Zhang Yutong, Palanisamy Subramanian, Kwon Mi-Hye, Ge Yunfei, Kou Fang, Uthamapriya Rajavel Arumugam, Lee DongKi, Lee Dong-Jin, Bao Honghui, You SangGuan, Zhang Yanjun
Spice and Beverage Research Institute, Chinese Academy of Tropical Agricultural Sciences, National Center of Important Tropical Crops Engineering and Technology Research, Key Laboratory of Processing Suitability and Quality Control of the Special Tropical Crops of Hainan Province, Wanning 571533, Hainan, China; Sanya Research Institute, Chinese Academy of Tropical Agriculture Science, Sanya 572025, Hainan, China.
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. 2025 Jan;285:138107. doi: 10.1016/j.ijbiomac.2024.138107. Epub 2024 Nov 27.
To mitigate adverse reactions induced by 5-fluorouracil (5-FU), Cnidium officinale fraction 2 (F2) polysaccharides served as the macromolecular carrier, facilitating its reaction with carboxymethyl-5-fluorouracil (C-5-FU) for producing F2-C-5-FU. Subsequently, this compound could react with folic acid (FA) through the ester bond, forming F2-C-5-FU-FA, as verified through NMR analysis. The in vitro anticancer efficacy of F2-C-5-FU-FA was evaluated using SKOV-3 cells that expressed folate receptor (FR) and FR-deficient A549 cells, showing greater cytotoxicity in the SKOV-3 cell line due to the FRs on the cell membrane. In vivo experiments were conducted on SKOV-3-bearing xenograft mice using an in vivo imaging system (IVIS). Animals injected with F2-C-5-FU-FA exhibited significantly stronger targeting of tumor tissue compared to those injected with F2-C-5-FU. These findings highlighted enhanced drug delivery and accumulation in targeted tumor regions facilitated by folate-targeted conjugates. Moreover, F2-C-5FU-FA showed reduced cardiac toxicity in mice and minimal spleen accumulation, indicating a negligible effect on the immune system. Overall, this study introduced a novel strategy for achieving highly efficient anticancer drug delivery into tumor cells that express FR.
为减轻5-氟尿嘧啶（5-FU）引起的不良反应，蛇床子提取物2（F2）多糖作为大分子载体，促进其与羧甲基-5-氟尿嘧啶（C-5-FU）反应生成F2-C-5-FU。随后，该化合物可通过酯键与叶酸（FA）反应，形成F2-C-5-FU-FA，这一结果经核磁共振分析得到证实。使用表达叶酸受体（FR）的SKOV-3细胞和FR缺陷型A549细胞评估了F2-C-5-FU-FA的体外抗癌效果，结果显示由于细胞膜上的FRs，F2-C-5-FU-FA在SKOV-3细胞系中具有更大的细胞毒性。使用体内成像系统（IVIS）对荷SKOV-3异种移植瘤小鼠进行了体内实验。与注射F2-C-5-FU的动物相比，注射F2-C-5-FU-FA的动物对肿瘤组织的靶向性明显更强。这些发现突出了叶酸靶向缀合物促进药物在靶向肿瘤区域的递送和积累。此外，F2-C-5FU-FA在小鼠体内的心脏毒性降低，脾脏积累极少，表明对免疫系统的影响可忽略不计。总体而言，本研究引入了一种新策略，可实现将高效抗癌药物递送至表达FR的肿瘤细胞中。
