Polymer

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Making polymeric nanoparticles stimuli-responsive with

dynamic covalent bonds
Cite this: Polym. Chem., 2013, 4, 31

Alexander W. Jackson and David A. Fulton*

This review article highlights recent progress in the development of new polymeric nanoparticles which
display stimuli-responsiveness on account of their incorporation of dynamic covalent bonds (DCBs). These
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bonds can form and cleave in response to changes in environmental parameters, such as pH or presence
of reducing/oxidizing agents, and chemists have utilized this reversibility to make increasingly
sophisticated stimuli-responsive polymeric nanoparticles. Another key feature of DCBs is their capacity to
undergo component exchange processes involving the exchange for one reaction partner for another
(for example, the reaction of an imine with an amine to produce a different imine and amine), which can
present polymeric nanoparticles opportunities to modify their constitutions by reshuffling, incorporating
or releasing components. The utilization of the responsive nature of DCBs presents an alternative
Received 7th September 2012
Accepted 11th October 2012
approach towards stimuli-responsive polymeric nanoparticles which does not rely upon the utilization of
‘conventional’ stimuli-responsive polymers such as poly(N-isopropylpolyacrylamide). These new stimuli-
DOI: 10.1039/c2py20727c
responsive polymeric nanoparticles could find application in contemporary fields such as drug delivery or
[Link]/polymers diagnostics, or within novel products in the established fields of paints, coatings and adhesives.

Introduction
Polymeric nanoparticles have long been utilized as key compo-
Chemical Nanoscience Laboratory, School of Chemistry, Newcastle University,
nents in established everyday products such as paints, coatings
Newcastle upon Tyne, NE1 7RU, UK. E-mail: [Link]@[Link]; Tel: +44 (0)191
222 7065
and adhesives.1 More recently, polymeric nanoparticles are also

Alexander W Jackson grew up in David A Fulton is a Lecturer in

the small coastal town of Whit- the School of Chemistry at
ley Bay, not far from Newcastle, Newcastle University. A native of
and completed his MChem at the town of Kilbirnie in north
Newcastle University in 2008. Ayrshire, Scotland, he received
His Masters research project was his BSc (Hons) from Strathclyde
spent in the labs of Prof Michael University in 1996 and PhD in
North studying the insertion of 2001 from the University of
waste carbon dioxide into California, Los Angeles under
terminal epoxides to form useful the direction of Prof Sir J Fraser
cyclic carbonates, utilizing a Stoddart FRS, working on
new class of catalysts based on carbohydrate and supramolec-
dimeric aluminium salen ular chemistry. Aer a brief spell
complexes. Alex became the rst graduate student in the group of in industry he then spent two and half years as a postdoctoral
David Fulton in October 2008, where he developed the utilization research associate with Prof David Parker FRS at the University of
of dynamic covalent bonds within polymeric nanoparticles, co- Durham working on the synthesis of gadolinium-centered den-
authoring eight peer-reviewed publications in the process. In drimers as new MRI contrast agents. In 2006 he moved up the road
September 2012 aer completing his PhD he moved to Singapore to to take up his present position within the School of Chemistry and
take up a position as a research scientist at A* STAR with the as a member of its Chemical Nanoscience group. His research
Institute of Chemical and Engineering Sciences (ICES) where he interests are focused on using synthetic polymer chemistry to
works on the development functional and biocompatible polymeric address problems in medicine, nanoscience and materials science.
nanoparticles for targeted PET imaging.

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Polymer Chemistry Review

starting to nd application in biomedical elds, where they hold micellization of a wide range of diblock copolymers,8 and
promise in applications such as drug delivery, diagnostics and similar design principles can be applied to pH-responsive
bioimaging.2 For both established and up-and-coming applica- polymers to prepare pH-responsive micelles. Micellar systems
tions, there is drive to develop new polymeric nanoparticles which incorporate thermo- or pH-responsive characteristics
which possess the virtues of stimuli-responsiveness, where a have been shown to release encapsulated cargos of small
nanoparticle can respond to the application of a stimulus by hydrophobic molecules upon micelle disassembly triggered by
changing its structure, and hence its physical properties, in a way changes in temperature,9 and have been extensively studied as
which ultimately enhances the utility of the nanoparticle. Such potential vehicles for the controlled release pharmaceuticals.10
advances would make polymeric nanoparticles better placed to Although very useful in making thermo- and pH-responsive
overcome some of the signicant challenges in biomedical micelle-based nanoparticles, ‘conventional’ stimuli-responsive
applications3 or allow the development of new everyday products polymers still present a rather limited palette of structure,
displaying responsive properties. property and responsiveness, and chemists have been actively
When considering how to introduce stimuli-responsiveness researching alternative means to endow polymers with the
into polymeric nanoparticles, chemists have usually relied virtues of stimuli-responsiveness.
heavily upon well-known polymers which possess an inherent
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stimuli-responsiveness. These polymers can respond to input

Dynamic Covalent Bonds (DCBs)
stimuli—in particular to changes in temperature or pH—by
undergoing a reversible phase transition.4 Arguably the most An approach of increasing importance towards stimuli-
utilized polymer here is the thermoresponsive polymer poly(N- responsive polymeric nanoparticles is the utilization of so-
isopropyl)acrylamide (Fig. 1a), which is readily soluble in water called dynamic covalent bonds11 (DCBs), which when judi-
at room temperature but precipitates reversibly from solution ciously placed either into or between polymer chains (Fig. 2)
when raised above its lower critical solution temperature present key features which can be exploited to endow polymeric
(LCST), changing from an extended chain conformation below nanoparticles with responsive properties. The use of the term
this temperature into a collapsed chain above this tempera- ‘dynamic’ to describe what many chemists would simply
ture.5 This feature presents what is in effect a way to switch a otherwise refer to as ‘reversible’ covalent bonds, was coined by
polymer from hydrophilic to hydrophobic simply by changing the supramolecular chemistry community with its focus on
temperature, and chemists have extensively exploited this studying and exploiting the dynamic nature of non-covalent
feature to make stimuli-responsive polymeric nanoparticles bonds to prepare larger superstructures.12 The inherent chem-
based upon diblock copolymer micelles. Diblock copolymers ical instability of non-covalent interactions, however, makes the
which incorporate a thermoresponsive block such as poly(N- resulting superstructures themselves unstable, and this lack of
isopropylacrylamide)-b-poly(ethylene glycol),6 are able to switch robustness prompted a resurgence of interest in applying
reversibly between hydrophilic-b-hydrophilic and hydrophobic- chemically more stable reversible covalent bonds to prepare
b-hydrophilic upon heating, a trigger which can be used to such molecules. The term ‘dynamic covalent bond’ describes
facilitate the non-covalent aggregation of multiple polymer any covalent chemical bond which possesses the capacity to be
chains into micelles7 (Fig. 1b), nano-sized assemblies of poly- formed and broken under equilibrium control.11 It should be
mer chains which to all intents and purposes can be considered noted that DCBs have long played a part in polymer chemistry,
as polymeric nanoparticles. The disassembly of these micelles where some types of polymerizations are performed under
can be triggered by cooling, as their constituent polymer chains equilibrium control e.g. the formation of polyesters. It is
loose their amphiphilicity and return to their hydrophilic-b- perhaps surprising, however, that it has only been in the last
hydrophilic state. This thermally-induced change in polymer decade or so that DCBs have become extensively employed to
solubility has been used extensively to facilitate reversible endow polymeric materials with responsive characteristics.

