Stealth polymeric vesicles via metal-free click coupling

Abstract

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.

Figure 1

Polymersome induced complement activation in the presence of human serum as a function of concentration. A decrease in the percent complement activated hemolytic activity indicates an increase in complement activation. Polymersomes coupled via SPAAC demonstrate negligible complement activation. CuAAC-coupled polymersomes purified with Na₂S induce complement activation due to the presence of copper, and subsequent MgSO₄ treatment reduces complement activation.

Scheme 1

Synthesis of ABA triblock copolymers via strain-promoted azide-alkyne cycloaddition.

Scheme 2

Synthesis of a) PMOXA A-block, b) cyclooctyne-terminated blocks PMOXA-BCN, and c) PEG-BCN.

Scheme 3

The synthesis of triblock copolymers a) Ox-ABA (8) and b) P-ABA (9) via strainpromoted azide-alkyne cycloaddition with bis-azide poly(dimethylsiloxane) B-block N₃-PDMS-N₃ (7).