Synthesis of terpolymer-lipid encapsulated diruthenium(II,III)-anti-inflammatory metallodrug nanoparticles to enhance activity against glioblastoma cancer cells

Abstract

Novel formulations of diruthenium(II,III)-NSAID (NSAID, non-steroidal anti-inflammatory drug) metallodrugs encapsulated into biocompatible terpolymer-lipid nanoparticles (TPLNs) to target glioblastoma cancer were developed. The nanoformulations of Ibuprofenate (RuIbp) and Naproxenate (RuNpx) metallodrugs were synthesized and characterized. The procedure rationally designed to avoid structural changes on the coordination sphere of the [Ru2(NSAID)4]+ paddlewheel unit succeeded in giving colloidally stable and nearly spherical shaped loaded [Ru2(NSAID)4]-TPLNs with appropriate parameters (~90% loading efficiency; drug loading around 10%; particle size ~130 nm; zeta potential around - 40 mV). The maintenance of the [Ru2(NSAID)4]+ framework was confirmed by spectroscopy and mass spectrometry. The encapsulation enhanced antiproliferative effects in U87MG cells for both metallodrugs. The RuIbp-TPLNs showed efficacy also against the cisplatin chemoresistant T98G cancer cells. Lack of significant effects for the loaded-Ibuprofen-TPLNs (HIbp-TPLNs) on both types of cells supports the key role of the dimetal core in the anticancer activity of the [Ru2(NSAID)4]+ metallodrugs. The high cell viability (>70%) found for both types of cells suggests activity associated mainly to antiproliferative effects. The blank-TPLNs internalized into U87MG cell cytoplasm mostly at the first 6 h, by energy-dependent mechanism. The cell uptake of the RuIbp-TPLNs occurred during the first 24 h and it was enhanced in relation to the non-encapsulated metallodrug. The development of these novel metallodrug-loaded TPLN nanoformulations, which exhibit colloidal stability suitable for intravenous injection and enhanced drug cellular uptake, expands the perspective for diruthenium(II,III)-NSAID metallodrugs targeting brain glioblastoma cancer.