Siderophore-inspired nanoparticle-based biosensor for the selective detection of Fe3+

Article abstract of DOI:10.1039/c4tb01501k

Inspired by nature's exploitation of the 1,2-dihydroxybenzene unit (or catechol) in mammalian and bacterial siderophores, we report the first example of a nanoparticle sensing system that utilises the strong catechol-Fe³⁺ binding motif to trigger nanoparticle aggregation, promoting a powerful optical response. Gold nanoparticles are functionalised with RAFT polymerisation-prepared water-soluble poly(N-hydroxyethyl acrylamide) containing a catechol moiety at the α-chain-end. A strong red-to-purple colorimetric response occurs in the presence of Fe³⁺ at serum concentrations (8-25 μM) in saline solution. Sodium chloride is critical in generating a strong optical output, as is the length of polymer used to coat the AuNPs. This behaviour is also demonstrated to be selective for Fe³⁺ over a host of other biologically relevant ions.

Full text of DOI:10.1039/c4tb01501k

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Siderophore-inspired nanoparticle-based
biosensor for the selective detection of Fe3+†
Cite this: DOI: 10.1039/c4tb01501k
a
a
ab
*
Daniel J. Phillips, Gemma-Louise Davies and Matthew I. Gibson
Inspired by nature's exploitation of the 1,2-dihydroxybenzene unit (or catechol) in mammalian and bacterial
siderophores, we report the first example of a nanoparticle sensing system that utilises the strong catechol–
Fe3+ binding motif to trigger nanoparticle aggregation, promoting a powerful optical response. Gold
nanoparticles are functionalised with RAFT polymerisation-prepared water-soluble poly(N-hydroxyethyl
acrylamide) containing a catechol moiety at the a-chain-end. A strong red-to-purple colorimetric
response occurs in the presence of Fe3+ at serum concentrations (8–25 mM) in saline solution. Sodium
chloride is critical in generating a strong optical output, as is the length of polymer used to coat the
AuNPs. This behaviour is also demonstrated to be selective for Fe3+ over a host of other biologically
relevant ions.
Received 10th September 2014
Accepted 5th November 2014
DOI: 10.1039/c4tb01501k
www.rsc.org/MaterialsB
complexes that bind iron with an association constant in excess
of 1050 – allowing effective competition with the host for iron
sequestration.7,8
Introduction
Iron is the most abundant metal in the body with the average
adult requiring around 5 g, using it for a range of functions
including oxygen transport, electron transport and a variety of
metabolic processes.1 The in vivo concentration is however
carefully regulated to avoid serious health implications. For
example, a common anaemia is caused by insufficient dietary
intake and absorption of iron, whilst elevated iron concentra-
tions, such as those present in genetic disorders such as
hemochromatosis, can produce excess levels of Reactive Oxygen
Species via Fenton chemistry.2,3 Undesirable iron levels have
also been linked to a variety of diseases including Alzheimer's
and Parkinson's,4 making the effective detection of iron species
a critical area of study.
The ability to sequester iron in the human body is compli-
cated by the poor bioavailability of the ferric ion (Fe3+), which
predominates in aerobic conditions, exhibiting compounds
with poor aqueous solubility of approximately 10ꢀ18 M.5 To
overcome this, it is sequestered within the porphyrin ring of
heme and as a co-factor in haemoglobin and myoglobin, whilst
its passage into cells depends heavily on transport proteins
such as transferrin.6,7 Bacteria also require sufficient levels of
the metal to survive and grow, abstracting it from their
mammalian hosts with siderophores – low molecular weight
A large number of bacterial siderophores are known in
comparison to the single mammalian siderophore, siderocalin,6
which sequesters the bacterial siderophore–iron complex to
prevent bacterial uptake.9–11 The majority of these species are
divided into three groups: a-hydroxycarboxylates, hydroxamates
and catecholates. These functionalities have inspired the
development of a number of compounds such as deferoxamine,
deferiprone and deferasirox for use in iron chelation thera-
pies,12,13 and have provided a focus for investigations into the
use of siderophore-mimics as pharmaceutical and antibiotic
drug targeting devices.14,15
The development of sensors capable of detecting a variety of
metal ions is a popular eld of research.16,17 A variety of detec-
tion platforms/responses can be used, including proteins and
DNA,18,19 eld-effect transistor devices,20–22 photonic crystals,23
metal electrodes,24,25 plasmonic resonance energy transfer-
based nanospectroscopy26 and graphene oxide,27 whilst the
ability to trigger a uorescent response upon metal ion binding
has received signicant study.28,29 A particularly attractive plat-
form is that of gold nanoparticles (AuNPs) due to their facile
preparation, control over size, ease of surface functionalisation
through simple coating strategies and, most importantly for
sensing applications, their varying optical properties.30–32
Specically, the extent of nanoparticle dispersion/aggregation
has a signicant effect on the nanoparticle colour due to shis
in surface plasmon resonance (SPR). This signature has been
applied for the detection of a variety of metal ions including
lithium,33 mercury,34,35 potassium,36 aluminium,37 lead38 and
chromium.39 However, there are few instances of the applica-
tion of AuNPs capable of detecting iron that have been reported.
