Triply-responsive boronic acid block copolymers: Solution self-assembly induced by changes in temperature, pH, or sugar concentration

Article abstract of DOI:10.1039/b900374f

Boronic acid-containing block copolymers capable of solution self-assembly into micelles and reverse micelles in response to changes in temperature, pH, and sugar concentration were prepared by reversible addition-fragmentation chain transfer (RAFT) polym

Full text of DOI:10.1039/b900374f

Showcasing research from Professor Brent Sumerlin’s
laboratory, Southern Methodist University, USA.
As featured in:
Title: Triply-responsive boronic acid block copolymers
Chemical Communications
www.rsc.org/chemcomm
Number 16 | 28 April 2009 | Pages 2053–2224
By including polymer segments that are sensitive to three different
stimuli, “schizophrenic”, triply-responsive block copolymers were
obtained. RAFT copolymerization with a boronic acid containing
monomer led to block copolymers capable of forming both
micelles and reverse micelles, with the self-assembly being
governed by the temperature, pH, and sugar concentration of the
local environment.
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Triply-responsive boronic acid block copolymers: solution self-assembly
induced by changes in temperature, pH, or sugar concentrationw
Debashish Roy, Jennifer N. Cambre and Brent S. Sumerlin*
Received (in Cambridge, UK) 8th January 2009, Accepted 10th February 2009
First published as an Advance Article on the web 26th February 2009
DOI: 10.1039/b900374f
Boronic acid-containing block copolymers capable of solution
self-assembly into micelles and reverse micelles in response to
changes in temperature, pH, and sugar concentration were
prepared by reversible addition–fragmentation chain transfer
(RAFT) polymerization.
monomers or silylated precursors that were borylated through
postpolymerization modification.10 We demonstrated the
polymerization of a styrenic boronic ester via RAFT polymer-
ization and subsequent postpolymerization deprotection to
yield well-defined boronic acid homo- and block copolymers.11
Subsequently, we reported a more straight-forward route to
block copolymers via direct RAFT polymerization of un-
protected boronic acid acrylamido monomers.12 Because of
the well-known ability of boronic acids to undergo a reduction
in pKa upon esterification with diols (e.g., glucose), these block
copolymers proved to be sugar-responsive, with micellar
aggregates undergoing dissociation in aqueous media when
exposed to glucose.
Stimuli-responsive or ‘‘smart’’ block copolymers offer promise
in drug delivery and medicine because of their ability to
undergo self-assembly or dissolution in response to variations
in the local environment. Upon the application of an appro-
priate stimulus, the responsive nature of the block copolymer
often leads to selective segmental dehydration and solution
self-assembly into micelles, vesicles, etc.1 The most common
examples of this type are block copolymers2 in which one
block is hydrophilic and the other stimuli-responsive, giving
rise to a copolymer that can be tuned such that it is either
double-hydrophilic or amphiphilic, depending on the presence
or absence of the stimulus.
Herein, we report the RAFT block copolymerization of a
boronic acid acrylamido monomer with N-isopropylacryl-
amide (NIPAM) and describe the preliminary solution
characterization of the resulting block copolymers. RAFT
polymerization was selected due to its tolerance of a wide
range of functional groups and its proven success for
the synthesis of well-defined, water-soluble acrylamido
polymers.14 Combining the thermoresponsive nature of
PNIPAM with the pH- and diol-responsive solubility of
polymeric boronic acids leads to triply-responsive block
copolymers capable of forming micelles or reverse micelles
depending on the environmental conditions.
Alternatively, another class of adaptive diblock copolymers
can be envisioned in which each of the two blocks respond to a
different stimulus. Such block copolymers self-assemble into
either micelles or reverse micelles, depending on which of the
blocks is rendered hydrophobic. Armes and co-workers coined
the term ‘‘schizophrenic’’ to describe these systems and
pioneered much of the original research regarding their
doubly-responsive behavior.3 Various double-hydrophilic or
zwitterionic block copolymers based on thermoresponsive4
and pH-responsive4,5 blocks have been used to study doubly-
responsive micellization behavior in aqueous media.
3-Acrylamidophenylboronic acid (APBA, 1) was polymer-
ized by RAFT at 70 1C with 2-dodecylsulfanylthiocarbonyl-
sulfanyl-2-methylpropionic acid15 (2) as the chain transfer
agent (CTA) and 2,20-azobis(isobutyronitrile) (AIBN) as the
initiator with [APBA] : [2] : [AIBN] = 100 : 1 : 0.1 (Scheme 1).
The polymerization was conducted in 95% DMF–5% water to
prevent crosslinking via boroxine anhydride formation. The
RAFT polymerization of APBA was well controlled, as
demonstrated by the pseudo-first-order kinetics and linear
evolution of Mn with conversion shown in Fig. 1. Importantly,
Boronic acid-containing macromolecules are a unique class
of stimuli-responsive polymers with potential applications as
self-healing materials, therapeutic agents, self-regulated drug-
delivery systems, and sensors for sugars and glycoproteins.6–8
Boronic acid-containing (co)polymers have primarily been
synthesized via conventional radical polymerization, which
typically results in ill-defined (co)polymers or crosslinked gels.
On the other hand, controlled radical polymerization (CRP)9
provides access to well-defined boronic acid (co)polymers,
either by atom transfer radical polymerization (ATRP)7,10 or
reversible addition–fragmentation chain transfer (RAFT)
polymerization.11–13 Jakle et al. reported the synthesis of
¨
boron-containing (co)polymers via ATRP of organoboron
Department of Chemistry, Southern Methodist University,
3215 Daniel Avenue, Dallas, TX, 75275-0314, USA.
E-mail: bsumerlin@smu.edu; Fax: +1 214 768 4089;
Tel: +1 214 768 8802
w Electronic supplementary information (ESI) available: Experimental
procedures and selected H NMR spectra and SEC traces. See DOI:
10.1039/b900374f
Scheme
1 Synthesis of poly(3-acrylamidophenylboronic acid)
(PAPBA) and PAPBA-b-poly(N-isopropylacrylamide) (PAPBA-b-
PNIPAM) via RAFT.
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This journal is The Royal Society of Chemistry 2009
2106 | Chem. Commun., 2009, 2106–2108

