David A Fultonwww.dafresearchgroup.com

Introducing Stimuli-Responsiveness IntoPolymeric Nanoparticles with

Dynamic Covalent Bonds

Polymer Synthesis

The length of the chain and the number of blocks

X Y

Y X Y

The number and density of functional groups on

the backbone

The end groups

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.

We utilise living radical polymerization techniques to prepare polymer chains which we use as building blocks for higher-order structures.

Mn (GPC) = 35 kDaPDI = 1.21

Mn (GPC) = 9 kDaPDI = 1.17

micellescore cross-linked

star polymers

linear polymer chains

Non-covalent aggregation Covalent

aggregation

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

nanogels

or

single chainpolymer nanoparticle

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

Poly-N-isopropylacrylamide is most widely studied thermoresponsive polymer (Lower Critical Solution Temperature ~ 32 oC).

The value of the LCST can be tuned.

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.

Incorporating Reversible (Dynamic) Covalent Bonds Into Polymer Assemblies

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

Introduce ‘smart’ properties into polymeric materials by incorporation of dynamic covalent bonds INTO or BETWEEN the polymer chains.

pH- and Thermoresponsive CCS Polymers

+

H N

pH = 11.0

pH = 5.5

= Nile Red

N

O

N

O

Alexander W. Jackson and David A. Fulton, Chem. Commun., 2011, 47, 6807 – 6809.

pH- and Thermoresponsive Core Cross-Linked Star (CCS) Polymers

= Nile Red

5 ˚C

45 ˚C

H N

N

O

N

O

Thermoresponsive cores switch from hydrophobic to hydrophilic with changes in temperature.

Alexander W. Jackson and David A. Fulton, Chem. Commun., 2011, 47, 6807 – 6809.

0

100

200

300

570 620 670

Wavelength (nm)

Em

issi

on In

tens

ity (a

.u.)

Initial Uptake

24 h (5 °C)

48 h (5 °C)

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.

Triggering Disassembly With the Simultaneous Application of Two Orthogonal Stimuli

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

Benjamin S. Murray, Alexander W. Jackson, Clare Mahon, David A. FultonChem. Commun, 2010, 8651-8653.

P1P2

P3

P4

P5

P6

lower critical solution temperature can be tuned

22 oC – 66 oC

A Thermoresponsive Polymer Scaffold

A Thermally-Induced Sol-Gel Transition

Daniel Whitaker and David Fulton unpublished results.

10 11 12 13 14 15 16 17 18

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

4:1 polymer with di-hydra...

Time / min

Nor

mal

ised

Vol

tage

sol

gel

SummaryLiving 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