Quantitative Measurement of Ligand Exchange on Iron Oxides via Radiolabeled Oleic Acid

Abstract

Ligand exchange of hydrophilic molecules on the surface of hydrophobic iron oxide nanoparticles produced via thermal decomposition of chelated iron precursors is a common method for producing aqueous suspensions of particles for biomedical applications. Despite the wide use, relatively little is understood about the efficiency of ligand exchange on the surface of iron oxide nanoparticles and how much of the hydrophobic ligand is removed. To address this issue, we utilized a radiotracer technique to track the exchange of a radiolabeled (14)C-oleic acid ligand with hydrophilic ligands on the surface of magnetite nanoparticles. Iron oxide nanoparticles functionalized with (14)C-oleic acid were modified with poly(ethylene glycol) with terminal functional groups including, L-3,4-dihydroxyphenylalanine, a nitrated L-3,4-dihydroxyphenylalanine, carboxylic acid, a phosphonate, and an amine. Following ligand exchange, the nanoparticles and byproducts were analyzed using liquid scintillation counting and inductively coupled plasma mass spectroscopy. The labeled and unlabeled particles were further characterized by transmission electron microscopy and dynamic light scattering to determine particle size, hydrodynamic diameter, and zeta potential. The unlabeled particles were characterized via thermogravimetric analysis and vibrating sample magnetometry. Radioanalytical determination of the (14)C from (14)C-oleic acid was used to calculate the amount of oleic acid remaining on the surface of the particles after purification and ligand exchange. There was a significant loss of oleic acid on the surface of the particles after ligand exchange with amounts varying for the different functional binding groups on the poly(ethylene glycol). Nonetheless, all samples demonstrated some residual oleic acid associated with the particles. Quantification of the oleic acid remaining after ligand exchange reveals a binding hierarchy in which catechol derived anchor groups displace oleic acid on the surface of the nanoparticles better than the phosphonate, followed by the amine and carboxylic acid groups. Furthermore, the results show that these ligand exchange reactions do not necessarily occur to completion as is often assumed, thus leaving a residual amount of oleic acid on the surface of the particles. A thorough analysis of ligand exchange is required to develop nanoparticles that are suitable for their desired application.

Synthesis and Magneto-Thermal Actuation of Iron Oxide Core–PNIPAM Shell Nanoparticles

“…The difficulty of totally replacing oleic acid even with a more strongly binding dispersant was recently demonstrated. 41 …”

Complete Exchange of the Hydrophobic Dispersant Shell on Monodisperse Superparamagnetic Iron Oxide Nanoparticles

“…Attention has been given recently to ligand replacement of OA for hydrophilic dispersants providing steric stabilization to SPIONs, which has demonstrated difficulties in terms of lower achieved grafting density than required for strong colloidal stability. 16 The likely cause is incomplete replacement of OA, as shown by isotope labeling, 17 and the contradicting requirements for exchanging residual OA and densely grafting bulky polar dispersants in its place.…”

Quantification of Surface Ligands on NaYF4 Nanoparticles by Three Independent Analytical Techniques

“…24 One of their goals was to overcome a shortcoming of TGA measurements, which determine mass loss from NPs without indicating which ligands were present. The trace of radiolabeled oleate allows them to identify oleate associated with the NPs and allows them to monitor residual oleates bound to the NPs after ligand exchange with functional PEGs.…”