Towards Biocompatible Shell Cross-Linked Micelles Colin D Turner, Steven P Armes, Andrew L Lewis School of Chemistry, Physics and Environmental Science, University of Sussex, Falmer, Brighton, BN1 9QJ, UK www.sussex.ac.uk/polymers e-mail: C.D.Turner@Sussex.ac.uk
Introduction Sythesise new biocompatible ABC triblock copolymers via Atom Transfer Radical Polymerisation A B C Self assembly Self-assembly of these ABC triblocks to form three-layer micelles in aqueous solution Cross-linking Covalent stabilisation of these micelles by cross-linking the central B block in aqueous solution
Atom Transfer Radical Polymerisation M verall: R X R ( M ) n X ATRP Snapshot: P X Initiator Monomer + X Cu(I)L 2 P + Dormant halide-capped chain (ATRP) [1-4] Rp X - Br or Cl P - Growing polymer radical L - Solubilising ligand ATRP is a so called pseudo living polymerisation M X Cu(II)L 2 Termination of chains is suppressed relative to propagation Near-monodisperse polymer chains (M w /M n = 1.1 1.3) Allows formation of controlled structure block copolymers X
ATRP in Protic media [5-7] Sussex Polymer Group has prepared well-defined water-soluble block copolymers via ATRP in protic media (much faster rates of polymerisation at 20ºC) Typical ATRP conditions Catalyst: Cu(I)Br or Cu(I)Cl Solubilising ligand: 2,2 -bipyridine Solvent: Lower alcohols or water/alcohol mixtures Initiator: Where R is water-soluble R CH 3 Br CH 3
Examples of water-soluble polymers [8] ( ) n ( ) n ( ) n ( ) n ( ) n H N H H N PolyP PolyDMA PolyGMA PolyHEMA PolyDEA Thermo-responsive solubility ph-responsive solubility. Can be quaternised hydroxy groups available for crosslinking hydroxy group available. Thermoresponsive solubility ph-responsive solubility. Block copolymers with ph or thermally tunable aqueous solution properties can be synthesised from these building blocks
Biocompatible water-soluble polymers [9] ( ) n P Poly 2-(methacryloyloxy ethyl phosphorylcholine) [polympc] N + Biomimetic monomer. MPC-based copolymers are used in stents, contact lenses and catheter guide wires Can be polymerised by ATRP Can be block copolymerised with other water-soluble monomers
% Conversion 100% 80% 60% 40% 20% 0% Preliminary results PP33GMA30 Kinetics 0 1 2 3 4 Time (h) 3 2.5 2 1.5 1 0.5 0 Ln([Mo]/[M]) Target Dp for GMA block = 30 Near linear 1 st order kinetics indicate that the polymer radical concentration remains constant >95% conversion within 4 hours at 20ºC Reasonable control: Polydispersity Mw/Mn <1.3 % Conversion 100% 80% 60% 40% 20% 0% EGBrMPC50 Kinetics 0 1 2 3 4 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Ln([Mo]/[M]) For Dp = 50 get 1 st order MPC kinetics >95% conversion within 4 hours at 20ºC PE 33 GMA 50 MPC 50 has been prepared with good control Mw/Mn <1.2 It is expected that PP 33 GMA n MPC m can be prepared with similar control Time (h)
Shell Cross Linked (SCL) Micelles [10] Self-assembly into micelles Shell Cross-linking Unimers Micelles Shell cross-linked micelles Stimuli-responsive block copolymers can self-assemble into micelles Micelles are then shell cross-linked to lock in the supramolecular structure. Cross-linking must be done at low solids to prevent intermicelle fusion
Cross-linking mechanisms Divinyl sulfone [11] Reacts via Michael addition with hydroxy groups H + + S S H Succinic anhydride [12] Partial esterification of H groups produces anionic carboxylate groups capable self cross-linking H H H + H H H
Shell cross-linking at high solids [13] Simple AB diblock copolymers cannot be cross-linked at high solids content without significant inter-micelle fusion. Self Assembly Shell cross-linking Unimers Micelles Fused SCL micelles ABC triblock copolymers allow cross linking at significantly higher solids content since the outer A block confers steric stabilisation. Self Assembly Inner shell cross-linking Unimers Micelles Inner SCL micelles no fusion at 10% solids
ABC Triblock Copolymers ( ) n ( ) ( ) n n Macro-initiator core block e.g. PP Below 15ºC PP block is hydrophillic Above 15ºC PP block is hydrophobic Temperature induced self assembly [14] H H Central block e.g. GMA The middle block contains groups that can be crosslinked PolyGMA is water-soluble and the hydroxy groups can react with divinyl sulfone or succinic anhydride Cross-linking stabilises the micelle structure. P N + Coronal block e.g. MPC PolyMPC is highly hydrophillic and biocompatible. A third block allows inner shell cross linking at relatively high solids content without intermicelle reactions.
Schematic representation of a Biocompatible SCL Micelle Biocompatible micelle corona based on polympc 10-100 nm Cross-linked inner shell based on polygma Thermoresponsive micelle core based on PP
Future Work Develop GPC protocols for triblock copolymers containing both PP and MPC blocks using methanol/water mixtures. Biocompatible SCL micelles with thermoresponsive cores Biocompatible SCL micelles with ph-responsive cores Investigate effect of varying block lengths on micelle size Investigate Ionically cross linked SCL micelles. Synthesis, characterisation and properties of biocompatible vesicles based on PE-GMA-MPC triblocks.
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Acknowledgements I would like to thank EPSRC (IMPACT) for DPhil studentship Biocompatibles Shiyong Liu, Iris Ma and John Weaver Sussex Polymer group