Fig. 1 (A) Pseudo first-order kinetic plot with selected molar ratios of
monomer (APBA)–chain transfer agent (CTA)–initiator (AIBN) and
(B) Mn versus monomer conversion ([APBA]–[CTA]–[AIBN]
=
100 : 1 : 0.1) for RAFT homopolymerizations of 3-acrylamidophenyl-
boronic acid (APBA, 1) at 70 1C in 95% DMF–5% water.
while the boronic acid monomer could be polymerized directly
by RAFT, molecular weight analysis by size exclusion chromato-
graphy (SEC) via the triple detection method required
conversion of the boronic acid groups to pinacolato boronic
esters by reacting with pinacol.12
Fig. 2 (A) Block copolymer self-assembly–dissociation in response to
changes in pH or temperature. (B) Hydrodynamic size distributions of
poly(3-acrylamidophenylboronic acid)-b-poly(N-isopropylacrylamide)
(PAPBA-b-PNIPAM) at 25 1C and pH 11, at 50 1C and pH 11, at
25 1C and pH 8.7, and at 25 1C and pH 8.7 in the presence of 135 mM
glucose. (C) Turbidimetry results at l = 600 nm for the determination
of lower critical solution temperature for PAPBA-b-PNIPAM.
The resulting APBA homopolymer (3) was used as a
macroCTA for block copolymerization with N-isopropylacryl-
amide (NIPAM, 4) ([NIPAM] : [3] : [AIBN] = 100 : 1 : 0.2;
70 1C; 95% DMF–5% water. While slight low molecular
weight tailing was observed in the SEC, likely due to either
the presence of a small amount of dead chain ends in the
macroCTA or inefficient pinacol protection prior to analysis,
copolymerization with NIPAM resulted in an increase in Mn
concentration of diol. The combination of these three stimuli
should lead to a copolymer with a PNIPAM block that is
sensitive to changes in temperature and a PAPBA block that
is sensitive to changes in either pH or diol concentration.
Therefore, it was anticipated that heating a solution of mole-
cularly dissolved unimers above the LCST of the PNIPAM
block would lead to micelles with PAPBA coronas and
PNIPAM cores. On the other hand, lowering the pH of a
solution of PAPBA–b-PNIPAM molecularly dissolved
unimers below the pKa of the boronic acid block should lead
to dehydration of the organoboron segment and subsequent
self-assembly to form micelles with a hydrophilic PNIPAM
corona and a hydrophobic PAPBA core. These aggregates
should be capable of dissociation to unimers when exposed to
either an increase in pH or the addition of low molecular
weight diol.
from 15 800
g
molꢁ1 for the PAPBA macroCTA to
28 100 g molꢁ1 (Mn,theory = 26 000 g molꢁ1) and a low
polydispersity index of 1.15 for PAPBA-b-poly(N-isopropyl-
acrylamide) (PAPBA81-b-PNIPAM109). 1H NMR spectro-
scopy of the block copolymer confirmed the presence of
the peaks associated with each segment. Block copolymer
compositions calculated with data from both 1H NMR and
SEC were in reasonable agreement (ESIw).
The PAPBA-b-PNIPAM block copolymers were expected
to be triply-responsive and to self-assemble in response to
changes in temperature, pH, and diol concentration (Fig. 2A).
PNIPAM was expected to impart thermoresponsive behavior.
It is well known that PNIPAM exhibits a sharp phase transi-
tion around 32 1C. Below this lower critical solution tempera-