aDepartment of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4
7AL, UK. E-mail: m.i.gibson@warwick.ac.uk; Fax: +44 (0)2476524112; Tel: +44 (0)
2476524803
bWarwick Medical School, University of Warwick, Gibbet Hill Raod, Coventry, CV4
7AL, UK
† Electronic supplementary information (ESI) available: Experimental details,
additional small molecule, polymer and gold nanoparticle characterisation;
additional data as described in main text. See DOI: 10.1039/c4tb01501k
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Bai et al. functionalised gold nanoparticles with a hydrophilic reacted with a slight excess of dopamine hydrochloride
ligand, to ensure water solubility, and a 4-piperazinyl-1,8-nap- (Dop$HCl), in the presence of triethylamine (TEA), to furnish
thalimide-based ligand which was able to complex with Fe3+
,
3 in good yield (Scheme 1). Importantly, the product could be
generating a colorimetric and uorescent output.40 Mehta et al. isolated by precipitation in hexane, negating the need for
have used p-amino salicylic acid dithiocarbamate functional- column chromatography which may be complicated by
ised gold nanoparticles as colorimetric probes for the detection the presence of an unprotected catechol unit. Moreover, no
of Fe3+ in both aqueous and urine samples.41 Tripathy et al. have by-product generated by aminolysis of the trithiocarbonate53,54
prepared a colorimetric detection system based on gold, where was observed, as conrmed 1H, 13C NMR, FTIR and HRMS
the addition of Fe3+ in the presence of thiourea and hydro- (Fig. S1–S3, ESI†).
chloric acid catalyses leaching of the gold, damping the SPR and
hence resulting in a visible colour change.42 Wu et al. have
Catechol-functional Au nanoparticles
functionalised gold nanoparticles with pyrophosphate which
underwent a pink-to-violet change in the presence of Fe3+
,
To effectively furnish catechol-functional gold nanoparticles, a
showing excellent selectivity for Fe3+ over a host of other ions.43
Inspired by the structure and action of siderophores, we
hypothesised that the binding between catechols, the key
functional group in siderophores synthesised mainly by
bacteria,44 and Fe3+ may be sufficient to affect the aggregation
behaviour of a gold nanoparticle suspension in order to
generate an optical response. To date, catechol groups have
been used in the formulation of nanoparticles as a way of sta-
bilising the metallic cores, but not as a means of preparing
nanoparticles whereby the catechol unit is available to undergo
further chemistry. For instance, their use in stabilising iron
oxide nanoparticles is obvious given the affinity between the
two.45 Catechol groups have been graed onto mesoporous
silica nanoparticles46 and have also been used as a stabiliser in
the synthesis of gold nanoparticles from their parent Au(III) salt
due to the redox chemistry involved in the interchange of
catechol to quinone species.47–49 To the best of our knowledge
however, there are few examples whereby (gold) nanoparticles
have been prepared with a catechol group protruding from the
particle surface, allowing active use.50
Developments in controlled radical polymerisation (CRP)
methodologies over the past two decades have enabled the
routine generation of vast arrays of polymeric architectures with
high levels of control over functionality, chain-end structure
and topology. Moreover, polymers derived from the Reversible
Addition-Fragmentation Chain Transfer (RAFT) methodology51
are ideally suited for further reaction with gold nanoparticles
given the inherent affinity between gold and the thiol groups
derived from the u-end of the preceding polymer chains.32
Herein, inspired by the structure and biological importance of
siderophores, we detail the rst example of a gold nanoparticle
system capable of sensing physiologically relevant Fe3+
concentration through the powerful catechol–Fe3+ binding
motif.