Fig. 1 (a) Poly(N-isopropyl)acrylamide changes from an extended chain conformation below its LCST (about 32  C) into a collapsed chain above this temperature. (b)
The thermally induced reversible micellization of poly(N-isopropylacrylamide)-b-poly(ethylene glycol).6

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Fig. 3 The features of DCBs which make them of such interest in polymer
chemistry are highlighted using the imine bond as an example. The condensation
of an amine with a carbonyl (in this instance an aldehyde) to form an imine bond
and a molecule of water. The position of this equilibrium is sensitive to environ-
mental conditions such as temperature, concentration, pH, etc. DCBs can also
undergo component exchange process, illustrated here with the reaction of the
imine bond with another amine to afford a new imine bond. Exchange processes
can allow polymers to reshuffle or incorporate/deincorporate their components,
changing their structures and thus their properties and function.

in utilizing the reversibility of DCBs to make increasingly

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sophisticated stimuli-responsive polymeric species.

Another important feature of DCBs is their capacity to
undergo component exchange processes involving the exchange
for one reaction partner for another, which can be illustrated
(Fig. 3) by again using the imine bond as an example. The imine
Fig. 2 Cartoons showing some of the different classes of polymeric nanoparticles
which have been endowed with stimuli-responsive properties on account of their bond can react with an amine to produce a different imine and
incorporation of DCBs. (a) Two different polymer blocks can be linked through a amine (transimination), and this component exchange feature
single DCB to form an amphiphilic diblock copolymer, which can then self-assemble can present polymeric species opportunities to modify their
into a micelle. (b) Diblock copolymers possessing appropriate functional groups constitutions by reshuffling, incorporating or releasing
within one of the blocks can be cross-linked through DCBs into core cross-linked
components, and thus changing their structures, properties
star (CCS) polymers. (c) Copolymer chains possessing appropriate functional
groups can be cross-linked through DCBs into nanogel-type particles. (d) A single and functions.
copolymer chain can be intramolecularly cross-linked through DCBs. DCBs possess further important features which makes them
appealing in polymeric nanoparticles. Dynamic covalent reac-
tions are usually performed with the help of a suitable catalyst
Since the pioneering work13 by the Lehn group, the use of DCBs to aid kinetics, and so the option exists to halt these reversible
in polymer chemistry has seen an explosion of interest by many processes and kinetically ‘x’ the products simply by quenching
academic groups around the world, witnessing the develop- the catalyst, an option which is not available within supramo-
ment of many new dynamic covalent polymers and polymeric lecular systems where dynamic processes cannot be easily
materials. Much of this progress has been recently reviewed,14 ‘turned-off’. Hydrazone bond formation, for example, displays
and the reader is strongly recommended to visit this literature optimal kinetics at pH 4.5,17 and raising the pH to 7.0 can
should they desire to further their knowledge of DCBs in other drastically slow down the rate of reaction to such an extent that
areas of polymer chemistry beyond the nanoparticle focus of it essentially becomes ‘xed’. Alternatively, DCBs can also be
this review. ‘xed’ through a chemical process, for example, through
The important features of DCBs which make them of such reduction of the imine bond with hydride reducing agents to
potential are best highlighted by considering, as an example, a afford the secondary amine. Another hugely important feature
well-known and exploited DCB: the imine bond.15 Imines are of DCBs is their chemical robustness, which is an important
made (Fig. 3) from the condensation of an amine with an alde- point when considering possible applications where the
hyde or ketone, also producing a molecule of water in the resulting polymeric species must possess the required levels of
process. This is an equilibrium process, and the position of the robustness to operate in ‘real’ environments.
equilibrium is thus sensitive to environmental parameters There exist an extensive range of DCBs, and some of the
including pH, temperature, and concentration of water. Lehn more commonly used DCBs utilized in the eld of stimuli-
and co-workers have performed16 an in-depth investigation of responsive polymeric nanoparticles are highlighted in Fig. 4. To
the pH-sensitivity of the imine bond, one outcome of which nd out more about DCBs, the reader is recommended strongly
shows that the position of the imine equilibrium can be shied to consult the rather excellent reviews by Rowan et al.11 and
from almost complete imine to starting materials over about Sanders et al.,18 both of which have helped to dene the elds of
three pH units. By tuning the electronics of the reaction partners, dynamic covalent chemistry.
it is possible to control the precise pH at which these processes Rather than being a comprehensive catalogue of work, in
occur through careful choice of amine and aldehyde. This this review article we will focus on some highlights which we
capacity to modulate the position of equilibrium of a DCB believe best demonstrate how polymer chemists have started to
presents the opportunity to form and cleave bonds in response to harness the appealing features of DCBs to make stimuli-
environmental parameters such as pH or presence of reducing/ responsive polymeric nanoparticles. We apologise in advance to
oxidizing agents, and chemists have made good progress those researchers whose work we have le out for reasons of

