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

2. 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.

3. 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.

4. Polymeric Nanoparticlesor
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.

5. 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.

6. 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.

7. 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

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

9. 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.

10. 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.

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

12. 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.

13. 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,

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unpublished results.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

15. 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)

16. 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