Poly(2-oxazoline) and poly(2-oxazine)-based nanomedicines: Advancements, opportunities and challenges

For 50 years poly(ethylene glycol) (PEG) has been regarded as the gold standard of biocompatible, hydrophilic, and stealthy nanomedicine excipients. PEG has demonstrated improved pharmacokinetic profile, improved physical stability, and reduced toxicity for a variety of therapeutic molecules. PEG and PEG derivatives are ubiquitous, present in nearly all lipid nanoparticle vaccines, oncology nanomedicines, and over a third of solid oral dosage forms. PEG is also frequently used as a stabiliser in food and PEGylated surfactants dominate in cosmetic products. However, there is a growing body of research in which PEG immunogenicity is observed not only through repeated doses of PEGylated therapeutics, but also in so-called PEG-naïve individuals who have not yet been exposed to PEGylated drugs or formulations. Due to the potential overuse of PEG and the apparent subsequent sensitization that arises in individuals, research into PEG alternatives has garnered significant attention. Poly(cyclic imino ether)s (PCIE) are a promising family of biocompatible synthetic polymers, including poly(2-oxazoline)s (POx) and poly(2-oxazine)s (POz), which have attracted significant attention due to their potential for broad functionalisation, and tuneable physicochemical properties. Hydrophilic PCIEs have been presented as PEG alternatives with the aim of providing an alternative to PEG in nanomedicine and reducing the potential for adverse events in an increasingly PEG-sensitized population. Reports of preclinical studies involving PCIE nanomedicines are growing and show promise in terms of their application in the medical field, however, instances of clinical translation for this class of nanomedicines are disproportionately few. This review discusses the general motivation for developing PEG alternatives and their potential benefits using PCIEs as an example. It encompasses a critical appraisal of the preclinical research space surrounding PCIEs, with a view to understanding the lack of a preclinical-to-clinical translation pipeline. In reviewing the development, application and translation challenges of PCIE nanomedicines, we aim to highlight the promise of these materials for the next decade of PCIE nanomedicine research.