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Metallacarboranes on the road to anticancer therapies

This work demonstrates that the pristine Na[3,3’-M(1,2-closo-C2B9H11)2], [COSAN]-, molecules enter into the cells cytoplasm reaching the nucleus The strong interaction between Na[COSAN] and CT-dsDNA has been demonstrated and the formed nanohybrid biomaterial fully characterized. The non-cytotoxic profile of [COSAN]- has been demonstrated on V79 fibroblast cells.

The most studied metallacarborane is cobaltabisdicarbollide [3,3’-M(1,2-closo-C2B9H11)2]- (M= Co, Fe) that are metal sandwich complexes similar to ferrocene and as this one, have a nice reversible electroactive couple, M3+/ M2+, but unlike ferrocene they are water-soluble. Metallacarboranes are becoming a subject of growing interest to the broad chemical community owing to their unique combination of features and properties, including the rigidity of the cages and their relative rotary motion, hydrophobicity, as well as chemical and thermal stability due to delocalized charge.

Herein we focus on the studies of relevant tumor cell uptake and intracellular [COSAN]- distribution by cells, its accumulation in the cell nucleus, which is a particularly desirable target, because the nucleus is the cells’ control center in which DNA and transcription machinery reside. The interaction of [COSAN]- with DNA is detailed studied. The interaction of [Na·2.5H2O][COSAN] with double stranded calf thymus DNA in aqueous solutions and physiological media by spectroscopic measurements (IR and RAMAN) is studied in detail. Once proved the interaction, melting temperature, ultraviolet-visible spectrophotometry, cyclic voltammetry, circular dicroism, dynamic light scattering and 11B{1H} NMR techniques have been used to discern on the nature of such interaction, which is intercalative or electrostatic depending on the ionic strength of the solution. Optical and electronic microscopies (TEM and CryoTEM) displayed better understanding of this interaction with regard to its potential applications. Finally, biodistribution studies of the Na[COSAN] in normal mice were run. After administration, Na[COSAN] was distributed into many organs but mainly accumulates in the RES, including liver and spleen. At 1h the formation of aggregates by plasma protein interaction play a role in the biodistribution profile accumulating mostly in the lungs. Na[COSAN], which display low toxicity and high uptake by relevant cancer cells accumulating boron within the nucleus, could act as a suitable compound for further developments as BNCT agents.

Authors:
Isabel Fuentes,1 Tania García-Mendiola,2 Shinichi Sato,3 Marcos Pita,2 Hiroyuki Nakamura,3 Encarnación Lorenzo,2 Francesc Teixidor,1 Fernanda Marques,4 and Clara Viñas,1

Affiliations:
1 Institut de Ciència de Materials de Barcelona (ICMAB-CSIC), Spain.
2. Departamento Química Analítica y Análisis Instrumental, Universidad Autónoma de Madrid, Spain
3 Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Japan.
4 Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto Superior Técnico, Universidade de Lisboa, Portugal.

Publication:
Metallacarboranes on the road to anticancer therapies: cellular uptake, DNA interaction and biological evaluation of cobaltabisdicarbollide ([COSAN]-).
Chemistry-A European Journal, 24, 17239 – 17254 (2018)
DOI: 10.1002/chem.201803178

Figure caption:
[3,3’‐Co(1,2‐closo‐C2B9H11)2]-, which can self-assembly and present no relevant cytotoxicity, interacts with ds-DNA.

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