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Fig. 4 Examples of DCBs commonly used in to endow polymeric nanoparticles with the virtues of stimuli-responsiveness. (a) Hydrazone formation, (b) oxime
formation, (c) disulfide formation, (d) acetal/ketal formation, (e) boronic ester formation, (f) thermally induced radical cross-over reactions, and (g) Diels–Alder [4 + 2]
cycloadditions.

brevity. It is hoped that this review will provide the reader with a major weakness in applications such as drug delivery, where
avour of the creativity and imagination within the state-of-the- dilution effects as the nanoparticle passes through the body could
art, and some future directions and challenges. lead to unwanted “burst” release of the encapsulated active
compounds. To address this stability issue, cross-linking strate-
Micelles gies have been developed in which the micellar cores20 or shells21
are covalently cross-linked, kinetically xing the micelles. This
A tried-and-tested methodology for making polymeric nano- cross-linking, however, can hinder drug release and make it
particles is the micellization of amphiphilic diblock copolymers.7 harder for the body to clear the polymeric drug carriers. Conse-
Normally these diblock copolymers possess a hydrophobic-b- quently, chemists have been actively investigating the potential of
hydrophilic structure with their self-assembly into micelles using DCBs as cross-links which can be cleaved upon application
occurring in water, but wholly organic systems are also well- of a desired stimulus, triggering nanoparticle disassembly and
known.19 A major limitation of micelles is their inherent insta- release of the encapsulated cargos.
bility, as at low concentrations (below their critical micelle The McCormick group have reported (Fig. 5) a particularly
concentration) they can spontaneously disassemble into their interesting recent example which neatly highlights
component polymer chains. This feature of polymer micelles is a these concepts.22 The polymeric building block used was a

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Fig. 5 Imine shell cross-linked micellar assemblies possessing pH- and thermoresponsive characteristics.22

hydrophilic triblock copolymer (1) comprising of poly(ethylene responsiveness of the imine bond to prepare surfactant micelles
glycol)-b-poly(3-aminopropyl methacrylamide)-b-poly(N-iso- whose disassembly/reassembly can be triggered by changes in
propylacrylamide) (PEG-b-PAPMA-b-PNIPAm), which was pH. Condensation of the water-soluble aromatic aldehyde (3)
prepared via RAFT polymerization. This triblock copolymer was (Fig. 6) with aliphatic amines (4) at pH 11.8 forms the imine
shown to form micellar assemblies (2) possessing a core–shell– amphiphile (5), which spontaneously self-assembles into
corona architecture above the lower critical solution tempera- micelles (6) possessing hydrodynamic radii of 5 nm. These
ture of the PNIPAm block. The hydrophobic nature of the cores micelles can complex a cargo of Nile Red, a uorescent
of these micelles means they can encapsulate the hydrophobic
anti-inammatory prednisolone 21-acetate (PA), which has
been used as a model drug in this study. To facilitate the cross-
linking of the polymer chains, the dialdehyde tereph-
thaldicarboxaldehyde was used to cross-link the shell blocks
through imine bond formation with the amine functions of the
poly(3-aminopropyl methacrylamide) blocks. The resulting
nanoparticles possess both pH- and thermoresponsive proper-
ties, and the group have shown how these can be harnessed to
control the release of the encapsulated drug. When the
temperature is lowered to 25  C the core becomes hydrophilic,
triggering the relatively slow release of the PA cargo. Complete
disassembly of the micelle is achieved through the adjustment
of the pH to 5.5 at 25  C, triggering imine hydrolysis and the fast
“burst” release of PA. The ability to use different stimuli to
control the rate of drug release is potentially very powerful, and
this study provides much encouragement for the further
development of stimuli-responsive polymeric nanoparticles in
drug delivery.
Another interesting application of DCBs in polymeric
micelles is the concept that two polymer blocks can be linked
through a single DCB to form an amphiphilic diblock copol-
ymer (Fig. 2a). These diblock copolymers should be able to self-
assemble into micelles in the same way as ‘conventional’
diblock copolymers, with the advantage that the DCB allows the
incorporation of the dynamic element of the DCB into the
resultant micellar nanoparticle. This concept has been investi-
gated, initially on the smaller scale of surfactant micelles which
although not polymeric in nature are still worthwhile high- Fig. 6 The formation of a dynamic covalent surfactant which self-assembles into
lighting. The group of van Esch have exploited23 the pH- surfactant micelles.23

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hydrophobic small-molecule dye which makes a useful model to increase the susceptibility of the resulting acylhydrazone
cargo. When the pH of the solution was lowered to 7.2, the bond to acid-catalysed hydrolysis.
imine linkages were hydrolysed causing the micelles to disso- As previously mentioned, the study of Lehn and co-workers16
ciate. This process is completely reversible, and when the pH into structure-stability correlations of the imine bond in
was changed back to alkaline the micelles reform. In addition to aqueous solution suggests that shiing the equilibrium of
pH, the imine bond is also sensitive to changes in temperature imine bond from the side of starting materials to products will
which can also be used to trigger micelle assembly/disassembly. occur over about three pH units. Many applications would
When the temperature of the micelle solution was raised to benet from a sharper ‘on/off’ effect over a far narrower pH
55  C, the equilibrium constant of the imine bond drops to a value, and the group of Zhang have described27 (Fig. 7a) a
sufficiently low value to trigger cleavage of the amphiphile and ‘superamphiphile’ system which goes some way to addressing
subsequent micelle disassembly. This work nicely illustrates this limitation. The key to this system is its exploitation of the
how the pH- and temperature-responsiveness of the imine bond fact that small changes in the hydrophilic–hydrophobic balance
can be exploited, and represents a simple and potentially low- of an amphiphilic diblock copolymer can have a very signicant
cost approach to a stimuli-responsive delivery system, but its effect on the stability of its resultant micelle. The group have
relatively small size may prohibit its further development in prepared pH-responsive superamphiphiles by conjugating
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some elds. multiple hydrophobic aldehydes (7) onto a doubly hydrophilic

