Reversible Imine Shell Cross-Linked Micelles from Aqueous RAFT-Synthesized Thermoresponsive Triblock Copolymers as Potential Nanocarriers for pH-Triggered Drug Release

A temperature-responsive triblock copolymer, a-methoxypoly( ethylene oxide)-b-poly(N-(3-aminopropyl)methacrylamide)-b-poly(N-isopropylacrylamide) (mPEO-PAPMA-PNIPAM), was synthesized via aqueous RAFT (aRAFT) polymerization. At room temperature, the polymer is hydrophilic and exists as unimers in aqueous solution. Increasing the solution temperature above the lower critical solution temperature (LCST) of the PNIPAM block leads to self-assembly into micelles with PNIPAM cores, PAPMA shells, and mPEO coronas with hydrodynamic diameter (D-h) values of ca. 52 nm. The PAPMA shell was cross-linked with terephthaldicarboxaldehyde (TDA) at pH 9.0 to generate shell cross-linked (SCL) micelles with cleavable imine linkages. The reversible pH- and temperature-dependent formation and cleavage of the (SCL) micelles was followed by dynamic light scattering and NMR spectroscopy. As well, the release of the model hydrophobic drug prednisolone 21-acetate (PA) from loaded SCL micelles was studied at specific pH and temperature conditions. PA was released at pH < 6.0 as hydrolytic cleavage of the imine cross-links within the swollen SCL micelles occurred. Such pH-triggered release behavior conceptually demonstrates that the reversible SCL micelles prepared by this simple procedure from temperature-responsive triblock copolymers have promise as therapeutic nanocarriers in biomedicine.