Main-chain water-soluble polyphosphoesters: Multi-functional polymers as degradable PEG-alternatives for biomedical applications

Polyphosphoesters (PPEs) are a class of (bio)degradable polymers with high chemical versatility and functionality. In particular, water-soluble PPEs with the phosphoester group in the polymer backbone are currently discussed as a potential alternative to poly(ethylene glycol) (PEG). Ring-opening polymerization of typically 5-membered cyclic phosphoesters gives straightforward access to various well-defined PPEs. Several PPE candidates have proven their biocompatibility in vitro in terms of cytocompatibility, antifouling properties, stealth effect, degradability (hydrolytic and enzymatic), and some promising in vivo results in drug delivery vehicles. The possibility to control the properties with the appropriate tuning of the lateral chain makes PPEs especially appealing. This review summarizes recent developments of such PPEs for biomedical applications, e.g. in protein-polymer conjugates, hydrogels for tissue engineering, or nanocarriers for drug and gene delivery. We summarize the progress made over the years, highlighting the strengths and the shortcomings of PPEs for these applications to date. We critically evaluate the current state of the art, try to assess their potential and to predict future perspectives, shedding light on the pathway that needs to be followed to translate into clinics.