David A Fulton www.dafresearchgroup.com Introducing Stimuli-Responsiveness Into Polymeric Nanoparticles with Dynamic Covalent Bonds David A Fulton www.dafresearchgroup.com

Polymer Synthesis Living radical polymerizations techniques allow the synthesis of polymers with a high level of molecular precision. Polymerizations can be performed in a range of solvents, including water, and are experimentally straightforward.

Example Polymer Synthesis with Reversible Addition-Fragmentation chain Transfer Polymerization (RAFT) Review on RAFT: G. Moad, E. Rizzardo, S. H. Thang Aust. J. Chem. 2005, 59, 669–692. Mn (GPC) = 35 kDa PDI = 1.21 Mn (GPC) = 9 kDa PDI = 1.17 We utilise living radical polymerization techniques to prepare polymer chains which we use as building blocks for higher-order structures.

Polymeric Nanoparticles or linear polymer chains Non-covalent aggregation Covalent aggregation core cross-linked star polymers single chain polymer nanoparticle micelles nanogels Many other structures are accessible e.g. hyperbranched polymers. Sizes can be tuned to be several nm to several hundred nm. Structural precision is not as good as for dendrimers, but far easier to synthesize.

Polymeric Nanoparticles Some applications of polymeric nanoparticles: Materials applications: adhesives, coatings, encapsulation of fragrances Biomedical applications: drug delivery, imaging, diagnostics Polymeric nanoparticles which are ‘smart’ can change their structures, and hence their properties, in response to stimuli and will find new applications.

Stimuli-Responsive Polymers Some classes of polymer possess stimuli-responsive properties. They can undergo a non-linear response to an external signal e.g. a phase change. Thermoresponsive polymers are most widely studied. Poly-N-isopropylacrylamide is most widely studied thermoresponsive polymer (Lower Critical Solution Temperature ~ 32 oC). The value of the LCST can be tuned.

Incorporating Reversible (Dynamic) Covalent Bonds Into Polymer Assemblies Introduce ‘smart’ properties into polymeric materials by incorporation of dynamic covalent bonds INTO or BETWEEN the polymer chains. Position of equilibrium is sensitive to changes in pH, concentration and temperature. Products can undergo component exchange via trans-imination. Covalent bonds are chemically robust. Potential to kinetically fix products via imine reduction. Other well-known reversible covalent bonds are: disulfides, hydrazones, oximes

pH- and Thermoresponsive CCS Polymers + pH = 5.5 = Nile Red Alexander W. Jackson and David A. Fulton, Chem. Commun., 2011, 47, 6807 – 6809.

pH- and Thermoresponsive Core Cross-Linked Star (CCS) Polymers = Nile Red Thermoresponsive cores switch from hydrophobic to hydrophilic with changes in temperature. Alexander W. Jackson and David A. Fulton, Chem. Commun., 2011, 47, 6807 – 6809.

Triggering Disassembly With the Simultaneous Application of Two Orthogonal Stimuli Interest in triggering events requiring the simultaneous application of multiple stimuli. pH responsive redox responsive Provide the opportunity to trigger events upon the simultaneous application of low pH and presence of a reductant.

Nanoparticle Assembly Alexander Jackson and David Fulton Macromolecules, 2012, In press.

Alexander Jackson and David Fulton Macromolecules, 2012, In press. Triggering Disassembly With the Simultaneous Application of Two Orthogonal Stimuli Alexander Jackson and David Fulton Macromolecules, 2012, In press.

A Thermoresponsive Polymer Scaffold lower critical solution temperature can be tuned 22 oC – 66 oC Benjamin S. Murray, Alexander W. Jackson, Clare Mahon, David A. Fulton Chem. Commun, 2010, 8651-8653.

A Thermally-Induced Sol-Gel Transition Daniel Whitaker and David Fulton unpublished results. gel

Summary Living radical polymerization chemistry allows access to useful polymers which possess a high level of structural precision. Polymer chains can be used as building blocks to form a range of nanoparticle-like structures It is possible to endow polymers/polymeric assemblies with stimuli responsive properties using reversible (dynamic) covalent reactions—these systems are becoming increasingly sophisticated. Intracellular siRNA delivery (with Olaf Heidenreich, Northern Institute of Cancer Research)

Acknowledgments Group Members: Ben Murray (now EPFL) Alex Jackson Clare Mahon Niza Harun Daniel Colman Daniel Whitaker Marta Omedes Pujol Majid Al Nakeeb DAF group, October 2010