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Carriers for metal complexes on tumour cells: the effect of cyclodextrins vs CNTs on the model guest phenanthroline-5,6-dione trithiacyclononane ruthenium(II) chloride

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Abstract

The complex [Ru[9]aneS3(pdon)Cl]Cl (pdon = 1,10-phenanthroline-5,6-dione) was readily obtained from the stoichiometric reaction of Ru[9]aneS3(dmso)Cl2 with pdon. Recrystallisation in ethanol using salicylic acid as a co-crystallisation helper afforded single-crystals suitable for the collection of X-ray diffraction data which afforded a reasonable structural description. Two different kinds of molecular carriers were tested as vehicles for this complex: carbon nanotubes (CNTs) and cyclodextrins. CNTs had an insufficient loading rate for the ruthenium complex at CNT concentrations deemed non-cytotoxic on cultured cells. The cyclodextrin (CD) carriers, β-CD and TRIMEB (standing for permethylated β-CD), were able to form two adducts, studied by powder X-ray diffraction, thermogravimetric analysis (TGA), 13C{1H} CP/MAS NMR and FT-IR spectroscopies. The DNA thermal denaturation studies showed that the complex 1 is able to intercalate with DNA. The in vitro cytotoxicity of the free complex [Ru[9]aneS3(pdon)Cl]Cl (1) and of its two CD adducts (2 and 3) was assessed on both rodent and human cell lines. By using the mouse K1735-M2 melanoma cell line and the non-tumour rat H9c2 cardiomyoblasts, the results showed that 1 and 2 significantly inhibited the growth of the tumour cell line while displaying a good safety profile on cardiomyoblasts. Compound 3 at 100 μM inhibited the proliferation of both cell lines, with a higher activity towards the melanoma cell line. The cytotoxicity of the compounds 1–3 was further assessed on human breast cancer cell lines. Against the MDA-MB-231 line, growth inhibition occurred only with 1 and 3 at the incubation time of 96 h, both with approximate inhibition rates of 50 %; against the MCF-7 line, mild cytotoxicity was observed at 48 h of incubation, with IC50 values calculated above 100 μM for 1, 2 and 3.

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Abbreviations

[9]aneS3 :

1,4,7-Trithiacyclononane

ANOVA:

Analysis of variance

CD:

Cyclodextrin

CNT:

Carbon nanotube

CP/MAS:

Cross-polarisation with magic-angle spinning

DMEM:

Dulbecco’s modified eagle’s medium

dmso:

Dimethylsulfoxide

DNA:

Deoxyribonucleic acid

dppz:

Dipyrido[3,2-a:2′,3′-c]phenazine

EDTA:

Ethylenediaminetetraacetic acid

EAT:

Ehrlich ascites tumour

EtOH:

Ethanol

FBS:

Fetal bovine serum

FT-IR:

Fourier-transform infrared spectroscopy

H9c2:

Non-tumoural H9c2 cardiomyoblast cell line

IC50 :

Half maximal inhibitory concentration

K1735-M2:

Mouse melanoma cell line

MCF-7:

Human epithelial breast adenocarcinoma cell line (estrogen dependent)

MDA-MB-231:

Human epithelial breast adenocarcinoma cell line (estrogen independent)

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

NMR:

Nuclear magnetic resonance

oxCNT:

Oxidised carbon nanotube

PBS:

Phosphate buffered saline

phen:

1,10-Phenanthroline

pdon:

1,10-Phenanthroline-5,6-dione

SRB:

Sulforhodamine B

TGA:

Thermogravimetric analysis

XRD:

X-ray diffraction

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Acknowledgments

The supply of β-CD (Kleptose) by Roquette Laboratoires (Lestrem, France) is gracefully acknowledged. We are also grateful to Fundação para a Ciência e a Tecnologia (FCT, Portugal), European Union, QREN, European Fund for Regional Development (FEDER), through the programme COMPETE, for general funding to the QOPNA research unit (project PEst C-QUI/UI0062/2013; FCOMP-01-0124-FEDER-037296), to the Associated Laboratory CICECO (PEst C-CTM/LA0011/2013) and to the CNC (PEst-C/SAU/LA0001/2013-2014), and for specific funding towards the purchase of the single-crystal diffractometer. The FCT and the European Social Fund, through the Programa Operacional Potencial Humano (POPH), are acknowledged for a PhD grant to J. M. (SFRH/BD/44791/2008).

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Authors and Affiliations

  1. Department of Chemistry, QOPNA Research Unit, University of Aveiro, 3810-193, Aveiro, Portugal

    Susana S. Braga & Joana Marques

  2. Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK

    Elena Heister

  3. CNC - Center for Neuroscience and Cell Biology, Largo Marquês de Pombal, University of Coimbra, 3004-517, Coimbra, Portugal

    Cátia V. Diogo & Paulo J. Oliveira

  4. CICECO and Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal

    Filipe A. Almeida Paz & Teresa M. Santos

  5. Molecular Physical-Chemistry R&D Group and Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, PO Box 3046, 3001-401, Coimbra, Portugal

    Maria Paula M. Marques

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  1. Susana S. Braga
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Braga, S.S., Marques, J., Heister, E. et al. Carriers for metal complexes on tumour cells: the effect of cyclodextrins vs CNTs on the model guest phenanthroline-5,6-dione trithiacyclononane ruthenium(II) chloride. Biometals 27, 507–525 (2014). https://doi.org/10.1007/s10534-014-9725-8

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