Engineered magnetic hybrid nanoparticles with enhanced relaxivity for tumor imaging

Clinically used contrast agents for magnetic resonance imaging (MRI) suffer by the lack of specificity; short circulation time; and insufficient relaxivity. Here, a one-step combinatorial approach is described for the synthesis of magnetic lipid-polymer (hybrid) nanoparticles (MHNPs) encapsulating 5nm ultra-small super-paramagnetic iron oxide particles (USPIOs) and decorated with Gd³⁺ ions. The MHNPs comprise a hydrophobic poly(lactic acid-co-glycolic acid) (PLGA) core, containing up to ~5% USPIOs (w/w), stabilized by lipid and polyethylene glycol (PEG). Gd³⁺ ions are directly chelated to the external lipid monolayer. Three different nanoparticle configurations are presented including Gd³⁺ chelates only (Gd-MHNPs); USPIOs only (Fe-MHNPs); and the combination thereof (MHNPs). All three MHNPs exhibit a hydrodynamic diameter of about 150nm. The Gd-MHNPs present a longitudinal relaxivity (r₁=12.95±0.53 (mms)^-1) about four times larger than conventional Gd-based contrast agents (r₁=3.4 (mms)^-1); MHNPs have a transversal relaxivity of r₂=164.07±7.0 (mms)^-1, which is three to four times larger than most conventional systems (r₂~50 (mms)^-1). In melanoma bearing mice, elemental analysis for Gd shows about 3% of the injected MHNPs accumulating in the tumor and 2% still circulating in the blood, at 24h post-injection. In a clinical 3T MRI scanner, MHNPs provide significant contrast confirming the observed tumor deposition. This approach can also accommodate the co-loading of hydrophobic therapeutic compounds in the MHNP core, paving the way for theranostic systems.