3-7-11-15-tetramethyl-1-2-3-hexadecanetriol and nitroxyl

The purpose of this work was to synthesize and screen, for their effectiveness to act as T1-enhancing magnetic resonance imaging (MRI) contrast agents, a small library of nitroxide lipids incorporated into cubic-phase lipid nanoparticles (cubosomes). The most effective nitroxide lipid was then formulated into lower-toxicity lipid nanoparticles (hexosomes), and effective MR contrast was observed in the aorta and spleen of live rats in vivo. This new class of lower-toxicity lipid nanoparticles allowed for higher relaxivities on the order of those of clinically used gadolinium complexes. The new hexosome formulation presented herein was significantly lower in toxicity and higher in relaxivity than cubosome formulations previously reported by us.

Topics: Animals; Aorta; Cell Line, Tumor; Cell Survival; CHO Cells; Contrast Media; Cricetulus; Erythrocytes; Fatty Alcohols; Female; Glycerides; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Myristates; Nanoparticles; Nitrogen Oxides; Rats; Rats, Sprague-Dawley; Spleen

The development of improved, low toxicity, clinically viable nanomaterials that provide MRI contrast have tremendous potential to form the basis of translatable theranostic agents. Herein we describe a class of MRI visible materials based on lyotropic liquid crystal nanoparticles loaded with a paramagnetic nitroxide lipid. These readily synthesized nanoparticles achieved enhanced proton-relaxivities on the order of clinically used gadolinium complexes such as Omniscan™ without the use of heavy metal coordination complexes. Their low toxicity, high water solubility and colloidal stability in buffer resulted in them being well tolerated in vitro and in vivo. The nanoparticles were initially screened in vitro for cytotoxicity and subsequently a defined concentration range was tested in rats to determine the maximum tolerated dose. Pharmacokinetic profiles of the candidate nanoparticles were established in vivo on IV administration to rats. The lyotropic liquid crystal nanoparticles were proven to be effective liver MRI contrast agents. We have demonstrated the effective in vivo performance of a T1 enhancing, biocompatible, colloidally stable, amphiphilic MRI contrast agent that does not contain a metal.

Topics: Animals; Cell Death; CHO Cells; Cricetinae; Cricetulus; Cryoelectron Microscopy; Fatty Alcohols; HEK293 Cells; Humans; Liquid Crystals; Magnetic Resonance Imaging; Male; Metals; Nanoparticles; Nitrogen Oxides; Rats; Rats, Sprague-Dawley; Scattering, Small Angle; Synchrotrons; X-Ray Diffraction