Dithiolane-Crosslinked Poly(ε-caprolactone)-Based Micelles: Impact of Monomer Sequence, Nature of Monomer, and Reducing Agent on the Dynamic Crosslinking Properties.

Dithiolanes are used to obtain dynamic and reversible crosslinks between polymer chains. Copolymers of two different dithiolane-containing cyclic carbonate monomers and ε-caprolactone (CL) were synthesized by ring-opening polymerization using a methoxy-poly(ethylene glycol) (mPEG) initiator and different catalysts (diphenyl phosphate (DPP), methanesulfonic acid (MSA), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or Sn(Oct)2). Each catalyst required a different temperature, which had a pronounced influence on the reactivity ratio of the monomers and occurrence of transesterification reactions and, therefore, the monomer sequence. Self-crosslinkable copolymers were obtained when the dithiolane units were connected closely to the polymer backbone, whereas the presence of a linker unit between the dithiolane and the backbone prevented self-crosslinking. The former amphiphilic PEGylated block copolymers formed micelles by nanoprecipitation in the aqueous environment and crosslinked spontaneously by disulfide exchange during subsequent dialysis. These dithiolane-crosslinked micelles showed reduction-responsive dissociation in the presence of 10 mM glutathione, making them promising drug delivery systems for the intracellularly triggered cargo release.