Facile fabrication of reversible core cross-linked micelles possessing thermosensitive swellability

Poly(ethyleneoxide)-b-poly(N-isopropylacrylamide-co-N-acryloxysuccinimide), PEO-b-P(NIPAM-co-NAS), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization in dioxane at 70°C employing a poly(ethylene oxide) (PEO)-based macroRAFT agent. The obtained double hydrophilic block copolymer molecularly dissolves in aqueous solution at room temperature. Above the lower critical solution temperature (LCST) of P(NIPAM-co-NAS) block, it self-assembles into micelles consisting of thermoresponsive P(NIPAM-co-NAS) cores and well-solvated PEO coronas. Cross-linking of the P(NIPAM-co-NAS) cores was facilely achieved via the reaction of NAS residues with cystamine at elevated temperatures in aqueous media, forming structurally permanent core cross-linked micelles. Most importantly, the disulfide bonds within the cross-linker can be conveniently cleaved in the presence of dithiothreitol and re-formed again upon addition of cystamine as a thiol/disulfide exchange promoter, leading to the reversible core cross-linking of micelles. The P(NIPAMco-NAS) cores of the obtained core cross-linked (CCL) micelles exhibit tunable swelling/deswelling behavior below and above the critical phase transition temperature. Dynamic laser light scattering, optical transmittance, ¹H NMR, and transmission electron microscopy were used in combination to investigate the thermoresponsive micellization of PEO-b-P(NIPAM-co-NAS) and the subsequent reversible core cross-linking.