Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada 18014, Spain.
Department of Microbiology, Faculty of Sciences, University of Granada, Granada 18071, Spain.
Bioorg Chem. 2024 Oct;151:107693. doi: 10.1016/j.bioorg.2024.107693. Epub 2024 Aug 3.
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.
针对磷脂生物合成，特别是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，已发现恶性细胞和肿瘤中胆碱激酶 α1 (ChoKα1)同工型过表达，因此成为一个极好的抗肿瘤靶标。目前正在合成 ChoKα1 抑制剂，它们表现出很大的抑制活性。在本研究中选择了两种作为不同结构家族的代表：一种是带有环状胺取代的噻吩并[3,2-d]嘧啶基双阳离子联苯衍生物（简称 Fa22），另一种是带有吡咯烷基取代的 7-氯喹啉基双阳离子联苯硫乙腈衍生物（简称 PL48）。然而，由于这些化合物的特异性低，它们在系统治疗中的潜在应用受到阻碍。事实上，为了进入细胞并达到其靶标，这些抑制剂使用胆碱转运蛋白并抑制胆碱摄取，这也是它们毒性的原因之一。解决这个问题的一种方法可能是通过替代途径允许它们进入细胞。为此，已经证明有效的药物纳米载体 MamC 介导的磁性纳米颗粒 (BMNPs) 已被用于固定 Fa22 和 PL48。其想法是让 BMNPs 携带这些分子进入细胞（它们通过胞吞作用进入细胞），从而为这些化合物提供另一种进入细胞的途径。在本研究中，我们证明了将 Fa22 和 PL48 偶联到 BMNPs 上可以使这些分子进入肿瘤细胞而不完全抑制胆碱摄取，因此，与可溶性药物相比，Fa22 和 PL48 在这些纳米制剂中的使用降低了毒性。此外，Fa22-BMNPs 和 PL48-BMNPs 纳米组装体允许化疗和局部热疗联合使用，对 HepG2 肿瘤细胞系产生增强的细胞毒性作用。这种行为可扩展到其他 ChoKα1 抑制剂的结果一致性，为它们在临床中的潜在应用开辟了可能性。
