Towards Biocompatible Shell Cross-Linked Micelles

Transcription

1 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 C.D.Turner@Sussex.ac.uk

2 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

3 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 = ) Allows formation of controlled structure block copolymers X

4 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

5 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

6 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

7 % Conversion 100% 80% 60% 40% 20% 0% Preliminary results PP33GMA30 Kinetics Time (h) 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 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)

8 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

9 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

10 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

11 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.

12 Schematic representation of a Biocompatible SCL Micelle Biocompatible micelle corona based on polympc nm Cross-linked inner shell based on polygma Thermoresponsive micelle core based on PP

13 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.

14 References 1. Wang, J. S.; Matyjaszewski, K. Macromolecules 1995, 28, Wang, J. S.; Matyjaszewski, K. J. Am. Chem. Soc. 1995, 117, Kato, M.; Kamagaito, M.; Sawamoto, M.; Higashimura, T. Macromolecules 1995, 28, Beers, K. L.; Boo, S.; Gaynor, S. G.; Matyjaszewski, K. Macromolecules 1999, 32, Robinson, K. L.; Paz de Banez, M. V.; Wang, X. S.; Armes, S. P. Macromolecules 2001, 34, Robinson, K. L.; Khan, M. A.; Paz de Banez, M. V.; Wang, X. S.; Armes, S. P. Macromolecules 2001, 34, Save, M.; Weaver, J. V. M.; Armes, S. P.; McKenna, P. Macromolecules 2002, 35, Lobb, E. J.; Ma, I.; Billingham, N. C.; Armes, S. P.; Lewis, A. L.; J. Am. Chem. Soc., 2001, 123, Lewis, A. L.; Tolhurst, L. A.; Stratford, P. W. Biomaterials, 2002, 23, Thurmond, K. B., II; Kowalewski, T.; Wooley, K. L.; J. Am. Chem. Soc.,1996; 118; Liu, S.; Weaver, J. V. M.; Save, M.; Armes, S. P.; Langmuir, 2002, 18, Li, Z.; Liu, G.; Law, S.-J.; Sells, T.; Biomacromolecules; (Article); 2002; 3; Butun, V.; Wang, X.-S.; de Paz Banez, M. V.; Robinson, K. L.; Billingham, N. C.; Armes, S. P.; Tuzar, Z.; Macromolecules, 2000, 33, Robinson, K. L.; de Paz-Banez, M. V.; Wang, X. S.; Armes, S. P.; Macromolecules, 2001, 34, 5799.

15 Acknowledgements I would like to thank EPSRC (IMPACT) for DPhil studentship Biocompatibles Shiyong Liu, Iris Ma and John Weaver Sussex Polymer group