Nature relies on self-assembly to generate biological membranes that utilize hydrophobic-hydrophilic interactions to assemble into bilayers and other structures. If we hope to mimic natural cellular architectures, the membrane is a key component. Polymeric amphiphiles offer an attractive synthetic alternative to biological membranes. Amphiphilic block copolymers are often the architecture of choice, and readily self-assemble into vesicles, micelles, or tubular structures under appropriate conditions. These polymeric nanostructures have been utilized for a variety of biomedical applications including drug delivery, nanoreactors, biomedical coatings, and virus-assisted gene delivery. Click chemistry has emerged as a powerful tool for the synthesis of well-defined polymeric architectures. Polymeric blocks may be clicked in a modular fashion, often in near-quantitative yields using equimolar equivalents of reactants.

By allowing for the synthesis and characterization of individual blocks prior to coupling, well-defined polymeric amphiphiles are provided. Furthermore, the modular click approach allows for the systematic investigation into the effects of single parameter variations, such as block length or identity, on the resulting nanostructures physical properties or biological interactions. Although the click approach is a superb method for block copolymer synthesis, not all click reactions meet the stringent requirements for use in biomedical applications. This thesis explores the synthesis of siloxane-based amphiphilic ABA triblock copolymers using click chemistry. Our ultimate goal was to develop an optimal click methodology leading to biomedically useful polymeric vesicles. We sought to develop an elite polymer-polymer coupling methodology that is clickable, versatile, scalable, and biocompatible.

Our initial efforts utilized the prevalent copper-catalyzed click reaction to provide a versatile and scalable route towards ABA triblock copolymers. These amphiphiles demonstrated the ability to self-assemble into polymeric vesicles (polymersomes) upon hydration. Subsequent in vitro studies demonstrated that even minute amounts of residual copper severely diminish pivotal stealth and biocompatibility attributes of polymersomes. A metal-free strain-promoted click method was developed that was versatile and provided biocompatible polymersomes, but was synthetically cumbersome and therefore not scalable. Thus, we developed an elite polymer coupling method using the nitrile oxide cycloaddition reaction that met all the requirements of an optimal macromolecular coupling strategy.