The group of Zhang have extended24 this concept to prepare PEG-polylysine diblock copolymer (8). At pH 7.4 the imine
dynamic covalent bolaform amphiphiles, where the compo- equilibrium is sufficiently high such that all of the lysine
nents are linked through imine bonds. Bolaform amphiphiles amines have reacted to form a toothbrush-type amphiphile (9),
usually possess relatively lower critical micelle concentrations essentially switching the polylysine block from hydrophilic to
than ordinary micelles and are thus of potentially higher utility. hydrophobic. These amphiphiles self-assemble into micelles
The group have shown that micelles possessing diameters of (10) possessing hydrodynamic diameters of 70 nm, which
about 18 nm can be formed which encapsulate Nile Red as a were shown to complex the hydrophobic dye Nile Red. At pH 6.5
model hydrophobic cargo. As expected, a drop in pH causes the imine bonds are sufficiently hydrolysed to remove the
hydrolysis of the imine bonds, cleavage of the bolaform amphiphilicity of the component polymer building blocks, and
amphiphile and subsequent release of the encapsulated cargo the micelle consequently disassembles whilst releasing the Nile
as the micelle disassembles, and the group have shown that the Red cargo. One would expect the aromatic imine bond utilized
rate of release is pH-dependant, being fastest at low pH and in this work not to be completely hydrolysed at pH 6.5, but it is
slower at high pH. Like the system of van Esch, this in not a likely that because of the poor solubility of the aldehyde
polymer-based micelle, but is also worthy of mention as the component, it precipitates from solution as the imine bond is
concepts could be readily ‘scaled-up’ by using polymeric hydrolysed. This precipitation probably helps push the equi-
building blocks. librium further in the direction of hydrolysis. A further impor-
By transposing the simple idea of an amphiphile where the tant factor is that as the micelle destabilizes, the imine bond
two components are linked through a DCB into the realm of becomes more unstable and is hydrolysed further. The impor-
true polymeric nanoparticles, it should be possible to prepare tant feature of this work is that the micelle system completely
larger structures possessing bigger loading capacities. In our disassembles over a narrower pH range, and thus displays a
own work we linked25 a polystyrene block with a polyisoprene sharper “on–off” behaviour. Further development of this system
block through a single dynamic covalent oxime bond, and could lead to improved sharpening of the switching behaviour,
found that the resultant dynamic covalent diblock copolymer and it should also be possible to tune the ‘on–off’ pH-switch to
could self-assemble into micellar nanoparticles in DMF. We be matched to a desired application by altering the electronics
showed that addition of an excess of small molecule alkoxy- of the aromatic aldehyde residues.
amine could undergo component exchange with the oxime Polymeric micelles are very popular candidates in drug
bond, resulting in scission of the diblock copolymer and delivery research programmes,28 and the work presented here
subsequent micelle disassembly. The groups of He and Zhu would very much suggest that the exploitation of the DCB to
have looked26 at preparing polymeric micelles from diblock endow micelles with responsive behaviours will further
copolymers where a PEG block is joined to a polystyrene block enhance the usefulness of micelles in this eld.
through a dynamic covalent acyl hydrazone bond, and the
resultant diblock copolymers was shown to form a range of Nanogels
morphologies in dilute DMF/water solutions. In water at pH 7 it
was shown that stable micelles can be formed which are able to The polymer nanogel architecture has several features which
complex a cargo of the hydrophobe methyl porphyrin. Upon make it attractive in the eld of drug delivery, with their porous
lowering the pH to 4, the disassembly of the micelles was trig- architectures in particular allowing high levels of encapsulation
gered leading to the gradual release of the cargo. This work and scope for tuneable kinetics of release. The incorporation of
demonstrates an interesting exploitation of acylhydrazone DCBs as cross-links into nanogels allows the introduction of
bonds, which are normally rather stable at mildly acidic pH stimuli-responsiveness, enhancing considerably their potential
values.18 Presumably in this instance the choice of an electron- in delivery applications. The research group of Thayumanavan
rich aromatic aldehyde component as a reaction partner helps have lead the way in utilizing the redox-responsiveness of the

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Fig. 7 Multiple hydrophobic aldehyde units (7) conjugate onto a polylysine diblock copolymer (8) to prepare a ‘superamphiphile’ (9) which spontaneously self-
assembles into a micelle (10). Lowering the pH to 6.5 causes partial hydrolysis of the imine linkages, reducing the amphiphilicity of the diblock copolymers and
triggering micelle disassembly.27
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Fig. 8 Formation of disulfide cross-linked nanogels and subsequent disassembly through disulfide bond reduction in the presence of glutathione.29

disulde bond to develop responsive nanogels for possible polymer chains. The Thayumanavan group have demonstrated
delivery applications.29 Although nanogels are easily prepared the capability to tune the rates of Nile Red release, adjust the
using emulsion polymerization techniques, it is not straight- nanoparticle size and adorn the nanoparticle periphery through
forward to introduce DCBs using this approach. Instead, the US post-formation functionalisation. It was shown that the rate of
group have developed a sophisticated polymeric system based cargo release is dependent upon the concentration of gluta-
upon linear copolymer chains (11) (Fig. 8) possessing hydro- thione, and the kinetics of cargo release can therefore be tuned
philic (oligoethylene glycol methacrylate) and hydrophobic (2- by adjusting the density of disulde cross-links, either by
pyridyldisulde ethylmethacrylate) monomer units, which were altering the amount of 2-pyridyldisulde ethyl methacrylate in
shown to non-covalently aggregate into nano-sized polymeric the linear polymer building block or by adjusting the amount of
assemblies (12) upon heating in aqueous media as a conse- DTT added. The hydrodynamic radius of the cross-linked
quence of the thermoresponsive nature of the oligoethylene nanoparticles can be tuned from 10–200 nm through altering
glycol methacrylate monomer units. The addition of a decient the ratio of the hydrophilic and hydrophobic monomer units in
amount of dithiothreitol (DTT) reduces a portion of the pyr- the linear polymer building blocks, or by altering the overall
idyldisulde functions present upon the polymer chains to length of the polymer building blocks. Particle size is very
alkylthiols, which then intermolecularly cross-link with the important in the eld of drug delivery, as it plays a crucial role
remaining pyridyldisulde functions. The resulting cross- in cell permeability and retention.30 Excess pyridyldisulde
linked nanogel assemblies (13) were shown to be very stable at functions not employed in cross-linking can be used as handles
lower temperatures on account of the covalent cross-links, and for the post-functionalisation of the nanogel assemblies, which
were shown to non-covalently encapsulate Nile Red. The trig- to demonstrate this possibility were adorned with thiol-modi-
gered release of the encapsulated Nile Red cargo is achieved ed peptides. The potential to perform post-functionalisation is
through exposure to the biologically-active reducing agent very important as biomolecules conjugated onto the nano-
glutathione, which cleaves the disulde cross-links and triggers particle periphery may increase specicity in cell targeting.
the disassembly of the nanogel into water-soluble linear This example highlights the chemical robustness and

