Working in stealth mode: Towards the development of biomolecular corona-resistant hydrophilic nanomaterials for biomedical applications

The interaction of nanoparticles (NPs) with biomolecules depends on their surface characteristics and has a major influence on their ultimate metabolic fate. Attempts to modulate the NP-biomolecule interaction in complex biological conditions has led to intensive research on the role of NP size, shape, charge, surface structure and the capping molecules in their eventual pharmacokinetic response. Research shows that to avoid accumulation in the organs of the mononuclear phagocyte system (MPS), engineered NPs must resist nonspecific adsorption of proteins (biomolecular corona) onto their surface. To date the most common approach to make NPs corona-resistant includes formation of a hydrophilic, neutral-charged polyethylene glycol coating (PEGylation) on their surface. This route, widely used by many groups, furnishes hydrophilic NPs, but suffers from some serious drawbacks, such as, a substantial increase in the hydrodynamic diameter (Dh) after PEGylation, and the formation of anti-PEG antibodies in vivo.
Herein, we present our efforts towards tackling the problem of biomolecular corona formation. To this end, we have explored the use of amphiphilic zwitterionic polymers and low molecular weight entities as capping ligands on the surface of ultrasmall iron oxide nanoparticles (USPIONs) and lanthanide-doped upconverting nanoparticles (UCNPs). Following such surface modification, the hydrophobic NPs were rendered water-dispersible and showed reduced adsorption of serum proteins, but without any significant increase in particle size. Additionally, the availability of reactive functional groups on the surface of the modified NPs makes them ready for further functionalization with, for example, small molecules, peptides, proteins, and antibodies. The presented results highlight the usefulness of our surface functionalization strategy to produce biocompatible materials suitable for multimodal diagnostic/therapeutic applications.