针对磷脂生物合成，特别是在肿瘤细胞中增强的磷脂酰胆碱（PC），已被证明是一种合适的抗肿瘤策略。事实上，胆碱激酶α1（ChoKα1）亚型在恶性细胞和肿瘤中过度表达，从而成为极好的抗肿瘤靶点。目前正在合成显示出强大抑制活性的ChoKα1抑制剂。本研究中选择了其中两个作为不同结构家族的代表：被环胺取代的噻吩并[3,2-d]嘧啶鎓的双阳离子联苯衍生物（此处称为Fa22）和7的双阳离子联苯硫乙醇衍生物。被吡咯烷部分取代的-氯喹啉鎓（此处称为PL48）。然而，由于这些类型的化合物特异性低，其在全身治疗中的潜在应用受到阻碍。事实上，为了进入细胞并到达目标，这些抑制剂使用胆碱转运蛋白并抑制胆碱摄取，这是其毒性的原因之一。解决这个问题的一种方法可能是允许它们通过其他方式进入细胞。为了实现这一目标，MamC 介导的磁性纳米粒子 (BMNP)（已被证明是有效的药物纳米载体）已被用于固定 Fa22 和 PL48。这个想法是让 BMNP 携带这些分子进入细胞（它们通过内吞作用进入细胞），从而为这些化合物提供另一种途径。在本研究中，我们证明 Fa22 和 PL48 与 BMNP 的偶联允许这些分子进入肿瘤细胞，而不会完全抑制胆碱摄取，因此，与其他纳米制剂相比，在这些纳米制剂中使用 Fa22 和 PL48 降低了毒性。可溶性药物。此外，纳米组件 Fa22-BMNP 和 PL48-BMNP 允许化疗和局部热疗相结合，以增强对肿瘤 HepG2 细胞系的细胞毒性作用。结果的一致性（与药物结构无关）可能表明这种行为可以扩展到其他 ChoKα1 抑制剂，从而为它们在临床中的潜在应用提供了可能性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Targeting phospholipid biosynthesis, specifically phosphatidylcholine (PC), which is enhanced in tumor cells, has been proven a suitable antitumor strategy. In fact, the overexpression of the choline kinase α1 (ChoKα1) isoform has been found in malignant cells and tumors, thus becoming an excellent antitumor target. ChoKα1 inhibitors are being synthesized at the present that show a large inhibitory activity. Two of them have been chosen in this study as representatives of different structural families: a biscationic biphenyl derivative of thieno[3,2-d]pyrimidinium substituted with a cyclic amine (here referred to as Fa22) and a biscationic biphenyl thioethano derivative of 7-chloro-quinolinium substituted with a pyrrolidinic moiety (here referred to as PL48). However, the potential use of these types of compounds in systemic treatments is hampered because of their low specificity. In fact, to enter the cell and reach their target, these inhibitors use choline transporters and inhibit choline uptake, being that one of the causes of their toxicity. One way to solve this problem could be allowing their entrance into the cells by alternative ways. With this goal, MamC-mediated magnetic nanoparticles (BMNPs), already proven effective drug nanocarriers, have been used to immobilize Fa22 and PL48. The idea is to let BMNPs enter the cell (they enter the cell by endocytosis) carrying these molecules, and, therefore, offering another way in for these compounds. In the present study, we demonstrate that the coupling of Fa22 and PL48 to BMNPs allows these molecules to enter the tumoral cell without completely inhibiting choline uptake, so, therefore, the use of Fa22 and PL48 in these nanoformulations reduces the toxicity compared to that of the soluble drugs. Moreover, the nanoassemblies Fa22-BMNPs and PL48-BMNPs allow the combination of chemotherapy and local hyperthermia therapies for a enhanced cytotoxic effect on the tumoral HepG2 cell line. The consistency of the results, independently of the drug structure, may indicate that this behavior could be extended to other ChoKα1 inhibitors, opening up a possibility for their potential use in clinics.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.