Directing novel ChoKα1 inhibitors using MamC-mediated biomimetic magnetic nanoparticles: a way to improve specificity and efficiency

• Published in: Bioorganic chemistry 2024-10, Vol.151, p.107693, Article 107693
• Main Authors: Sola-Leyva, Alberto, Jabalera, Ylenia, Jimenez-Carretero, Monica, Lázaro, Marina, Pozo-Gualda, Tamara, García-Vargas, Pedro J., Luque-Navarro, Pilar M., Fasiolo, Alberto, López-Cara, Luisa C., Iglesias, Guillermo R., Paz Carrasco-Jiménez, María, Jiménez-López, Concepción
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Cancer; Cell Proliferation - drug effects; Choline kinase; Choline Kinase - antagonists & inhibitors; Choline Kinase - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Magnetite Nanoparticles - chemistry; Molecular Structure; Nanoparticles; Photothermia and hypertermia magnetic therapies; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107693

[Display omitted] •Overexpression of ChoKα1 in cancer cells makes it an excellent antitumor target.•Fa22 and PL48 inhibit ChoKα1 but have low specificity.•Coupling ChoKα1 inhibitors to BMNPs enhances specificity.•ChoKα1 inhibitors-BMNPs enable combined chemo and hyperthermia therapies. 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.