Phase Transfer of Hydrophobic Nanoparticles Functionalized with Zwitterionic Bisphosphonate Ligands for Renal-Clearable Imaging Nanoprobes

Renal clearance of inorganic nanoparticles is a desired feature for their transition to clinic practice. High-quality ultrafine inorganic nanoparticles, which are generally prepared via thermal decomposition of organic precursors, are usually extremely hydrophobic, and must be encapsulated or ligand-exchanged with hydrophilic molecules, such as PEG-coupled ligands and proteins, prior to biomedical applications. However, these macromolecules will unavoidably increase hydrodynamic diameters (HDs) of particles by tens of nanometers, precluding their urinary excretion even though the particles have core sizes smaller than the kidney filtration threshold. Therefore, approaches that can transfer the hydrophobic inorganic nanoparticles into aqueous solutions while keeping their surface compact are what we demand. Herein, we report a class of zwitterionic bisphosphonate (ZBP) ligands. These ligands exhibit much higher affinity than oleate ligands for various hydrophobic inorganic nanoparticles, so that they can replace the original oleate ligands on the particles efficiently and provide the particles with biocompatible surfaces. The phase transition process can be accomplished in a one-pot and one-step manner, and is adaptable to many transition metal or lanthanide ion-based inorganic nanoparticles. Interestingly, the ZBP-modified particles show a minimal hydrodynamic size, excellent colloidal stability, and reduced nonspecific binding. Therefore, the desired renal-clearing characteristic can be achieved for ultrasmall nanoparticles. Due to these features, the ZBP-based phase transfer method reported in this work is considerably advantageous over the previous polymer-based methods, and has high potential for the provision of imaging nanoprobes with high biosafety for clinical use.