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Covalent Surface Modification of Lipid Nanoparticles by Rapid Potassium Acyltrifluoroborate Amide Ligation

Oriana, Sean, Fracassi, Alessandro, Archer, Corey, Yamakoshi, Yoko
Langmuir 2018 v.34 no.44 pp. 13244-13251
ambient temperature, atomic absorption spectrometry, bioactive compounds, biomimetics, boron, chemical bonding, chemoselectivity, drugs, extrusion, fluorescein, fluorescence, image analysis, light scattering, nanoparticles, oleic acid, pH, phosphates, phosphatidylcholines, potassium, sonication, triolein
Because of the recent increasing demand for the synthetic biomimetic nanoparticles as in vivo carriers of drugs and imaging probes, it is very important to develop reliable, stable, and orthogonal methods for surface functionalization of the particles. To address these issues, in this study, a recently reported chemoselective amide-forming ligation reaction [potassium acyltrifluoroborate (KAT) ligation] was employed for the first time, as a mean to provide the surface functionalization of particles for creating covalent attachments of bioactive molecules. A KAT derivative of oleic acid (OA-KAT, 1) was added to a mixture of three lipid components (triolein, phosphatidyl choline, and cholesteryl oleate), which have been commonly used as substrates for lipid nanoparticles. After sonication and extrusion in a buffer, successfully obtained lipid nanoparticles containing OA-KAT (NP-KAT) resulted to be well-dispersed with mean diameters of about 40–70 nm by dynamic light scattering. After preliminary confirmation of the fast and efficient KAT ligation in a solution phase using the identical reaction substrates, the “on-surface (on-particle)” KAT ligation on the NP-KAT was tested with an N-hydroxylamine derivative of fluorescein 2. The ligation was carried out in a phosphate buffer (10 mM, pH 5.2) at room temperature with reactant concentration ranges of 250 μM. Reaction efficiency was evaluated based on the amount of boron (determined by inductively coupled plasma mass spectrometry) and fluorescein (determined by fluorescence emission) in the particles before and after the reaction. As a result, the reaction proceeded in a significantly efficient way with ca. 40–50% conversion of the OA-KAT incorporated in the particles. Taken together with the fact that KAT ligation does not require any additional coupling reagents, these results indicated that the “on-surface” chemical functionalization of nanoparticles by KAT ligation is a useful method and represents a powerful and potentially versatile tool for the production of nanoparticles with a variety of covalently functionalized biomolecules and probes.