Quantitative biodistribution and pharmacokinetics of multimodal gadolinium-based nanoparticles for lungs using ultrashort TE MRI

Abstract

To study the biodistribution and lung pharmacokinetics of tracheally administered gadolinium-based contrast agents [gadoteric acid and multimodal ultra-small rigid platforms (USRPs)], to validate their pharmacokinetics against optical imaging of fluorescent USRPs, and to test their short-term toxicity. Ultrashort echo-time (UTE) lung proton magnetic resonance imaging (MRI) was performed at 4.7-Tesla (T) after the intratracheal instillation of different concentrations of contrast agent solutions in mice. Pharmacokinetic models were implemented on the absolute concentration calculated from the MRI signal enhancement measurements. Fluorescent USRPs were used to obtain optical images with the same protocol. Bronchoalveolar lavage inflammatory cell count and serum creatinine measurement were performed on four groups of instilled mice (sham, saline, USRPs, lipopolysaccharide). MR and optical imaging showed similar kinetics of the USRPs, passing from the airways to the lung tissue and to the kidneys, with negligible hepatic clearance. No significant increase of lung and renal inflammation markers were observed in USRP-instilled animals. A T 1-weighted radial UTE sequence was found to be valuable in quantitatively monitoring the biodistribution and pharmacokinetics of nanoparticles in the lungs of mice. The observed favorable pharmacokinetics, which was validated by fluorescence imaging, ensures the negligible toxicity of the nanoprobes, making the USRPs and the developed protocol good candidates for applications on selected lung diseases.