prolonged drug circulation, and reduced organ toxicity to non-target organs. The treatment promoted cancer cell apoptosis by inhibiting the expression of apoptosis-related proteins. Overall, F2-C-5-FU-FA conjugates demonstrate potential as an effective drug delivery system for targeted colorectal cancer therapy.
该研究聚焦于利用当归多糖（F2）作为药物载体开发用于结直肠癌治疗的叶酸靶向缀合物。我们通过酯键将羧甲基-5-氟尿嘧啶（C-5-FU）与叶酸（FA）连接，合成了F2-C-5-FU缀合物。F2-C-5-FU-FA的药物释放行为依赖于pH值，在碱性条件下有利于释放。在磷酸盐缓冲液（pH 7.4）中放置96小时后，该缀合物的累积释放率为54.7%，与其他pH环境相比更高。在体外，与A549细胞相比，F2-C-5-FU-FA在叶酸受体阳性的HCT-116细胞中表现出增强的细胞毒性和增加的细胞摄取。该缀合物还通过丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路诱导G2/M期细胞周期阻滞并调节BAX/BCL-2 mRNA表达比率。在体内，F2-C-5-FU-FA增加了肿瘤荧光强度，延长了药物循环时间，并降低了对非靶器官的器官毒性。该治疗通过抑制凋亡相关蛋白的表达促进癌细胞凋亡。总体而言，F2-C-5-FU-FA缀合物显示出作为靶向结直肠癌治疗的有效药物递送系统的潜力。
