Insight into the antitumor activity of carbosilane Cu(II)–metallodendrimers through their interaction with biological membrane models

Natalia Sanz del Olmo; Riccardo Carloni; Ana M. Bajo; Paula Ortega; Alberto Fattori; Rafael Gómez; Maria Francesca Ottaviani; Sandra García-Gallego; Michela Cangiotti; F. Javier de la Mata

doi:10.1039/C9NR03313K

Insight into the antitumor activity of carbosilane Cu(ii)–metallodendrimers through their interaction with biological membrane models†

Natalia Sanz del Olmo,

‡^a Riccardo Carloni,

‡^b Ana M. Bajo,^c Paula Ortega,

^ade Alberto Fattori,^b Rafael Gómez,

^ade Maria Francesca Ottaviani,^b Sandra García-Gallego,

*^ade Michela Cangiotti*^b and F. Javier de la Mata

*^ade

Author affiliations

* Corresponding authors

^a Department of Organic and Inorganic Chemistry, and Research Institute in Chemistry “Andrés M. del Río” (IQAR), University of Alcalá, Madrid, Spain
E-mail: javier.delamata@uah.es, sandra.garciagallego@uah.es

^b Department of Pure and Applied Sciences, University of Urbino “Carlo Bo”, Urbino, Italy
E-mail: michela.cangiotti@uniurb.it

^c Department of Biology of Systems, Biochemistry and Molecular Biology Unit, University of Alcalá, Madrid, Spain

^d Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain

^e Institute Ramón y Cajal for Health Research (IRYCIS), Spain

Abstract

Current cancer therapies present serious drawbacks including severe side-effects and development of drug resistance. Strategies based on nanosized metallodrugs combine the structural diversity and non-classical modes of action of metal complexes with the selectivity arising from the unique interaction of nanoparticles with biological membranes. A new family of water-soluble copper(II) carbosilane metallodendrimers was synthesized and characterized as a nanotechnological alternative to current therapies. The interactions occurring over time between the dendrimers, at different generations (G₀ to G₂) and with different Cu(II) counter-ions (nitrate vs. chloride), and cell-membrane models (cethyl-trimethylammonium bromide (CTAB) micelles and lecithin liposomes) were investigated using a computer-aided analysis of the electron paramagnetic resonance (EPR) spectra. The EPR analysis provided structural and dynamical information on the systems indicating that the increase in generation and the change of the Cu(II) contra-ion – from nitrate to chloride – produce an increased relative amount and strength of interaction of the dendrimer with the model membranes. Interestingly, the stabilization effect produced a lower toxicity towards cancer cells. The cytotoxic effect of Cu(II) metallodendrimers was verified by an in vitro screening in a selection of tumor cell lines, revealing the impact of multivalency on the effectivity and selectivity of the metallodrugs. As a proof-of-concept, first-generation dendrimer G₁-Cu(ONO₂)₂ was selected for in-depth in vitro and in vivo antitumor evaluation towards resistant prostate cancer. The Cu(II)–metallodendrimers produced a significant tumor size reduction with no signs of toxicity during the experiment, confirming their promising potential as anticancer metallodrugs.

Nanoscale

Insight into the antitumor activity of carbosilane Cu(ii)–metallodendrimers through their interaction with biological membrane models†

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Insight into the antitumor activity of carbosilane Cu(II)–metallodendrimers through their interaction with biological membrane models

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