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redox-responsive nature of nanoparticles which possess DCBs: the pH-responsiveness of the imine bond, and the
dynamic covalent disulde cross-links. redox-responsiveness of the disulde bond. Our nanoparticles
Disulde bond formation is currently intensively investi- (Fig. 9) were prepared by cross-linking multiple polymer chains
gated in the preparation of polymeric drug delivery vehicles, as through both imine and disulde bonds to form nanoparticles
the intracellular environment is known to be highly reductive.31 possessing hydrodynamic radii of 80 nm. Application of either
The reducing agent glutathione has an intracellular concen- low pH or a reducing agent did not trigger the disassembly of
tration of 3 mM, which is 300 times greater than its concen- the nanoparticle into their component polymer chains as there
tration in blood (approximately 10 mM). It is therefore widely remains a sufficient density of either disulde or imine cross-
hypothesized that polymeric nanoparticles possessing disulde links to ensure the nanoparticle maintains its structural integ-
cross-links will only disassemble and release their encapsulated rity. The simultaneous application of both low pH and the
cargo within the intracellular environment, ensuring that drugs reducing agent cleaves both the disulde and imine cross-links,
are only released inside of cells where they are required and not triggering complete particle disassembly. Nanoparticle disas-
in the extracellular environment. In this regard, recent work by sembly, however, is not necessarily a particularly useful
the group of Shuai utilizing a dual-responsive pH-responsive response, and arguably a more desirable response would be the
disulde-cross-linked micelle to deliver the anti-cancer drug triggered release of a cargo from the nanoparticle. Experiments
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doxorubicin is noteworthy.32 This delivery system is designed to showed that the application of low pH does cause some cargo
encourage burst release of the drug cargo within the lysosomes, escape from these nanoparticles, presumably because the
intracelluar compartments formed during the endocytotic porosity of the particle increases even though the polymer
processes through which macromolecules oen enter cells. chains remain cross-linked by the disulde bonds. This work
Lysosomes possess reduced pH and high levels of glutathione, does demonstrate some progress, showing that two orthogonal
and the micellar nanoparticle developed by Shai and coworkers DCBs can be combined to afford a nanoparticle where two
has been shown to deliver rapidly a drug cargo specically stimuli have to be applied simultaneously to trigger a response,
within this unique environment, and thus displays much and we anticipate that future systems will possess higher levels
promise in delivery applications. of sophistication.
A limitation of many stimuli-responsive nanoparticles is
their reliance upon a single stimulus to trigger a response. By Core cross-linked polymers
requiring the simultaneous application of two different stimuli,
more control is gained over where and when a particular CCS polymers are a class of nano-sized polymeric nanoparticle
response is triggered, and thus there has been an impetus to whose structural features are dened by a central core consist-
develop such polymeric nanoparticle systems. Our own group ing of a network of cross-linked polymer chains surrounded by a
have recently reported33 a polymeric nanoparticle which corona of polymeric arms.34 Much of the interest in CCS poly-
requires the simultaneous application of two different stimuli mers is as a consequence of their architectures, possessing
to trigger its disassembly into its component polymer chains. compact structures whose cores can be utilized as carriers for
This system exploits the responsiveness of two orthogonal small molecules such as drugs or fragrances, and coronal
chains which help to solubilise and shield the cargo from its
external environment. CCS polymers also possess solubilities
and viscosities similar to linear polymers of relatively low
molecular weight, additional properties which make them
potentially very useful in a diverse range of elds, most notably
drug delivery35 as well as imaging,36 and catalysis.37
At Newcastle we became interested in introducing stimuli-
responsiveness into CCS polymer architectures using DCBs as
cross-links within the cores. Our synthetic strategy borrowed
from that described38 by the group of Otsuka and Takahara,
which uses the cross-linking of preformed linear diblock
copolymer chains. We prepared39 copolymer chains displaying
‘inert’ blocks (Fig. 10) to promote the formation of CCS poly-
mers and discourage macroscopic gel formation, and ‘reactive’
blocks which possess the reaction partners to promote cross-
linking through the formation of DCBs. In this work, we focused
on using aldehyde and amine functions for eventual cross-
linking through imine bond formation, which would allow us to
exploit the component exchange capabilities of this bond, and
Fig. 9 A polymeric nanoparticle requiring the simultaneous application of both
in latter work, its pH-responsiveness. Our initial work demon-
lowered pH and a reducing agent to trigger its disassembly into linear polymer
chains. Although the application of either lower pH or a reducing agent breaks
strated that imine bond formation was effective in driving the
the imine or disulfide bonds, respectively, there is a sufficiently high density of self-assembly of the polymer chains, and we found that the size
remaining cross-links to maintain the integrity of the nanoparticle structure.33 of the CCS polymers formed could be controlled through the

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Fig. 10 The self-assembly of CCS polymers from diblock copolymers which display either multiple amine or aldehyde functions within one of the blocks. The
self-assembly being driven by the formation of imine bond cross-links within the core.39