water-soluble polymer was rst required. Hence, N-hydroxyethyl
acrylamide (HEA) was polymerised using CTA 3 and 4,40-azo-
bis(4-cyanovaleric acid), ACVA, as thermal initiator. This poly-
mer was also deliberately chosen as it does not possess thermo-
responsive behaviour and hence removes any potential
complication of particle aggregation behaviour given the tran-
sition temperature of thermo-responsive polymers is known to
change when tethered to gold nanoparticles.55 The polymeri-
sation conditions used afforded rapid polymerisation rates
(at least 75% conversion aer 35 minutes) and polymers with a
range of molecular weights were prepared and characterised by
1
SEC and H NMR (Table 1, Fig. S4, ESI†). Narrow dispersities
(#1.20) were observed, an attractive feature of the RAFT
technique.
Nanoparticles can be routinely synthesised from Au3+ salts
and are ideally suited for RAFT-derived polymers given the
strong affinity between thiols, which are derived from the
u-trithiocarbonate terminus, and gold. This can be used to
prepare self-assembled monolayers and has been previously
exploited to generate large nanoparticle libraries.56 Commer-
cially-available citrate-stabilised nanoparticles with a diameter
of 40 nm (AuNP40) were used as a starting material and coated
with the polymers by a simple mixing procedure, washing
several times by centrifugation to remove excess polymer, to
yield pHEA-1/2/3@AuNP40 (Scheme 1).
Successful functionalisation of the nanoparticles was
conrmed by several techniques. UV-visible spectrophotometry
revealed a distinctive blue shi in maximum wavelength from
525 nm for the uncoated particles to between 531–534 nm
following polymer addition, implicit of a change in the
Results and discussion
Catechol-functional polymers
To prepare catechol-functional polymers, a new chain-transfer
agent (CTA) was synthesised based on an adaptation of the
method described by Zobrist et al.52 First, the carboxylic acid-
terminated trithiocarbonate 1 was activated using standard
coupling chemistry (N-hydroxysuccinimide (NHS)/N,N0-diiso-
Scheme 1 Synthetic scheme for preparation of catechol-functional
gold nanoparticles (pHEA-1/2/3@AuNP40): (i) NHS/DIC, THF, 0 ꢁC /
r.t, 16 h; (ii) Dop$HCl/TEA, MeOH, r.t, 48 h; (iii) HEA, 3, ACVA, MeOH/
propylcarbodiimide (DIC)) to give compound 2. This was then toluene, 70 ꢁC, 35 min; (iv) polymer/AuNP, 5 ꢁC, 16 h.
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Table 1 Poly(N-hydroxyethyl acrylamide) samples prepared
solution at room temperature and the UV/visible spectrum
between 450 and 700 nm was measured (Fig. 1A). Notably, in the
presence of 10 mM Fe3+, a shi in SPRmax from 532 nm to
547 nm was observed, together with an increase in Abs@700 nm
from 0.288 to 0.602. Interestingly, minimal response was seen
in the presence of any other iron concentration (vide infra). It
was found that the absence of salt in the nanoparticle suspen-
sion resulted in a lack of detectable change in their optical
properties (Fig. 1B). This was not entirely unexpected, since the
modulation of ionic strength has been known to tune particle
aggregation via interparticle electrostatic repulsion.58,59
Conversiona Mn (th)
Polymer [M] : [CTA] (%)
Mn (SEC)
a
b
(g molꢀ1
)
(g molꢀ1
)
Mw/Mn
b
pHEA-1
pHEA-2
pHEA-3 200
30
75
83.1
78.5
74.7
74.1
2900
6800
17200
6400
4800
9700
17500
10200
1.14
1.17
1.20
1.16
pHEA-4
75
a
Determined by 1H NMR relative to an internal standard (mesitylene).
