Long-circulating PEGylated manganese ferrite nanoparticles for MRI-based molecular imaging

Abstract

Magnetic resonance based molecular imaging has emerged as a very promising technique for early detection and treatment of a wide variety of diseases, including cancer, neurodegenerative disorders, and vascular diseases. The limited sensitivity and specificity of conventional MRI are being overcome by the development of a new generation of contrast agents, using nanotechnology approaches, with improved magnetic and biological properties. In particular, for molecular imaging, high specificity, high sensitivity, and long blood circulation times are required. Furthermore, the lack of toxicity and immunogenicity together with low-cost scalable production are also necessary to get them into the clinics. In this work, we describe a facile, robust and cost-effective ligand-exchange method to synthesize dual T₁ and T₂ MRI contrast agents with long circulation times. These contrast agents are based on manganese ferrite nanoparticles (MNPs) between 6 and 14 nm in size covered by a 3 kDa polyethylene glycol (PEG) shell that leads to a great stability in aqueous media with high crystallinity and magnetization values, thus retaining the magnetic properties of the uncovered MNPs. Moreover, the PEGylated MNPs have shown different relaxivities depending on their size and the magnetic field applied. Thus, the 6 nm PEGylated MNPs are characterized by a low r₂/r₁ ratio of 4.9 at 1.5 T, hence resulting in good dual T₁ and T₂ contrast agents under low magnetic fields, whereas the 14 nm MNPs behave as excellent T₂ contrast agents under high magnetic fields (r₂ = 335.6 mM⁻¹ s⁻¹). The polymer core shell of the PEGylated MNPs minimizes their cytotoxicity, and allows long blood circulation times. This combination of cellular compatibility and excellent T₂ and r₂/r₁ values under low magnetic fields, together with long circulation times, make these nanomaterials very promising contrast agents for molecular imaging.