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Diruthenium(II,III) metallodrugs of ibuprofen and naproxen encapsulated in intravenously injectable polymer-lipid nanoparticles exhibit enhanced activity against breast and prostate cancer cells

Abstract

A unique class of diruthenium(II,III) metallodrugs containing non-steroidal anti-inflammatory drug (NSAID), Ru2(NSAID), have been reported to show anticancer activity in glioma models in vitro and in vivo. This work reports the encapsulation of the lead metallodrug of ibuprofen (HIbp), [Ru2(Ibp)4Cl] or RuIbp, and also of the new analogue of naproxen (HNpx), [Ru2(Npx)4Cl] or RuNpx, in the novel intravenously (i.v.) injectable solid polymer-lipid nanoparticles (SPLNs). A rationally selected composition of lipids/polymer rendered nearly spherical Ru2(NSAID)-SPLNs with mean size of 120 nm and zeta potential of about -20 mV. The Ru2(NSAID)-SPLNs are characterized by spectroscopic techniques and the composition in terms of ruthenium-drug species is analyzed by mass spectrometry. The metallodrug-loaded nanoparticles showed ~ 100% drug loading efficiency, high drug loading (17-18%) and good colloidal stability in serum at body temperature. Fluorescence-labeled SPLNs were taken up by the cancer cells in a time- and energy- dependent manner as analyzed by confocal microscopy and fluorescence spectrometry. The Ru2(NSAID)-SPLNs showed enhanced cytotoxicity (IC50 = 60-100 mol L-1) in relation to the corresponding Ru2(NSAID) metallodrugs in breast (EMT6 and MDA-MB-231) and prostate (DU145) cancer cells in vitro. The cell viability of both metallodrug nanoformulations is also compared with those of the parent NSAIDs, HIbp and HNpx, and their corresponding NSAID-SPLNs. In vivo and ex vivo fluorescence imaging revealed good biodistribution and high tumor accumulation of fluorescence-labeled SPLNs following i.v. injection in an orthotopic breast tumor model. The enhanced anticancer activity of the metallodrug-loaded SPLNs in these cell lines can be associated to the advantages of the nanoformulations, assigned mainly to the stability of the colloidal nanoparticles suitable for i.v. injection and to the enhanced cellular uptake by SPLNs. The findings of this work encourage future in vivo efficacy studies to further exploit the potential of the novel Ru2(NSAID)-SPLN nanoformulations for future clinical application.

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Publication details

The article was received on 04 Mar 2017, accepted on 12 Jun 2017 and first published on 13 Jun 2017


Article type: Paper
DOI: 10.1039/C7NR01582H
Citation: Nanoscale, 2017, Accepted Manuscript
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    Diruthenium(II,III) metallodrugs of ibuprofen and naproxen encapsulated in intravenously injectable polymer-lipid nanoparticles exhibit enhanced activity against breast and prostate cancer cells

    S. Rodrigues Alves Rico, A. Z. Abbasi, G. Ribeiro, T. Ahmed, X. Y. Wu and D. de Oliveira Silva, Nanoscale, 2017, Accepted Manuscript , DOI: 10.1039/C7NR01582H

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