concentration at which the cross-linking was performed, Much of the work discussed so far has focused on exploiting
although as the particle size increased so did the particle the pH-responsiveness of the imine bond, but of course it
polydispersity. Particle disassembly could be triggered by should be possible to utilize the other DCBs. Another pH-
addition of a low molecular weight alkyl amine, which responsive bond which has very recently been explored within
undergoes transimination with the imine cross-links within the polymeric nanoparticles is the boronic ester, which is formed41
core. Because this initial work was performed in organic from the condensation of boronic acids with 1,2- or 1,3-diols in
solvents, it was not possible to exploit the pH responsiveness of aqueous or organic solution (Fig. 4e). Arguably the major
the imine bond to its full, and so we next turned our attention to application of this reaction has been the use of boronic acids in
water-soluble nanoparticles. carbohydrate sensing,42 and a consequence of this research is
This system40 was conceptually similar, but utilized water- that much is known about the kinetics and thermodynamics of
soluble acrylamide-based diblock copolymer building blocks to this reaction. In basic conditions, the reaction between a
make CCS polymers possessing hydrodynamic radii of 18 nm, boronic acid and a hydroxide anion occurs, affording a tetra-
and a molecular weigh estimated to be 23 MDa (which corre- hedral boron anion which can then reversibly react with a 1,2- or
sponds to about 49 arms). These CCS polymers possessed 1,3-diol to form a cyclic boronic ester. In acidic conditions the
excellent water-solubility, allowing the exploitation of the pH- hydrolysis of the boronic ester back to the boronic acid is
responsiveness of the imine bonds. Because of the presence of N- favourable. Another interesting feature of boronic acids is that
isopropylacrylamide monomers within the reactive blocks, the they can trimerize to form a six-membered boroxine in anhy-
CCS polymers also possessed thermoresponsive cores, and so drous organic solvents and in the presence of a Lewis base such
these CCS polymer species can be considered pH- and temper- as piperidine, a process which is reversible upon the addition of
ature-responsive. By changing pH between 11.0 and 5.5, we were water.
able to trigger the assembly/disassembly of the CCS polymer The Jäkle group has prepared43 poly(styreneboronic acid)-b-
from its component copolymer building blocks, following this polystyrene (PSBA-b-PS) diblock copolymers which were shown
process by dynamic light scattering through multiple cycles. By to non-covalently aggregate in aqueous environments into
loading the cores of the CCS polymers with a cargo of hydro- micellar assemblies on account of the amphiphilicity of the
phobic Nile Red, we were able to show that the pH-induced linear diblock copolymers. This micellar system utilises the pH-
disassembly process lead to release of the cargo molecules. By sensitive sp2 to sp3 interconversion of boronic acids to trigger
holding the pH at 11 and modulating the temperature from 5  C structural changes in micelle morphology. At high pH, when sp3
to 45  C we were able to show that the release and uptake of the hybridization is favourable, the formation of spherical micelles
dye molecule could be triggered by changes in temperature. This is observed as a consequence of high interface curvature,
work hints that conventional stimuli-responsive polymers can be caused by the electrostatic repulsion of the B(OH)3 groups. At
combined with the responsiveness of DCBs to make polymeric low pH, when sp2 hybridization is favourable, worm-like
species with multiple properties, and although this example can assemblies were observed as the neutral B(OH)2 functions do
be considered rather simplistic, we are currently exploring more not induce any repulsion, reducing the interface curvature. This
sophisticated dual-responsive systems. early boronic acid-containing polymeric system does not utilise

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Fig. 11 Core cross-linked star polymers are formed via boronic ester formation between pendant boronic acid functions along a diblock copolymer chain and 1,2-diols
within multifunctional small molecule cross-linkers.46

pH-sensitive formation of dynamic covalent boronic esters to overcome will also open-up possibilities to exploit the
trigger a structural change, however it does emphasises the pH-responsive properties of the boronic ester.
versatility and potential of boronic acids in polymeric nano- Another class of DCB of interest is the acetal bond,47 which is
particles as a consequence of the pH-induced switch in reversibly formed through the reaction of an aldehyde with two
hybridization. primary alcohols (Fig. 4d). This group is very closely related to
Building upon their earlier work44 with boronic acid-con- the ketal, which is formed through the reaction between a
taining polymers, the Sumerlin research group have focused on ketone and two primary alcohols, and these functional groups
utilising the dynamic nature of boronic esters to introduce are oen prepared in organic solvents under acidic conditions.
responsiveness into CCS polymeric nanoparticles. The group The resulting acetal/ketal functionality will readily hydrolyse
has demonstrated45 that boronic acid end-functionalized poly- back to its component partners in aqueous media, and the rate
mers prepared by RAFT can form three-arm star polymers as a of this hydrolysis is pH-sensitive. This pH-responsive feature
consequence of boroxine cyclisation of the polymer end-groups makes the incorporation of acetal/ketal functional groups
in the presence of the Lewis base piperidine. The hydrolysis- within polymeric nanoparticles very appealing, as their acid-
triggered disassembly back to linear polymer chains was ach- catalysed hydrolysis can be utilised to trigger nanoparticle
ieved through the addition of water. In subsequent work the disassembly and subsequent cargo release within low pH
Sumerlin group prepared46 (Fig. 11) diblock copolymers con- environments.48 It is also possible to tune their stabilities by
taining pendant boronic acid functions within one of the blocks altering the electronic characteristics of the component alde-
(14), and showed that these linear polymer chains can self- hydes and alcohols. This feature could prove very useful in the
assemble through boronic ester formation with multifunctional eld of controlled drug delivery, as certain tissue targets display
small molecule 1,2- or 1,3-diols into CCS polymers (15) pos- low pH, such as inammatory tissues and the phagolysosomes
sessing hydrodynamic diameters of about 20–30 nm, depending of antigen presenting cells.49 The groups of Haddleton and
on the actual polymers and cross-linkers used. These CCS Davis have developed50 stimuli-responsive biodegradable CCS
polymers possess chemoresponsiveness, as demonstrated by polymers (Fig. 12) which exploit the pH-responsiveness of
the addition of mono-diol which causes transesterication, ketals. The synthetic approach employed is highly modular, and
triggering disassembly of the star polymer into linear polymer disulde cross-linkers can be substituted for the ketal functions
chains. The assembly process can be re-initiated through the allowing CCS polymers which can alternatively exploit the
addition of further tris-diol, and the Sumerlin group have redox-responsiveness of the disulde linkage. RAFT polymeri-
shown that the assembly/disassembly process can be cycled zation techniques were employed to synthesise poly(OEGMA)
repeatedly at least six times, a remarkable feat when one (16), which forms the coronal arms of the CCS polymers. The
considers the build-up of diols in the reaction mixture. Because polymerization is then continued in the presence of dimetha-
of the diversity of 1,2- and 1,3-diols in nature, this work opens crylate monomer units to cross-link the growing polymer chains
up the possibility that polymeric nanoparticles whose disas- into CCS polymers. Two different cross-linkers have been
sembly can be triggered by the presence of biologically relevant employed containing either a disulde (17) or ketal (18) linkage,
species. One limitation of the current system is its lack of resulting in the formation two types of CCS polymer possessing
aqueous solubility at physiological pH, although this fact either redox- or pH-responsive degradability on account of
should not present a signicant hurdle and which when either disulde or ketal cross-links present within their cores.

