【摘要】 目的 针对七甲川菁染料母体Cy7-CH₃水溶性差的问题,通过三甘醇（TEG）及磺酸钾（-SO₃K）修饰,设计合成新型七甲川菁染料Cy7-TEG与Cy7-TEG-SO₃K;对比三者体外抗结直肠癌活性差异,并初步探究Cy7-TEG的抗肿瘤机制。方法 经亲核取代和Knoevenagel缩合反应制备目标菁染料;通过光学性能、溶解性及油水分配系数测定、MTT法、细胞共染实验、细胞内活性氧（ROS）及线粒体膜电位检测和抑制剂干预实验,评价其理化性质、体外抗结直肠癌活性及作用机制。结果 Cy7-TEG与Cy7-TEG-SO₃K的结构经过¹H-NMR、¹³C-NMR和HR-ESI-MS的表征。三者在水（H₂O）和二甲基亚砜（DMSO）中均表现出优异的近红外荧光特性,与Cy7-CH₃相比,Cy7-TEG和Cy7-TEG-SO₃K水溶性增加。Cy7-TEG对结直肠癌细胞SW480和HCT116的抑制作用优于Cy7-CH₃、Cy7-TEG-SO₃K及阳性对照5-氟尿嘧啶（5-Fu）。Cy7-TEG可借助正电荷与线粒体膜负电位的静电作用靶向肿瘤细胞线粒体,通过升高胞内ROS水平、降低线粒体膜电位,诱导ROS相关的细胞凋亡以抑制结直肠癌细胞活性。结论Cy7-TEG作为新型七甲川菁染料,经TEG链对菁染料结构的调控作用实现了水溶性与膜透性的平衡,通过ROS相关细胞凋亡途径发挥高效抗结直肠癌活性,为近红外有机阳离子抗肿瘤药物研发提供了重要的依据。更多还原

【Abstract】 Objective To address the poor water solubility of the parent heptamethine cyanine dye Cy7-CH3,two novel heptamethine cyanine dyes（Cy7-TEG and Cy7-TEG-SO₃K） were designed and synthesized via modification with triethylene glycol（TEG） and potassium sulfonate（-SO₃K） groups.This study aimed to compare the in vitro anti-colorectal cancer activity of the three dyes（Cy7-TEG,Cy7-TEG-SO₃K,and Cy7-CH₃） and explore the anti-tumor mechanism of Cy7-TEG.Methods The target cyanine dyes were prepared by the nucleophilic substitution reaction and the Knoevenagel condensation reaction.Their physicochemical properties,in vitro anti-colorectal cancer activities,and antitumor mechanisms were evaluated through the determination of optical properties,solubility,and oil-water partition coefficients,as well as MTT assay,cell co-staining assay,intracellular reactive oxygen species（ROS） detection,mitochondrial membrane potential measurement,and inhibitor intervention experiment.Results The structures of Cy7-TEG and Cy7-TEG-SO₃K were characterized by ¹H-NMR,¹³C-NMR,and HR-ESI-MS.All three dyes exhibited excellent near-infrared fluorescence properties in H₂O and DMSO.Compared with Cy7-CH₃,Cy7-TEG and Cy7-TEG-SO₃K showed improved water solubility.Cy7-TEG exerted a stronger inhibition on colorectal cancer cells（SW480and HCT116） than that of Cy7-CH₃,Cy7-TEG-SO₃K,and the positive control 5-Fu.Cy7-TEG targeted the mitochondria of cancer cells via electrostatic interaction between its positive charge and the negative potential of the mitochondrial membrane,which further increased the intracellular ROS levels,reduced the mitochondrial membrane potential,and ultimately inhibited the activity of colorectal cancer cells by inducing ROS-related apoptosis.Conclusion Cy7-TEG,as a novel heptamethine cyanine dye,may balance water solubility and membrane permeability through the structural regulation of the cyanine dye by TEG chains.It shows an efficient anti-colorectal cancer effect via the apoptotic pathways related to ROS,thereby providing an important foundation for the development of near-infrared organic cationic antitumor drugs.更多还原