Hybrid Lipid Nanoparticles Containing Iron Oxide Nanoparticles and Doxorubicin

In previous work, we have shown that negatively charged gold nanoparticles (GNPs) can be coencapsulated into lipid nanoparticles (LNPs) containing ionizable cationic lipids using a process similar to that employed for encapsulating nucleic acids. These systems can subsequently be used to encapsulate weak base drugs such as doxorubicin (DOX), enabling triggered release systems employing laser stimulation. Here we develop an improved process for encapsulating metallic nanoparticles that does not rely on the presence of ionizable lipids. Specifically, we have shown elsewhere that dual-compartment lipid nanoparticles can be constructed by the simple step of adding triolein to equimolar mixtures of distearoylphosphatidylcholine (DSPC) and cholesterol dissolved in ethanol and subsequently dispersing the mixture in an aqueous buffer. At low proportions of triolein, bilayer structures with an internal electron dense region coexisting with an aqueous compartment are observed. These structures can be interpreted as consisting of DSPC and cholesterol in bilayers or monolayers surrounding an internal hydrophobic region consisting of triolein. Here we examine whether hydrophobic iron oxide nanoparticles (IONPs) can be loaded into the hydrophobic region. We show that by judicious choice of the hydrophobic coating, 5 nm diameter IONPs can be loaded into the triolein compartment and that DOX can be efficiently loaded into the aqueous compartment. The hybrid iron oxide/lipid nanoparticles (IONP-LNPs) exhibit improved drug retention properties and represent a promising candidate formulation for in vivo-triggered release applications.