Overcoming Resistance of Caco-2 Cells to 5-Fluorouracil through Diruthenium Complex Encapsulation in PMMA Nanoparticles

  1. Coloma, Isabel 1
  2. Parrón-Ballesteros, Jorge 2
  3. Cortijo, Miguel 1
  4. Cuerva, Cristián 1
  5. Turnay, Javier 2
  6. Herrero, Santiago 1
  1. 1 MatMoPol Research Group, Inorganic Chemistry Department, Faculty of Chemical Sciences, Complutense University of Madrid, E-28040 Madrid, Spain
  2. 2 Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, E-28040 Madrid, Spain
Revue:
Inorganic Chemistry

ISSN: 0020-1669,  1520-510X

Année de publication: 2024

Type: Article

DOI: 10.1021/ACS.INORGCHEM.4C01323 GOOGLE SCHOLAR lock_openAccès ouvert editor

D'autres publications dans: Inorganic Chemistry

Résumé

Drug resistance, one of the main drawbacks in cancer chemotherapy, can be tackled by employing a combination of drugs that target different biological processes in the cell, enhancing the therapeutic efficacy. Herein, we report the synthesis and characterization of a new paddlewheel diruthenium complex that includes 5-fluorouracil (5-FU), a commonly used anticancer drug. This drug was functionalized with a carboxylate group to take advantage of the previously demonstrated release capacity of carboxylate ligands from the diruthenium core. The resulting hydrophobic complex, [Ru2Cl(DPhF)3(5-FUA)] (Ru-5-FUA) (DPhF = N,N′-diphenylformamidinate; 5-FUA = 5-fluorouracil-1-acetate) was subsequently entrapped in poly(methyl methacrylate) (PMMA) nanoparticles (PMMA@Ru-5-FUA) via a reprecipitation method to be transported in biological media. The optimized encapsulation procedure yielded particles with an average size of 81.2 nm, a PDI of 0.11, and a zeta potential of 29.2 mV. The cytotoxicity of the particles was tested in vitro using the human colon carcinoma cell line Caco-2. The IC50 (half maximal inhibitory concentration) of PMMA@Ru-5-FUA (6.08 μM) was just slightly lower than that found for the drug 5-FU (7.64 μM). Most importantly, while cells seemed to have developed drug resistance against 5-FU, PMMA@Ru-5-FUA showed an almost complete lethality at ∼30 μM. Conversely, an analogous diruthenium complex devoid of the 5-FU moiety, [Ru2Cl(DPhF)3(O2CCH3)] (PMMA@RuA), displayed a reduced cytotoxicity at equivalent concentrations. These findings highlight the effect of combining the anticancer properties of 5-FU with those of diruthenium species. This suggests that the distinct modes of action of the two chemical species are crucial for overcoming drug resistance.

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Références bibliographiques

  • 10.1016/j.ccr.2021.214307
  • 10.3389/fonc.2019.00464
  • 10.1016/j.ica.2019.118987
  • 10.1517/14656566.2012.643870
  • 10.1039/C7CS00195A
  • 10.1016/j.ica.2020.120184
  • 10.1158/1078-0432.CCR-03-0746
  • 10.1016/j.jinorgbio.2006.02.013
  • 10.1136/esmoopen-2016-000154
  • 10.1021/acs.inorgchem.7b00072
  • 10.1039/D1MD00220A
  • 10.2147/DDDT.S275007
  • 10.1595/147106708X255987
  • 10.1039/D1DT02765D
  • 10.1038/s41598-017-18639-6
  • 10.1016/0305-7372(90)90057-M
  • Van Rensburg C. E. J., (2002), Anticancer Res., 22, pp. 889
  • 10.1016/j.poly.2007.12.011
  • 10.1007/s00775-014-1143-4
  • 10.1039/C7NR01582H
  • 10.1016/j.jinorgbio.2019.110984
  • 10.1080/02652048.2023.2258967
  • 10.1039/D1DT01492G
  • 10.1039/c3dt51763b
  • 10.1021/ic300168t
  • 10.1002/anie.201403337
  • 10.1021/acs.inorgchem.2c02516
  • 10.1016/j.ica.2021.120684
  • 10.1021/acs.inorgchem.2c04103
  • 10.1039/D3QI01192E
  • 10.1016/j.ijbiomac.2023.126666
  • 10.1021/acs.inorgchem.3c03441
  • 10.1021/acs.inorgchem.4c01218
  • 10.1016/j.jinorgbio.2018.06.010
  • 10.1261/rna.054353.115
  • 10.1039/D3QI00399J
  • 10.1021/acs.inorgchem.0c00844
  • 10.1002/mabi.201300363
  • 10.1038/s41598-020-73967-4
  • 10.4172/2161-0398.1000214
  • 10.1038/srep09908
  • 10.2147/IJN.S124021
  • 10.3389/fonc.2021.688919
  • 10.1007/s11033-024-09431-7
  • Nakamoto, K. Applications in Coordination Chemistry. In Infrared and Raman Spectra of Inorganic and Coordination Compounds; John Wiley & Sons, Ltd: Hoboken, NJ, 2009; vol Part B; pp 1–273.
  • 10.1021/ic052174t
  • 10.1016/j.poly.2009.07.036
  • 10.1039/D2DT00909A
  • 10.3109/02652048.2011.651500
  • 10.1080/21691401.2019.1577886
  • 10.1038/sj.bjc.6605780
  • 10.1016/S1773-2247(09)50005-6
  • 10.1002/jps.22628
  • 10.1038/s41598-020-80708-0
  • 10.1002/chem.200700494
  • 10.1016/j.inoche.2003.09.016
  • 10.1177/088391159701200401
  • 10.1107/S0021889808042726
  • 10.1107/S2053273314026370
  • 10.1107/S2053229614024218
  • 10.1038/nmeth.2089
  • 10.1039/D1PY00415H
  • 10.1207/s15327914nc5302_10