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
Revista:
Inorganic Chemistry

ISSN: 0020-1669,  1520-510X

Any de publicació: 2024

Tipus: Article

DOI: 10.1021/ACS.INORGCHEM.4C01323 GOOGLE SCHOLAR lock_openAccés obert editor

Altres publicacions en: Inorganic Chemistry

Resum

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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