Zwitterionic polyethylene glycol for therapeutic delivery

Project Summary Biologic drugs and nanomedicines with conjugated polyethylene glycol (PEG) show extended circulation in the blood, increasing therapeutic efficacy. The U.S. FDA has approved more than 30 PEGylated biologics, including proteins, nucleotides, and peptides, and a few PEGylated nanomedicines, for example COVID-19 mRNA vaccines. Attached PEG chains increase the hydrodynamic radiuses of these therapeutics to reduce their renal clearance during blood circulation. More importantly, PEG conceals therapeutics from immune cells by repelling plasma proteins, rendering therapeutics stealth behavior. The adsorption of a few types of plasma proteins onto therapeutics can lead to the removal of therapeutics by immune cells. PEG chains are hydrophilic and flexible. They can repel plasma proteins through a thermodynamic-driven entropic repulsion. Despite the unique advantage, the application of PEGylated therapeutics is limited by the presence of anti-PEG antibodies (aPEG Abs). These antibodies not only accelerate the clearance of PEGylated therapeutics and attenuate their efficacies but may also cause severe side effects. Varied percentages of populations were found to have pre- existing aPEG Abs in different studies, with the percentage as high as 40%. The high prevalence is likely due to the broad use of PEG in cosmetic and healthcare products. To further improve the pharmacokinetics of therapeutics and circumvent the problem of aPEG Abs, researchers have strived to find PEG alternatives. Among these alternative polymers, zwitterionic polymers have attracted the most attention. In contrast to PEG, zwitterionic polymers repel protein adsorption by forming a hydration layer around the polymers. We hypothesize that zwitterionic PEG (ZPEG) that combines the advantageous characteristics of both PEG and conventional zwitterionic polymers will be superior to them in extending the circulation of therapeutics and minimize the generation of anti-ZPEG antibodies. To develop a ZPEG to replace PEG for therapeutic delivery, we propose the following research plans: 1) synthesize and characterize ZPEG with different chemical structures and reveal the mechanism of enhanced blood circulation of ZPEG-modified proteins; 2) investigate the immunogenicity of ZPEG; 3) investigate the pharmacokinetics and immune responses of nanoparticles covered with ZPEG. Because of the broad application of PEG, an excellent PEG replacement will generate tremendous societal impact. This project will pave the way to replace PEG with ZPEG in therapeutic delivery for minimized side effects and consistent efficacy.