Stealth Polymeric Vesicles via Metal-Free Click Coupling

The strain-promoted azide–alkyne cycloaddition represents an optimal metal-free method for the modular coupling of amphiphilic polymer blocks. Hydrophilic poly(oxazoline) (PMOXA) or poly(ethylene glycol) (PEG) A-blocks were coupled with a hydrophobic poly(siloxane) B-block to provide triblock copolymers capable of self-assembling into vesicular nanostructures. Stealth properties investigated via a complement activation assay revealed the superior in vitro stealth attributes of polymeric vesicles synthesized via a metal-free approach to those coupled via the widely used copper-catalyzed click method. Furthermore, the ability to change a single parameter, such as the hydrophilic block, allowed the direct comparison of the biocompatibility properties of triblock copolymers containing PMOXA or PEG. Our studies convincingly demonstrate the need for a metal-free approach, both in preventing cytotoxicity while imparting optimal stealth properties for potential biomedical applications.