Aldehyde surface-functionalized shell cross-linked micelles with pH-tunable core swellability and their bioconjugation with lysozyme

Two approaches were attempted for the syntheses of alpha-aldehyde terminally functionalized double hydrophilic diblock or triblock copolymers of 2-(dimethylamino)ethyl methacrylate (DMA), 2-(diethylamino)ethyl methacrylate (DEA), and oligo(ethylene glycol)methyl ether methacrylate (OEGMA) via an atom transfer radical polymerization (ATRP) process. The first approach employed 2-(2,2-dimethoxyethoxy)ethyl alpha-bromoisobutyrate as the ATRP initiator for the sequential polymerization of DMA and DEA monomers. However, after deprotection of the terminal acetal into aldehyde groups, the obtained Ald-PDMA-b-PDEA diblock copolymer was prone to aldol condensation at alkaline pH, leading to extensive formation of dimers. Directly using 4-aldehydephenyl alpha-bromoisobutyrate as the ATRP initiator, the sequential polymerization of OEGMA, DMA, and DEA led to the successful preparation of the alpha-aldehyde terminally functionalized triblock copolymer, Ald-POEGMA-b-PDMA-b-PDEA. This triblock copolymer molecularly dissolves in acidic media and self-assembles into three-layer onion-like micelles consisting of PDEA cores, PDMA inner shells, and POEGMA outer coronas at alkaline pH. Selective cross-linking of the PDMA inner shell with 2-bis(2-iodoethoxy)ethane led to structurally stabilized shell cross-linked (SCL) micelles functionalized with surface aldehyde groups. Possessing the PDEA cores, the obtained SCL micelles exhibited reversible pH-responsive swelling/deswelling behavior, as revealed by dynamic laser light scattering. The surface aldehyde groups of SCL micelles enabled their facile conjugation with a model protein, lysozyme, via the formation of Schiff bases. The micelle-protein bioconjugate was characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The previous results suggest promising applications of SCL micelles in fields such as targeted drug delivery and controlled release.