Random Copolymers Enabling Nonimmunogenic PEGylation for Medical Therapeutics

PEGylation, the attachment of the highly hydrophilic, biocompatible polymer polyethylene glycol (PEG) 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. 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 nanoparticles (LNP) transporting mRNA vaccines, used worldwide 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. 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 formation of antibodies. The project will thus exploit monomer sequence statistics to eliminate immunogenicity, representing a radically new approach in polymer therapeutics. One pivotal aim is precise understanding of monomer sequence statistics in the anionic copolymerization of glycidyl ether monomers with ethylene oxide (EO). At the interface of polymer synthesis, pharmaceutical chemistry and medicine this project aims at preserving the benefits of PEGylation for the future. Based on our preliminary results and the hypothesis that anti-PEG antibodies cannot be formed against random PEG copolymers, this concept will have vast therapeutic implications for polymer conjugates, therapeutic nanoparticles and stealth liposomes.