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), Ru(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), [Ru(Ibp)Cl] or RuIbp, and also of the new analogue of naproxen (HNpx), [Ru(Npx)Cl] or RuNpx, in novel intravenously (i.v.) injectable solid polymer-lipid nanoparticles (SPLNs). A rationally selected composition of lipids/polymers rendered nearly spherical Ru(NSAID)-SPLNs with a mean size of 120 nm and zeta potential of about -20 mV. The Ru(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 high drug loading (17-18%) with ∼100% drug loading efficiency, 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 Ru(NSAID)-SPLNs showed enhanced cytotoxicity (IC at 60-100 μmol L ) in relation to the corresponding Ru(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 with the advantages of the nanoformulations, assigned mainly to the stability of the colloidal nanoparticles suitable for i.v. injection and enhanced cellular uptake. The findings of this work encourage future in vivo efficacy studies to further exploit the potential of the novel Ru(NSAID)-SPLN nanoformulations for clinical application.

Rationally Designed Ruthenium Complexes for Breast Cancer Therapy

“…Whereas examples of ruthenium complexes bearing ligands that have a specific target in hormone receptor positive breast cancers are limited, several complexes bearing other types of bioactive ligands with different targets were also found to display a considerable activity for hormone receptor positive cancers. For example, several reports have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) have promising anticancer properties, making them suitable ligands for the design of multifunctional anticancer ruthenium complexes [75][76][77]. The main mode of action of NSAIDs in different cancer types, including breast cancer, is believed to be associated with the inhibition of the cyclooxygenase (COX) enzyme [75,78].…”

“…It is noteworthy that NSAIDs may not only induce an anticancer activity in hormone receptor positive breast cancers, but also in TNBC, making them versatile moieties for the design of ruthenium species for breast cancer treatment. de Oliveira Silva et al (2017) reported diruthenium(II,III) metallodrugs, (16) (Figure 4), of ibuprofen (Ru-Ibp) and naproxen (Ru-Npx) encapsulated into intravenously injectable solid-polymer-lipid nanoparticles (Ru-NSAID-SPLNs), which were prepared from a combination of two lipids (myristic acid and ethyl arachidate ester) [77]. The in vitro cytotoxicity of both dimeric metallodrugs was first studied in a triple negative breast cancer cell line, MDA-MB-231, and compared with that of ibuprofen and naproxen alone, and that of a ruthenium complex used as a control (which does not contain any bioactive ligand, [Ru 2 (O 2 CCH 3 ) 4 Cl]).…”

“…Notably, a higher cytotoxicity was noted for Ru-Ibp-SPLNs in MDA-MB-231 cells (IC 50 = 70.3 ± 8.1 µM) than for Ru-Npx-SPLNs (IC 50 = 101.8 ± 6.7 µM) in the same cell line. It was postulated that the reported SPLN formulation can promote the cellular uptake of metallodrugs and, as a result, improve their anticancer potential [77].…”

Synthesis, characterization, and evaluation of biological activities of new 4′‐substituted ruthenium (II) terpyridine complexes: Prospective anti‐inflammatory properties

“…Alves Rico et al reported diruthenium (II,III) metallodrugs of ibuprofen and naproxen encapsulated into intravenously injectable solid–polymer–lipid nanoparticles to show anticancer activity in glioma models in vitro and in vivo. [ 59 ] Higher cytotoxicity was observed for the Ru‐complexes compared with the separate ligands, suggesting a contribution from the metal in both cases.…”

Ultrasound-assisted synthesis of water-soluble monosubstituted diruthenium compounds

“…Since mid-1960’s when Stephenson and Wilkinson [1] described the synthesis of the first mixed-valent [Ru 2 Cl(O 2 CR) 4 ] (R = alkyl) compound and Cotton and col [2] the first crystal structure, a big number of Ru 2 5+ paddlewheel diruthenium complexes with Ru-Ru bond order of 2.5 have been synthesized and characterized [3] , [4] , [5] , [6] , [7] , [8] . These compounds have attracted interest for their practical applications in catalysts [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , biomedicine [17] , [18] , [19] , [20] , biotechnology [21] , [22] , [23] , [24] , [25] , [26] or by their potential in material science due to their unique magnetic [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] and redox properties [37] .…”