Design of reversibly core cross-linked micelles sensitive to reductive environment

Azido-functional amphiphilic macromolecules based on a biodegradable aliphatic polyester (poly-epsilon-caprolactone, PCL) and a bioeliminable hydrophilic poly(ethylene oxide) (PEO) block have been used in order to build micellar drug delivery systems. Such azido groups being able to react by alkyne-azide 1,3 Huisgens cycloaddition (a click reaction) have been used further in order to cross-link the micelles via redox-sensitive disulfide bridges. This reversible cross-linking allows to prevent micelles dissociation at high dilution upon injection and to trigger their dissociation in more reductive environment, such as the cytosol. Copolymers having three different architectures, i.e. able to crosslink either the core or the shell of core-shell-corona system have been used to investigate their micellization, cross-linking and cross-linking reversibility. The stealthiness of these micelles crosslinked in the hydrophobic segment has also been studied in vitro.