Facile 'One-Pot' Preparation of Reversible, Disulfide-Containing Shell Cross-Linked Micelles from a RAFT-Synthesized, pH-Responsive Triblock Copolymer in Water at Room Temperature

A pH-responsive triblock copolymer, α-methoxy poly(ethylene oxide)-b-poly(N-(3-aminopropyl) methacrylamide)-β-poly(2-(diisopropylamino)ethyl methacrylate) (mPEO-PAPMA-PDPAEMA), was synthesized via aqueous RAFT polymerization. This triblock copolymer dissolves in aqueous solution at low pH (<5.0) due to protonation of primary amine residues on the PAPMA block and tertiary amine residues on the PDPAEMA block. Above pH 6.0, the copolymer unimers self-assemble into micelles consisting of PDPAEMA cores, PAPMA shells, and mPEO coronas. Dynamic light scattering studies indicated a hydrodynamic diameter of 92 nm at pH 9.0. A bifunctional, reversible cross-linker, dimethyl 3,3′-dithiobispropionimidate (DTBP), was used to cross-link the micelles. The ‘one-pot’ formation of shell cross-linked (SCL) micelles was accomplished at room temperature in water by mixing the triblock copolymers and DTBP at pH 3.0, and slowly increasing the solution pH to 9.0 leading to the simultaneous formation of micelles and cross-linking. These SCL micelles are readily cleaved by the addition of the reducing agent, dithiothreitol, and can be re-cross-linked simply by exposure to air. Such SCL micelles have potential as nanocarriers for controlled release of therapeutic and diagnostic agents because the in situ cleavage of the disulfide linkages would not only allow release of bioactive agents, but also permit renal clearance of the resulting unimeric components.