Ultrasmall cationic superparamagnetic iron oxide nanoparticles as nontoxic and efficient MRI contrast agent and magnetic-targeting tool

Abstract

Mayara Klimuk Uchiyama,1 Sergio Hiroshi Toma,1 Stephen Fernandes de Paula Rodrigues,2 Ana Lucia Borges Shimada,2 Rodrigo Azevedo Loiola,2 Hernán Joel Cervantes Rodríguez,3 Pedro Vitoriano Oliveira,4 Maciel Santos Luz,4 Said Rahnamaye Rabbani,3 Henrique Eisi Toma,1 Sandra Helena Poliselli Farsky,2 Koiti Araki11Laboratory of Supramolecular Chemistry and Nanotechnology, Department of Fundamental Chemistry, Institute of Chemistry, 2Laboratory of Experimental Toxicology, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, 3Magnetic Resonance Laboratory, Department of General Physics, Institute of Physics, 4Analysis and Research Group in Spectrometry, Department of Fundamental Chemistry, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, BrazilAbstract: Fully dispersible, cationic ultrasmall (7 nm diameter) superparamagnetic iron oxide nanoparticles, exhibiting high relaxivity (178 mM-1s-1 in 0.47 T) and no acute or subchronic toxicity in Wistar rats, were studied and their suitability as contrast agents for magnetic resonance imaging and material for development of new diagnostic and treatment tools demonstrated. After intravenous injection (10 mg/kg body weight), they circulated throughout the vascular system causing no microhemorrhage or thrombus, neither inflammatory processes at the mesentery vascular bed and hepatic sinusoids (leukocyte rolling, adhesion, or migration as evaluated by intravital microscopy), but having been spontaneously concentrated in the liver, spleen, and kidneys, they caused strong negative contrast. The nanoparticles are cleared from kidneys and bladder in few days, whereas the complete elimination from liver and spleen occurred only after 4 weeks. Ex vivo studies demonstrated that cationic ultrasmall superparamagnetic iron oxide nanoparticles caused no effects on hepatic and renal enzymes dosage as well as on leukocyte count. In addition, they were readily concentrated in rat thigh by a magnet showing its potential as magnetically targeted carriers of therapeutic and diagnostic agents. Summarizing, cationic ultrasmall superparamagnetic iron oxide nanoparticles are nontoxic and efficient magnetic resonance imaging contrast agents useful as platform for the development of new materials for application in theranostics.Keywords: cationic USPIOs, MRI, contrast agent, magnetic targeting, in vivo toxicity, intravital microscopy