Determined by SEC (DMF inc. 5 mM NH4BF4) relative to PMMA
b
standards.
This ionic-concentration behaviour was further tuned by
xing the concentration of FeCl3$6H2O at 10 mM and varying the
concentration of NaCl in the AuNP suspensions up to saline
concentration (150 mM). Fig. 2A demonstrates a noticeable,
non-linear increase in both SPRmax and Abs@700 nm with
increasing levels of NaCl. This is likely due to an increased
screening of any negative charge on the particle surface caused
by residual citrate or the catecholate complex, allowing greater
interparticle interactions. The initial Fe3+ assay (Fig. 1) was thus
repeated in 150 mM NaCl (saline) and similar optical shis were
observed, but with amplied behaviour (SPRmax shied by
20 nm and Abs@700 nm by 0.412 compared to the absence of
salt) due to the ionic environment (Fig. 2B). As the optical
responses in 150 mM NaCl were signicantly larger, providing a
noticeable change in appearance (Fig. 2A inset), these condi-
tions were employed in the rest of the study. Particle stability
over time in 150 mM NaCl was conrmed by DLS (Fig. S7, ESI†).
Interestingly, a linear trend in SPRmax and Abs@700 nm with
increasing Fe3+ concentration is not observed. There is a
refractive index of the coating (Fig. S5A, ESI†). DLS analysis also
indicated an increase in particle size from 41.5 ꢂ 0.2 nm for the
uncoated particles to between 80 and 126 nm when polymer-
coated, with the size increasing as polymer length increases
(Table 2, Fig. S5, ESI†). TEM conrmed core particle sizes of
ꢃ40 nm (Table 2, Fig. S6, ESI†) with narrow size distributions in
all cases. Due to the low degrees of surface loading and low EM
contrast relative to gold, the surface polymer coating was not
clearly observed by this technique (Fig. S6, ESI†). Particle sizes
by DLS are larger for polymer-coated particles due to the pres-
ence of the hydrophilic polymer layer contributing to the
particles' hydrodynamic diameter as the functionalised parti-
cles undergo Brownian motion, as well as hydrogen bonding
and van der Waals interactions between neighbouring particles.
The larger particle sizes observed for pHEA-1/2@AuNP40 by DLS
may suggest a small degree of aggregation resulting during the
polymer coating process. However, given the lack of a signi-
cant colour change to either purple/blue (associated with large-
scale AuNP aggregation) or colourless (associated with AuNP
precipitation), these particles were still deemed sufficiently
dispersed for further testing.
Selective Fe3+ detection
These catechol-functionalised nanoparticles were then probed
for their ability to detect Fe3+ in aqueous solution. Two points of
reference are oen used to assess changes in the aggregation
behaviour of gold: (i) any change in maximum SPRmax, where
aggregation results in a shi to longer wavelengths and (ii) any
Fig. 1 Response of pHEA-2@AuNP40 in the presence of various
concentrations of Fe3+ and (A) 50 mM NaCl, (B) 0 M NaCl.
change in absorbance at 700 nm (Abs@700 nm), which may
57
also be accompanied by a decrease in intensity of SPRmax
.
PHEA-2@AuNP40 was incubated with varying concentrations
(100 mM–1 nM) of FeCl3$6H2O for 30 min in a 50 mM NaCl
Table 2 Characterisation of gold nanoparticles used
DLS diameter
(nm)
TEM diameter
(nm)
SPRmax
(nm)
Code
Fig. 2 (A) Change in SPRmax and Abs@700 nm of pHEA-2@AuNP40 in
the presence of 10 mM Fe3+ as a function of NaCl concentration. Inset
shows the appearance of pHEA-2@AuNP40 in the presence of 10 mM
Fe3+ and either 0 or 150 mM NaCl. (B) UV/visible spectra demon-
strating response of pHEA-2@AuNP40 in 150 mM NaCl to various
AuNP40 (uncoated)
pHEA-1@AuNP40
pHEA-2@AuNP40
pHEA-3@AuNP40
pHEA-4@AuNP40
41.5 ꢂ 0.2
126.0 ꢂ 2.6
113.7 ꢂ 3.2
79.5 ꢂ 0.4
59.6 ꢂ 3.5
36.2 ꢂ 3.8
38.0 ꢂ 4.4
39.0 ꢂ 4.1
38.2 ꢂ 2.8
37.5 ꢂ 4.0
525
534
532
531
530
concentrations of Fe3+
.