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Fig. 12 The formation of core cross-linked star polymers through the incorporation of either acetal or disulfide containing dimethacrylate monomer units during
polymerization.50

These CCS polymers also possess dithiocarbonate functional- derivatives have been used to mediate polymerizations,
ities from the retention of the RAFT chain transfer agent, and furnishing polymers with narrow polydispersity indices and
aminolysis of these dithiocarbonate groups to thiol functions desired end-group functionality, and this particular class of
(19) permits post-formation functionalisation through either living radical polymerizations (LRP) has been named nitroxide-
disulde bond formation (20) or thiol–ene ‘click’ chemistry51 mediated polymerization (NMP).53
(21). This feature has been exploited to tag these CCS polymers The central C–O bonds within TEMPO-based alkoxyamine
with uorescent pyridyl disulde appendages. The disassembly derivatives behave as typical covalent bonds under ambient
of the ketal CCS polymers was found to be pH-sensitive, with conditions. Upon heating (Fig. 4f) this bond breaks homolyti-
complete disassembly occurring within 12 h and 1 h, at pH 5.0 cally and a styryl radical and a TEMPO-based radical are formed,
and 2.0 respectively. At pH 7.0 the CCS polymers were found to and different components can exchange via radical crossover
be stable for over 48 h. The disulde CCS polymers were shown processes. The early work of Otsuka and Takahara in this eld
to disassemble over 1 h in the presence of the reducing agent focused on preparing54 dynamic covalent polymers chains
tributyl phosphine. The work demonstrates that well-utilized incorporating thermally dynamic TEMPO-based alkoxyamines
“arm rst” CCS formation techniques can be evolved to intro- within the main chain. These TEMPO-containing monomer
duce dynamic covalent cross-links between the growing poly- units can readily dissociate upon heating and recombine to
mer chains, and that living radical polymerization techniques form polymer chains of varying lengths, demonstrating how
introduce the possibility of post-polymerization functionaliza- linear polymer chains can recongure their structural proper-
tion at specic sites as a consequence of CTA functionality ties at elevated temperatures through thermally exchangeable
retention. radical crossover reactions, which then become xed at ambient
Covalent bonds which can break at elevated temperatures conditions. Such thermally-responsive polymers could nd
but reform at ambient temperatures present particularly application in the eld of self-healing materials, and Otsuka
appealing possibilities when incorporated into polymeric and Takahara have recently reviewed the current progress and
materials. The groups of Otsuka and Takahara have exploited potential applications in the eld of dynamic covalent polymer
the thermally responsive nature of TEMPO-based alkoxyamine chains.14c
derivatives in the preparation of numerous thermally dynamic The group of Otsuka and Takahara have utilised the ther-
polymers and materials, including polymeric nanoparticles. moresponsive nature of TEMPO-based alkoxyamine derivatives
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) is a stable radical to prepare38 core cross-linked star (CCS) polymers (22, Fig. 13).
on account of the steric protection afforded by the four adjacent Linear diblock copolymer building blocks (23) which possess an
methyl groups, derivatives of which are oen referred to as a inert block comprised of methyl methacrylate, and a reactive
nitroxyl or nitroxide radicals.52 TEMPO-based alkoxyamine block which contains complimentary pendant alkoxyamine

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Fig. 13 Core cross-linked star polymer formation via a TEMPO-based thermally exchangeable radical crossover reaction between multiple linear copolymer building blocks.38
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derivatives, have been synthesised by atom-transfer radical groups within one of the blocks, and cross-linking is performed
polymerizations. These pendant functionalities within the by heating a solution of polymer at 50  C with a bis-maleimide
reactive block can undergo radical crossover reactions upon cross-linker. Heating a solution of star polymers to 120  C
thermal stimulation, which facilitates the cross-linking of causes almost complete dissociation of the star polymers back
multiple polymer chains into CCS polymeric nanoparticles, into linear polymer chains, and the group have demonstrated
whilst the inert block discourages macroscopic gelation. These the reversibility of this process by cycling the assembly disas-
CCS polymers become dynamic when heated and xed when sembly process four times. The group of Barthel and Rudolf
cooled, and this thermoresponsive nature can be used to trigger have also recently exploited62 the thermoreversibility of Diels–
disassembly upon the addition of a small molecule TEMPO- Alder adducts to prepare water-soluble core cross-linked
based alkoxyamine, which competes through a radical cross- micelles which can, at least in part, disassemble back into linear
over reaction above 110  C. The groups of Otsuka and Takahara polymer chains at elevated temperatures.
have also exploited this dynamic reaction to cross-link multiple
linear polymer chains into star-like nanogel assemblies,55
discrete spherical nanoparticles56 and macroscopically cross- Single-chain polymer nanoparticles
linked organo-57 and hydrogels.58
Another DCB which is useful in thermally-responsive poly- Single-chain polymer nanoparticles are formed from the intra-
meric materials is the Diels–Alder [4 + 2] cycloaddition reaction molecular cross-linking of a single polymer chain into a
between electron-rich dienes and electron-decient dien- collapsed well-dened nanoparticle whose sizes are typically in
eophiles (Fig. 4g). The Diels–Alder reaction of a substituted
furan with maleimide forms a Diels–Alder adduct at 80  C,
with the reverse reaction being favoured at higher temperatures
of 150  C. This reversibility was exploited in spectacular
fashion by the Wudl group to prepare59 so-called thermally-
mendable polymers, which consist of a macromolecular
network formed by cross-linking monomer units through
thermally-reversible Diels–Alder reactions. Fractures to this
material are likely to involve cleavage of the weakest covalent
bonds in the network, namely the Diels–Alder adducts. Frac-
tures can be mended simply by application of a heating/cooling
cycle, which causes the Diels–Alder bonds to reform. This
landmark work has inspired much effort in the eld of mend-
able polymers utilizing both reversible covalent bonds and non-
covalent bonds, and the reader is advised to consult the review60
of Colquhoun and Hayes to learn more. Only recently, however,
have researchers begun to look at utilizing thermally reversible
Diels–Alder chemistry in the preparation of responsive poly-
meric nanoparticles. In a particularly elegant study,61 the group
Fig. 14 Single chain polymer nanoparticles are formed through the intra-
of Sumerlin have used Diels–Alder chemistry to cross-link molecular cross-linking of polymer chains with a diimine cross-linker. Because of
diblock copolymers into thermally responsive core cross-linked the disulfide bond present within the cross-linker, the nanoparticles are redox
star polymers. The diblock copolymers possess appended furan responsive and can be reversibly switched to linear polymer chains.65

