Poly(2‐Hydroxymethyl‐2‐Oxazoline) as Super‐Hydrophilic Antifouling Polymer

Non-ionic "super-hydrophilic" polymers generally possess strong non-fouling characteristics and, therefore, can suppress non-specific and unwanted interactions with blood proteins when attached to in vivo nanomedicine ranging from drug or gene delivery to diagnostics. In this contribution, we revitalize a protected alcohol functionalized 2-oxazoline monomer, 2-acetoxymethyl-2-oxazoline, that was first reported almost fifty-five years ago and explore the possibility of making "super-hydrophilic" poly(2-oxazoline)s for biomedical applications. The synthesis of the 2-acetoxymethyl-2-oxazoline monomer and its cationic ring-opening homopolymerization and copolymerization kinetics are reported. The monomer showed unanticipated and intriguing reactivity during homopolymerization as it very slowly polymerizes at low temperature while the polymerization rate constant at high temperature is amongst the highest known values. Additionally, first order kinetic plots for the copolymerisation of AcOMeOx with EtOx at high temperature revealed that AcOMeOx is incorporated at a slower rate than EtOx confirming its lower nucleophilicity, while EtOx was accelerated in the copolymerization indicating chain-end activation by the ester side-chains. Subsequently, controlled hydrolysis of the resulting poly(2-acetoxymethyl-2-oxazoline) (PAcOMeOx) generates the alcohol (-OH) side chain functional poly(2-hydroxymethyl-2-oxazoline) (PHOMeOx). The relative hydrophilicity of PHOMeOx was analyzed and compared with the previously reported most hydrophilic poly(2-oxazoline)s, such as poly(2-methoxymethyl-2-oxazoline) and poly(2-methyl-2-oxazoline), revealing that PHOMeOx is the most hydrophilic poly(2-oxazoline) reported to date. Finally, the cytocompatibility of these different hydrophilic polymers with MDA-MB-231 breast cancer cells was explored where all polymers revealed high cytocompatibility. Most importantly, strong anti-fouling properties of the most hydrophilic PHOMeOx against serum protein were observed during the cell association studies. Hence, the "super-hydrophilic" and anti-fouling PHOMeOx might be an interesting candidate to be explored in the area of polymeric drug and gene delivery as well as anti-fouling surfaces.