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noticeable increase with increasing Fe3+ concentration up to a
In a bid to further tune the selectivity of the nanoparticles to
concentration of 10 mM; however, further increases in concen- the presence of iron, the effect of polymer molecular weight on
tration led to a decreased optical response (Fig. 3A). The fact aggregation behaviour was investigated. AuNPs coated with a
that the same general trend is observed for both SPRmax and short polymer (molecular weight ꢃ3000 g molꢀ1; pHEA-
Abs@700 indicates the applicability of both measurements as a 1@AuNP40) showed poor saline stability, with aggregation and
tool for assessing the aggregation behaviour of AuNPs.
precipitation occurring within 30 minutes, even at low NaCl
Aggregation behaviour was conrmed by DLS analysis concentrations, and a colour change from red/pink to blue/
(Fig. 3B). A signicant increase in particle size was rst observed purple (Fig. 4A). This precipitation is most likely due to the
at 10 mM Fe3+, peaking at 25 mM Fe3+, before decreasing when shorter polymer chain failing to offer sufficient steric stabili-
the concentration reached 100 mM. This trend at Fe3+ concen- sation in the presence of the electrolyte.
trations greater than 100 mM is likely due to increased
Coating the particles with a longer polymer (molecular
Coulombic repulsions as a result of excess Fe3+ ions.40 The weight ꢃ17 000 g molꢀ1; pHEA-3@AuNP40) provided good
change in particle size and the change in Abs@700 nm with saline stability, however no aggregation occurred at any Fe3+
respect to iron concentration yielded very similar trends concentration (Fig. 4B). The importance of polymer linker
(Fig. 3B). This is indicative of aggregation due to catechol–Fe3+ length on AuNP-based detection systems has been demon-
binding rather than due to non-specic response of the polymer strated previously: Richards et al. demonstrated that glycosy-
chains.
lated AuNPs, designed for the detection of FimH positive
Several control studies were carried out to further conrm bacteria, required the addition of a poly(ethylene glycol) spacer
that the observed response was due to selective catechol–Fe3+ between the nanoparticle core and carbohydrate extremity in
binding. Incubation of pHEA-2@AuNP40 in 150 mM NaCl with order to increase saline stability and specicity for bacterial
FeCl2$4H2O resulted in no signicant change in either SPRmax binding.57
or Abs@700 nm. A slight increase in Abs@700 nm was observed
Finally, the Fe3+ specicity of the nanocomposites was
with increasing Fe2+ (difference of 0.076 with 100 mM Fe2+) investigated by carrying out a comparative assay with a range of
which may be due to reduced stability of these particles leading biologically relevant cations (Fig. 5). The optical response of our
to the beginnings of a “salting-out” type phenomenon (Fig. S8,
ESI†). The binding of catecholate-based siderophores to Fe2+ is
signicantly weaker than that of Fe3+ due to the reduced charge
density on the coordinated cation.8 This is important as one of
the main known mechanisms for the release of iron from
siderophores comprises the reduction of siderophore-bound
Fe3+ to Fe2+ followed by spontaneous release or competitive
sequestration of this reduced species.60
A polymer of similar molecular weight containing a phenyl
end-group was prepared as a negative control to directly
compare with the catechol end-group containing polymers
(pHEA-4, Table 1, Fig. S8, ESI†). AuNPs were functionalised with
pHEA-4 using the same coating technique (pHEA-4@AuNP40
,
Table 2) to yield particles with a diameter of 59.6 ꢂ 3.5 nm
(DLS). Incubation with Fe3+ revealed no response to any
concentration tested, proving that the catechol end-group is
necessary to promote cross-linking and hence optical respon-
sive behaviour (Fig. S8, ESI†). A summary of the incubation of
pHEA-2/4@AuNP40 with Fe2+ and Fe3+ is shown in Scheme 2.