ture (LCST), the polymer exists as molecularly dissolved
unimers, but heating leads to dehydration and interchain
aggregation. Boronic acid-containing (co)polymers are
uniquely stimuli-responsive because their water solubility is
dictated by pH and solution diol concentration, the latter of
which has led to boronic acids being employed as saccharide
receptors.8 The PAPBA block should be hydrophilic at high
pH and hydrophobic under acidic conditions.
Solutions of PAPBA–b-PNIPAM at 25 1C and pH E 11
yielded unimers with an approximate hydrodynamic diameter
(Dh) of 8 nm, as determined by DLS, which is consistent with
both blocks being water soluble. Upon lowering the solution
pH to 8.7, below the pKa of the PABPA units (pKa E 9),
aggregates of approximately 55 nm were observed (Fig. 2B).
Returning the solution to pH E 11 by adding NaOH resulted
in dissociation of the aggregates back to unimers. Similarly,
the diol-responsive nature of the block copolymers was
investigated by DLS. Addition of glucose to a solution of
PAPBA-b-PNIPAM at pH 8.7 and 25 1C also caused aggre-
gate dissociation to unimers of approximately 7 nm (Fig. 2B).
The temperature-responsive nature of the PAPBA-b-
PNIPAM block copolymers was investigated by turbidimetry,
DLS, and NMR spectroscopy. Because the LCST of PNIPAM
can be affected by the nature of adjacent comonomers or block
segments, it was necessary to determine the critical aggrega-
tion temperature of the PNIPAM block in the PAPBA81-b-
PNIPAM109 block copolymer. Turbidimetry measurements
revealed a rather broad transition around 42 1C (Fig. 2C).
Above the pKa of the boronic acid, PAPBA exists as a
boronate polyanion; acidification to pH o pKa should result
in the boronate moieties being converted to neutral/hydro-
phobic boronic acid groups and subsequent chain dehydra-
tion. The diol-responsive nature of PAPBA arises from its
ability to reversibly form cyclic boronate esters with 1,2- and
1,3-diols, which effectively lowers the pKa of the boronic acid.
The net result of this process leads to neutral/hydrophobic
boronic acid polymers at pH o pKa and anionic/hydrophilic
boronate ester polymers in the presence of a sufficient
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Chem. Commun., 2009, 2106–2108 | 2107

pH, and the concentration of a model diol. The ready
availability of boronic acids with a range of easily tuned pKa
values indicate this general method can be used to prepare a
wide variety of novel triply-responsive block copolymers.
This material is based upon work supported by the National
Science Foundation under grant no. DMR-0846792. Any
opinions, findings, and conclusions or recommendations
expressed in this material are those of the authors and do
not necessarily reflect the views of the National Science
Foundation. Acknowledgement is made to the donors of the
American Chemical Society Petroleum Research Fund
(45286-G7). We thank Dr Sudershan R. Gondi for
synthesizing DMP.
Notes and references
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2108 | Chem. Commun., 2009, 2106–2108