Covalently stabilized temperature and pH responsive four-layer nanoparticles fabricated from surface ‘clickable’ shell cross-linked micelles

Alkynyl-terminated double hydrophilic ABC triblock copolymer, poly(oligo(ethylene glycol) monomethyl ether methacrylate)-b-poly(2-(dimethylamino) ethyl methacrylate)-b-poly(2(diethylamino) ethyl methacrylate) (alkynyl-POEGMA-b-PDMA-b-PDEA), was synthesized via atom transfer radical polymerization (ATRP) by sequential monomer addition using propargyl 2-bromoisobutyrate (PgBiB) as the initiator. The obtained triblock copolymer dissolves molecularly in acidic media and self-assembles into alkynyl surface-functionalized three-layer ‘‘onion-like’’ micelles consisting of a PDEA core, a PDMA inner shell, and a POEGMA corona at alkaline pH. Selective cross-linking of the PDMA inner shell with 2-bis(2-iodoethoxy)ethane (BIEE) results in structurally stable and surface ‘clickable’ shell cross-linked (SCL) micelles with pH-responsive PDEA cores. This new kind of SCL micelles could be further surface functionalized or conjugated with other azidoterminated polymer chains, functional groups, or biomolecules via Click chemistry. Four layer nanoparticles (SCL-PNIPAM) which have pH-responsive PDEA cores and temperature responsive PNIPAM outer coronas were fabricated from surface ‘clickable’ shell cross-linked (SCL) micelles and azide-terminated poly(N-isopropylacrylamide) (PNIPAM-N3) using Click chemistry. These novel four layer nanoparticles might act as suitable nano-sized drug delivery vehicles for the encapsulation and release of hydrophobic drugs as a function of either temperature or pH of the environment