Scheme 2 Gold nanoparticles functionalised with catechol or phenyl
end-groups and their response to Fe2+ and Fe3+. Dispersed and
aggregated particles have red and purple colours respectively, repre-
sentative of the optical absorbance changes observed experimentally.
Fig. 3 Response of pHEA-2@AuNP40 in 150 mM NaCl to various Fig. 4 (A) UV/visible spectra showing response of pHEA-1@AuNP40 to
concentrations of Fe3+
(A) SPRmax and Abs@700 nm and (B) NaCl (inset: appearance at 0 and 150 mM NaCl); (B) UV/visible spectra
:
comparison of Abs@700 nm (UV/vis) and particle size (DLS) as a showing response of pHEA-3@AuNP40 to various concentrations
function of Fe3+ concentration.
of Fe3+
.
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concentrations of NaCl, whilst long chains failed to generate
any noticeable response due to increased steric stability. Finally,
the nature and specicity of the aggregation behavior was
shown, notably giving between a 5- and 10-fold higher response
to Fe3+ than other biologically relevant cations tested.
Our system exhibits an optimal optical response between
8–25 mM Fe3+, offering valuable sensing potential as serum iron
concentration is also in this range.61 Ongoing work is focused
on tailoring the nanoparticle surface/surrounding environment
to promote a response to a wider range of Fe3+ concentrations
for use as a sensor in both deprived and iron-rich conditions.
Furthermore, the sensitivity of the catechol moiety to solution
pH, where differing degrees of complexation (mono, bis and
tris-catecholate species) are known62 is being pursued with a
view to even greater system tuning. Finally, the application of
this nano-bio sensory system in more complex biological media
is also ongoing.
Fig. 5 Response of pHEA-2@AuNP40, doped with 150 mM NaCl, to a
variety of metal cations.
optimised nanoparticulate system, as assessed by the change in
Abs@700 nm, was over 10-fold stronger in the presence of Fe3+
than the majority of ions tested. Some binding and optical
changes were observed in the presence of Fe2+, which is likely
due to the partial oxidation to Fe3+ over the duration of the assay
test. A minimal response was observed in the presence of Gd3+
,
Acknowledgements
another tribasic metal ion, further highlighting the specicity of
Equipment used was supported by the Innovative Uses for
Advanced Materials in the Modern World (AM2), with support
from Advantage West Midlands (AWM) and part funded by the
European Regional Development Fund (ERDF). MIG is a Bir-
mingham Science City Interdisciplinary Research Fellow fun-
a catechol unit to Fe3+.
Conclusions
Inspired by nature's need for iron acquisition, this study pres- ded by the Higher Education Funding Council for England
ents the rst example using the strong catechol–Fe3+ binding (HEFCE). DJP thanks the University of Warwick for a scholar-
motif as a route to manipulating the dispersion/aggregation ship. GLD acknowledges the Institute for Advanced Study
behaviour of gold nanoparticles as optical sensing devices. A (Warwick) for a Global Research Fellowship, the Royal Society,
small library of water-soluble poly(N-hydroxyethyl acrylamide) the Medical and Life Sciences Research Fund (Warwick) and the
was prepared using an a-chain end, catechol-functional chain General Charities of the City of Coventry for Bursaries sup-
transfer agent. These polymers were subsequently used to coat porting this research.
commercially-available 40 nm gold nanoparticles and charac-
terised by a range of techniques. The propensity for catechol–
Notes and references
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trophotometry and DLS-based assays. The addition of salt was
observed to be critical in the observation of particle aggregation,
due to successful shielding of residual negative charge on the
AuNP surface. The response was dependent on the amount of
salt used in a non-linear fashion, with physiologically-relevant
saline conditions (150 mM NaCl) providing the best response in
terms of both optical SPRmax band shiing and the observed
Abs@700 nm.
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