Facile one-pot fabrication of calcium phosphate-based composite nanoparticles as delivery and MRI contrast agents for macrophages

Abstract

We developed a facile one-pot fabrication process for magnetic iron oxide–calcium phosphate (IO–CaP) composite nanoparticles via coprecipitation in labile supersaturated CaP solutions containing IO nanocrystals. All the source solutions used were clinically approved for injection, including water and magnetic IO nanocrystals (ferucarbotran, used as a negative magnetic resonance imaging (MRI) contrast agent). This ensured that the resulting nanoparticles were pathogen- and endotoxin-free. The dispersants used were clinically approved heparin sodium (heparin) or adenosine triphosphate disodium hydrate (ATP), which were added to the IO-containing labile supersaturated CaP solutions. Both heparin and ATP coprecipitated with CaP and ferucarbotran to form heparin- and ATP-modified IO–CaP nanoparticles, respectively, with a hydrodynamic diameter of a few hundred nanometers. Both the resulting nanoparticles exhibited relatively large negative zeta potentials, caused by the negatively charged functional groups in heparin and ATP, which improved the particle dispersibility when compared to non-modified IO–CaP nanoparticles. The heparin-modified IO–CaP nanoparticles were effectively ingested by murine macrophages (RAW264.7) without showing significant cytotoxicity but barely ingested by non-phagocytotic human umbilical vein endothelial cells, indicating the potential of these nanoparticles for targeted delivery to macrophages. The heparin-modified IO–CaP nanoparticles exhibited a negative contrast enhancing ability for MRI. Our results show that IO–CaP nanoparticles have potential as delivery and MRI contrast agents for macrophages.