PEGylation, the attachment of the highly hydrophilic, biocompatible polymer polyethylene glycol (PEG) - common in many cosmetic and pharmaceutical products used every day to therapeutics, has become a key strategy in current nanomedicine. PEGylation is indispensable for a broad variety of commercial therapeutics. They range from protein drugs to relevant nanocarriers, such as liposomes and lipid nanoparticles (LNP). PEG leads to the particular “stealth effect”, i.e. strongly prolonged blood circulation times and apparent “invisibility” for the immune system. This is also used for lipid nano-particles (LNP) transporting mRNA vaccines, used worldwide in recent years against the COVID-19 pandemic. However, this powerful weapon is now in danger of becoming blunt: An increasing body of literature from immunologists, clinicians and biochemists shows a rapid increase of individuals (50-70% in industrialized countries) possessing anti-PEG antibodies (APAs). This causes undesirable rapid elimination of PEGylated drugs from the bloodstream, hypersensitivity and strong allergic reactions. The project RandoPEGMed introduces PEG-derived random copolymers for nanomedicine. These PEG copolymers with well-defined chain length possess randomly distributed “point mutations” along the chains, which both disables recognition by the immune system and the formation of antibodies. We systematically tested the effect of a varied concentration of “synthetic point mutations” (0 to 74 mol% GME) in the polymer chains on the binding capability of backbone- and end group-specific APAs via competitive ELISA. The concentration-dependent interaction between the antibodies and the polyether is detected by a decrease of fluorescence intensity. A major decrease of the recognition by anti-PEG antibodies was observed with increasing GME content, which translates to diminished antigenicity. A broad range of the modified PEG-structures, called "rPEGs" has been studied, showing that the interaction with anti-PEG antibodies can be eliminated. In several cell-line studies (murine cells and human cells) it has been demonstrated that these random PEG copolymers retain all favorable properties of PEG, such as high aqueous solubility and hydration as well as excellent cell viability. These findings open up a variety of new options for "rPEGs" in nanomedicine, particularly for improved nanocarriers and may help to avoid allergic reactions in patients in the future. Currently, collaboration with industry aims at making rPEG lipids available commercially.
