Nanoencapsulation of dirutenium (II, III) antitumor metallodrugs containing ibuprofen and naproxen. Study of a novel µ-oxo-ruthenium(III)-ibuprofen-4-aminopyridine metallodrug

Author(s)

Samara Rodrigues Alves

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2019-12-18

Examining board members

Denise de Oliveira Silva; Gianluca Camillo Azzellini; Sofia Nikolaou

• Advisor: Denise de Oliveira Silva

Abstract

Diruthenium(II,III) metallodrugs containing non-steroidal anti-inflammatory drugs investigated in our research group are reported to exhibit antitumor activity. In particular, the complex RuIbp, [Ru2(Ibp)4Cl], where Ibp = Ibuprofen anion, exhibits promising activity in vitro and in vivo against glioblastoma brain cancer. In the present work, the interaction of this compound with the 4-aminopyridine (4AP) biologically active molecule has been investigated. A new complex of formula [Ru2O(Ibp)2(4AP) 6]Cl2 bearing a dimetallic (III,III) center with µ-oxo bridge (Ru-O-Ru) has been synthesized and characterized by elemental analysis, electronic absorption spectroscopy, infrared spectroscopy (FTIR), electrospray ionization mass spectrometry (ESI-MS), magnetic susceptibility measurements, conductivity measurements and thermal analysis. Reactivity studies indicate reversible ligand replacement of 4AP by water molecules in an aqua / complexation equilibrium. The biological activity of the new complex was investigated in vitro in the U87MG human glioma cell line showing promising results. In this work, lipid nanoparticle systems in which the RuIbp and its analogue RuNpx [Ru2(Npx)4Cl], where Npx = Naproxen anion, have been encapsulated were also developed. These systems were characterized by size and zeta potential measurements, electronic absorption and FTIR spectroscopies, ESI-MS spectrometry and transmission electronic microscopy (TEM) or atomic force microscopy (AFM). Solid lipid polymeric nanoparticles (SPLNs) containing the metallodrugs RuIbp (RuIbp-SPLNs) and RuNpx (RuNpx-SPLNs) are nearly spherical, colloidally stable, with size around 120 nm, zeta potential ~ -20 mV, drug loading ~ 15 % and encapsulation efficiency ~ 90 %. The encapsulated compounds showed higher antiproliferative activity than the corresponding free complexes or the encapsulated organic drugs in breast cancer cells (EMT-6 and MDA-MB-231) and prostate cancer cells (DU145) in vitro. Studies on biodistribution and bioaccumulation in vivo and ex vivo by fluorescence microscopy showed good tumor accumulation of SPLNs. Terpolymer lipid nanoparticles (TPLNs) containing the metallodrugs RuIbp (RuIbp-TPLNs) and RuNpx (RuNpx-TPLNs), specially developed aiming the treatment of glioblastoma, showed nearly spherical shape, good colloidal stability, size around 130 nm, zeta potential ~ 40 mV, drug loading ~ 12 % and encapsulation efficiency ~ 90 %. The RuIbp-TPLNs and the RuNpx-TPLNs exhibited anticancer activity higher than the corresponding free complexes or the encapsulated organic Ibuprofen in the U87MG and the T98G glioma cell lines in vitro. The cell uptake of the TPLNs and the Ru were monitored by fluorescence microscopy and optical emission spectrometry (ICP-OES), respectively. (AU)

• FAPESP's process: 14/23481-7 - Study of lipid-based nanoparticles as carriers for anticancer ruthenium metallodrugs
• Grantee: Samara Rodrigues Alves
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)