Published: August 19, 2011 r2011 American Chemical Society 15707 dx.doi.org/10.1021/ja205887v | J. Am. Chem. Soc. 2011, 133, 15707–15713 ARTICLE pubs.acs.org/JACS Aqueous Dispersion Polymerization: A New Paradigm for in Situ Block Copolymer Self-Assembly in Concentrated Solution Shinji Sugihara,* ,† Adam Blanazs, ‡ Steven P. Armes,* ,‡ Anthony J. Ryan, ‡ and Andrew L. Lewis § † Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan ‡ Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield, South Yorkshire S3 7HF, United Kingdom § Biocompatibles UK Ltd., Chapman House, Farnham Business Park, Weydon Lane, Farnham, Surrey GU9 8QL, United Kingdom b S Supporting Information ’ INTRODUCTION Self-assembly of either AB diblock or ABC triblock copoly- mers to form spherical micelles, worms/rods, lamellae, toroids, vesicles, etc. is well-known in both the solid state and dilute solution. 111 Such polymeric nanostructures form the basis of so-called soft nanotechnology 12 and offer many applications as templates, coatings, and elastomers and also for nanomedicine. 1316 In a selective solvent for one of the blocks, either micelles, worms, or vesicles are most commonly formed, depending on the relative volume fraction of the core-forming block. 711,17 Particularly in the case of vesicles, significant processing is often required, and such self-assembly can normally only be achieved in dilute solution (<1% solids). Although the basic design rules are well understood, producing worms in solution is rather problematic because this phase normally occupies a rather narrow region of the block copolymer phase diagram. 10 Here we show that AB diblock copolymer self-assembly can be precisely controlled by sequential reorganization during in situ polymerization in con- centrated aqueous solution. The full sequence of phases is only observed by targeting sufficiently long core-forming blocks at sufficiently high concentration. This important advance is achieved using reversible additionfragmentation chain transfer (RAFT) chemistry 18,19 to prepare AB diblock copolymers under aqueous dispersion polymerization conditions at 70 °C. A biocompatible poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC) 20,21 chain transfer agent serves as the solvated “A” block. Chain extension of this zwitterionic block with 2-hydro- xypropyl methacrylate in water produces a hydrophobic poly- (2-hydroxypropyl methacrylate) (PHPMA) “B” block, which drives in situ self-assembly to form spheres, worms, or vesicles. A detailed phase diagram has been elucidated in which, for a given mean degree of polymerization (DP) of the PMPC block, the final particle morphology obtained at full conversion is solely dictated by (i) the target DP of the PHPMA block and (ii) the total solids concentration at which the HPMA polymerization is conducted. Moreover, if the final targeted phase is vesicles, the observed morphology evolves from spheres to worms to vesicles during the in situ polymerization of HPMA. Our approach is similar to the situation in nature, where lipids are produced in high concentrations to spontaneously form vesicles. Using the phase diagram as a predictive “roadmap” enables the direct, Received: June 24, 2011 ABSTRACT: Reversible additionfragmentation chain trans- fer polymerization has been utilized to polymerize 2-hydro- xypropyl methacrylate (HPMA) using a water-soluble macro- molecular chain transfer agent based on poly(2-(methacryloyloxy) ethylphosphorylcholine) (PMPC). A detailed phase diagram has been elucidated for this aqueous dispersion polymerization formulation that reliably predicts the precise block composi- tions associated with well-defined particle morphologies (i.e., pure phases). Unlike the ad hoc approaches described in the literature, this strategy enables the facile, efficient, and repro- ducible preparation of diblock copolymer spheres, worms, or vesicles directly in concentrated aqueous solution. Chain extension of the highly hydrated zwitterionic PMPC block with HPMA in water at 70 °C produces a hydrophobic poly(2-hydroxypropyl methacrylate) (PHPMA) block, which drives in situ self-assembly to form well-defined diblock copolymer spheres, worms, or vesicles. The final particle morphology obtained at full monomer conversion is dictated by (i) the target degree of polymerization of the PHPMA block and (ii) the total solids concentration at which the HPMA polymerization is conducted. Moreover, if the targeted diblock copolymer composition corresponds to vesicle phase space at full monomer conversion, the in situ particle morphology evolves from spheres to worms to vesicles during the in situ polymerization of HPMA. In the case of PMPC 25 PHPMA 400 particles, this systematic approach allows the direct, reproducible, and highly efficient preparation of either block copolymer vesicles at up to 25% solids or well-defined worms at 1625% solids in aqueous solution.