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

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

  • Bioorg Chem. 2024 Oct:151:107693. doi: 10.1016/j.bioorg.2024.107693.
Alberto Sola-Leyva 1,  Ylenia Jabalera 2,  Monica Jimenez-Carretero 3,  Marina Lázaro 4,  Tamara Pozo-Gualda 5,  Pedro J García-Vargas 6,  Pilar M Luque-Navarro 7,  Alberto Fasiolo 7,  Luisa C López-Cara 8,  Guillermo R Iglesias 9,  María Paz Carrasco-Jiménez 10,  Concepción Jiménez-López 11
Affiliations

Affiliations

  • 1 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. Electronic address: albertosola@ugr.es.
  • 2 Department of Microbiology, Faculty of Sciences, University of Granada, Granada 18071, Spain. Electronic address: yjabalera@ugr.es.
  • 3 Department of Microbiology, Faculty of Sciences, University of Granada, Granada 18071, Spain. Electronic address: monicajc@correo.ugr.es.
  • 4 NanoMag Lab. Department of Applied Physic, Faculty of Science, University of Granada, Granada 18071, Spain.
  • 5 Department of Microbiology, Faculty of Sciences, University of Granada, Granada 18071, Spain.
  • 6 Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain.
  • 7 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada 18071, Spain.
  • 8 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada 18071, Spain. Electronic address: lcarlotalopez@ugr.es.
  • 9 Instituto de Investigación Biosanitaria ibs.GRANADA, Granada 18014, Spain; NanoMag Lab. Department of Applied Physic, Faculty of Science, University of Granada, Granada 18071, Spain; MNat Unit of Excellence, University of Granada, Granada 18071, Spain. Electronic address: iglesias@ugr.es.
  • 10 Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain. Electronic address: mpazcj@ugr.es.
  • 11 Department of Microbiology, Faculty of Sciences, University of Granada, Granada 18071, Spain. Electronic address: cjl@ugr.es.
PMID: 39116523 DOI: 10.1016/j.bioorg.2024.107693
Abstract

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.

Keywords

Cancer; Choline kinase; Nanoparticles; Photothermia and hypertermia magnetic therapies.

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