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 azido-terminated 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-N-3) 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