Polyphosphoester surfactants as general stealth coatings for polymeric nanocarriers

Opsonization of nanocarriers is one of the most important biological barriers for controlled drug delivery. The typical way to prevent such unspecific protein adsorption and thus fast clearance by the immune system is the covalent modification of drug delivery vehicles with poly(ethylene glycol) (PEG), so-called PEGylation. Recently, polyphosphoesters (PPEs) were identified as adequate PEG substitutes, however with the benefits of controllable hydrophilicity, additional chemical functionality, or biodegradability. Here, we present a general strategy by non-covalent adsorption of different nonionic PPE-surfactants to nanocarriers with stealth properties. Polyphosphoester surfactants with different binding motifs were synthesized by anionic ring-opening polymerization of cyclic phosphates or phosphonates and well-defined polymers were obtained. They were evaluated with regard to their cytotoxicity, protein interactions, and corona formation and their cellular uptake. We proved that all PPE-surfactants have lower cytotoxicity as the common PEG-based surfactant (Lutensol® AT 50) and that their hydrolysis is controlled by their chemical structure. Two polymeric nanocarriers, namely polystyrene and poly(methyl methacrylate), and bio-based and potentially biodegradable hydroxyethyl starch nanocarriers were coated with the PPE-surfactants. All nanocarriers exhibited reduced protein adsorption after coating with PPE-surfactants and a strongly reduced interaction with macrophages. This general strategy allows the transformation of polymeric nanocarriers into camouflaged nanocarriers and by the chemical versatility of PPEs will allow the attachment of additional moieties for advanced drug delivery.