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the range of 5–20 nm. Such particles are of interest because of relatively under-exploited within polymeric nanoparticles, and
their small sizes and their intramolecular cross-links, which are chemists should think more creatively about how this particular
reminiscent of those found in natural biopolymers, in partic- feature of DCBs can be exploited. Natural macromolecules are
ular proteins. As such they have been proposed by some groups constantly reshuffling and changing their components, result-
as holding potential as synthetic mimics of the protein folding. ing in a change of function. For instance, proteins can change
Much of the work63 to date in the eld of single-chain polymer their function depending on their glycosylation patterns.66
nanoparticles has involved the application of either kinetically- DCBs can be utilized to mimic such features, allowing polymer
xed covalent cross-links, or non-covalent supramolecular nanoparticles to also change their components and thus their
interactions such as hydrogen bonding. The dynamic nature of function, but we need to be more imaginative in our exploita-
DCBs potentially allows single-chain polymer nanoparticles to tion of this possibility.
possess the chemical robustness of covalent bonds whilst being Our own beliefs are that the future direction of this eld
able to benet from the dynamic properties of non-covalent will be along multiple, but certainly not mutually exclusive
bonds. To this end we have developed64 a single chain polymer directions. We believe that future work has to become more
nanoparticle where a linear polymer chain is intramolecularly applications driven, taking the proof-of-principle knowledge
cross-linked through dynamic covalent acyl hydrazone bonds. gained so-far and exploiting it to develop stimuli-responsive
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We used a linear styrenic copolymer displaying aromatic alde- nanoparticles tailored for particular applications. For example,
hyde functions, which was cross-linked with small molecule many responsive polymeric nanoparticles are described as
dihydrazides to form the single chain polymer nanoparticle, having “potential” in drug delivery, but to make a real impact
and shown how exchange reactions could be used to drive the in this eld one must tailor a system to deliver a specic drug
cross-linking reaction. We believe that such dynamic covalent to a specic tissue/cell type, working in collaboration with
single-chain polymer nanoparticles which possess adaptable pharmacologists and other experts to overcome the many
structures may possess the abilities to be ‘molded’ around signicant challenges which must be addressed to develop
template molecules, and are further investigating this systems possessing high in vivo efficacy. Researchers should
possibility. also consider more seriously the development of polymer
The group of Berda have described65 how the redox-respon- nanoparticles which respond to other less explored stimuli
siveness of the disulde bond can be used to trigger the such as pressure, electrical or near-infrared, which would also
‘folding’ and ‘unfolding’ of polymer chains. This system is drive the eld onwards and open-up new possibilities in terms
based upon (Fig. 14) a linear copolymer (24) prepared by ring- of possible applications. DCBs may only play a part in more
opening olen metathesis polymerization, which is intramo- sophisticated nanoparticles, and it is likely that DCBs will
lecularly cross-linked through reaction with the difunctional enhance or work in synergy with the ‘conventional’ stimuli-
cross-linker (25) which features a premade disulde linkage. responsive polymers to provide nanoparticles whose respon-
The ‘unfolding’ of the single-chain polymer nanoparticle can be sive natures are more than the sum of their parts. The
triggered by reductive cleavage of the disulde cross-links with application of combinations of orthogonal DCBs is another
dithiothreitol, and this process can be followed by GPC. The way in which the levels of sophistication will likely be
‘folding’ of the linear polymer chain (26) back into the single- increased.
chain polymer nanoparticle can be triggered by oxidation with Many of the polymeric nanoparticles described here are
FeCl3. The group hope to expand the scope of this work, and by constructed from aggregates of polymer chains. This approach
utilizing multiple orthogonal interactions they aim to be able to allows the exploitation of the spectacular advances in poly-
program precisely the conformations of single polymer chains. merization methodologies, in particular living radical poly-
merizations, to prepare high-precision polymer building blocks
Conclusions for the construction of polymer nanoparticles. It must be
remembered, however, that emulsion polymerization methods
The examples covered in this review suggest strongly that DCBs are still by far the industrially most important way to make
can be used to impart stimuli-responsive features into poly- polymeric nanoparticles, and chemists should think further on
meric nanoparticles, and provide an additional and developing how DCBs can be incorporated into these important classes of
palette of responses which expands that already presented by nanoparticles. In this regard, a promising example reported67 by
‘conventional’ stimuli-responsive polymers. Much of the work the groups of Colson and Grinstaff are the so-called “expansive”
to date has focused on the pH-responsiveness of imine or acetal nanoparticles, which are prepared using miniemulsion tech-
bonds, or the redox responsiveness of the disulde bond, but niques. These nanoparticles contain pH-sensitive acetal link-
research groups are increasingly utilizing other less-explored ages, which when cleaved cause the nanoparticle to switch from
DCBs such as boronic esters or TEMPO-based alkoxyamines. hydrophobic to a hydrophilic hydrogel. As water enters this
Much is known about some DCBs with regards to the nanoparticle, it undergoes a several hundred-fold increase in
application of changes in their environments e.g. how the size and releases encapsulated drug. This class of nanoparticle
position of the imine equilbria changes with pH, and other less- possesses considerable potential in drug delivery, and Colson
explored DCBs would benet from in-depth studies to shed and Grinstaff have written an excellent review article68 which the
further light on how their equlibria change upon application of reader is advised to consult to learn more about this unique
a stimulus. The component exchange features of DCBs are also class of responsive nanoparticles.

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With sufficient imagination, creativity and tenacity, it is the C. S. Joiner and J. F. Stoddart, Chem. Soc. Rev., 2007, 36,
opinion of these authors that new responsive polymeric nano- 1705–1723; (c) M. E. Belowich and J. F. Stoddart, Chem.
particles will be developed which will go on to make big impacts Soc. Rev., 2012, 41, 2003–2024.
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