Surface-Enhanced Raman Scattering
Au@pNIPAM Colloids as Molecular Traps for Surface-Enhanced,
Spectroscopic, Ultra-Sensitive Analysis**
Ramon A. ?lvarez-Puebla,* Rafael Contreras-C?ceres, Isabel Pastoriza-Santos,
Jorge P?rez-Juste, and Luis M. Liz-Marz?n*
Surface-enhanced Raman scattering (SERS) is a powerful
analytical technique that allows ultra-sensitive chemical or
biochemical analysis.Since the first reported SERS on silver
and gold colloids in 1979,they have become one of the most
commonly used nanostructures for SERS, both as a testing
ground for the most thorough theoretical modeling, and for
the achievement of single-molecule detection (SMD).
Analytical applications based on average SERS are mature,
and current work is focused on specific tuning of the
experimental conditions for each particular analyte. For
example, the enhancement factors (EF) reported for organic
acids and alcohols are several orders of magnitude lower than
those achieved for thiols and amines. The main reason for this
situation is the different affinity of the functional groups in
the analyte toward colloidal gold or silver surfaces, and it is
the affinity which determines the analytes retention.To
circumvent this problem, various approaches have been
proposed, including the functionalization of silver nano-
particles with different surface functional groups (e.g. calix-
arenes, viologen derivatives),so as to increase their
compatibility with polycyclic aromatic compounds. A prob-
lem inherent to this alternative is that usually the assembled
molecules provide strong SERS signals that overlap and
screen those corresponding to the analyte. Another alterna-
tive relies on controlling the surface charge of the nano-
particles to promote the electrostatic attraction of the analyte
onto the particle surface.This approach has been reported
to consistently enhance the signal for acids and amines, but it
hardly helps in the case of alcohols, ethers, and other oxygen-
containing groups, as well as for non-functionalized mole-
cules. Therefore, there is a clear need for development of
colloidal systems containing a noble-metal component
together with a material that can trap a wide variety of
Herein we present the application of a recently developed
core–shell colloidal materialcomprising gold nanoparticles
coated with a thermally responsive poly-(N-isopropylacryla-
mide) (pNIPAM) microgel, which we denote Au@pNIPAM.
While the gold cores provide the necessary enhancing
properties, the pNIPAM shells can swell or collapse as a
function of temperature, this change is expected to serve as a
means to trap molecules and get them sufficiently close to the
metal core for providing the SERS signal. Although similar
systems have been proposed for applications in catalysis,
temperature and pH sensing,or light-responsive materi-
als,we propose that our particular configuration, with
sufficiently big metal cores, can function as a general sensor
for detection of all types of analytes. Apart from the SERS
enhancement, this system can also be used to modulate the
fluorescence intensity of adsorbed chromophores as a func-
tion of temperature. It is important to note that, the porous,
protective pNIPAM shell not only enhances the long-term
colloidal stability of the system in aqueous solutions, but
additionally prevents electromagnetic coupling between
metal particles, thus providing highly reproducible SERS
signal and intensity, which is crucial for quantitative applica-
tions. Through a rational choice of model analytes, we
demonstrate the application of these thermoresponsive
hybrid materials for surface-enhanced Raman scattering,
fluorescence, and resonance Raman scattering (SERS, SEF,
and SERRS, respectively). This demonstration includes the
first report of the SERS spectrum of 1-naphthol, which had
remained elusive to SERS ultra-sensitive analysis until now.
1-Naphthol is a relevant biomarker for quantifying the
exposure to polycyclic aromatic hydrocarbons in urine,as
well as the presence of carbaryl pesticides in the environment
and in fruits.Additionally, chronic exposure of humans to
1-naphthol has been reported to result in genotoxicity.
The synthesis of the core–shell Au@pNIPAM colloids has
been described in detail elsewhereand involves initial
growth of a thin polystyrene (PS) shell on cetyl trimethyl
ammonium bromide (CTAB) coated, 67 nm gold nanoparti-
cles, followed by polymerization of N-isopropylacrylamide
(NIPAM) and a cross-linker (N,N-methylenebisacrylamide;
see Experimental Section for details). NIPAM monomers are
polymerized in situ on the Au@PS surfaces using 2,2’-
azobis(2-methylpropionamidine) dihydrochloride (AAPH)
as an initiator (Scheme 1a and Figure 1a). Particles with
larger metal cores (116 nm) were prepared by seeded growth
of the coated gold cores through addition of HAuCl4and
ascorbic acid (Figure 1b). The SERS spectrum of Au@PS
[*] Dr. R. A. ?lvarez-Puebla, Dr. I. Pastoriza-Santos, Dr. J. P?rez-Juste,
Prof. L. M. Liz-Marz?n
Departamento de Qu?mica-F?sica and Unidad Asociada CSIC-
Universidade de Vigo, 36310 Vigo (Spain)
Departamento de F?sica Aplicada
Universidad de Almer?a, Almer?a (Spain)
[**] This work has been funded by the Spanish Ministerio de Ciencia e
Innovaci?n (MAT2007-62696 and MAT2008-05755/MAT), COST
action D43, the Xunta de Galicia (PGIDIT06TMT31402PR), and
Junta de Andalucia (“Excellence Project”: FQM-02353).
Supporting information for this article is available on the WWW
? 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2009, 48, 138–143
(Figure S1, Supporting Information), measured from a pre-
cipitated powder, shows the ring C=C stretching (1615 cm?1),
CH2scissoring (1461 cm?1), ring breathing (1012 cm?1), and
radial ring stretching mode (646 cm?1) bands, which are
characteristic of polystyrene.Notably, all these bands are
no longer observed upon formation of the pNIPAM shell
(Figure S1, Supporting Information), indicating either the
replacement of PS by pNIPAM or the absence of hot spots as
a result of the screening of plasmon coupling when the
separation between Au particles is increased. The SERS
spectra measured from Au@pNIPAM for both selected core
sizes (67 and 116 nm), fit band to band, both being charac-
terized by the NH bending (1447 cm?1), CN stretching
(1210 cm?1), CH3rocking (963 cm?1), CH deformation (866
and 841 cm?1), CC rocking (766 cm?1), CNO bending
(655 cm?1), and CCO out-of-plane deformation
(413 cm?1). The substantial differences in intensity
are indicative of a considerable increase in optical
enhancing properties of the larger gold cores, in
agreement with previous reports.Importantly,
the overallSERS intensity
obtained from pNIPAM is low, thus providing an
excellent background for detection applications.
Characterization of the localized surface plasmon
resonances (LSPR, Figure 1c) for both samples
show a notable red-shift when the particle size is
increased, whereas the effect of temperature on
the plasmonic response is modest. As we reported
earlier, the LSPR bands red-shift upon collapse of
the pNIPAM shell, owing to the associated local
refractive index increase around the gold parti-
The optical enhancing properties of the Au@pNIPAM
colloids were initiallytested using1-naphthalenethiol(1NAT)
as a model analyte, because it is a small molecule with a large
affinity for gold (through the thiol group), which should easily
diffuse through the porous polymer shell, and its SERS
spectrum is well established.The SERS spectrum of 1NAT
(Figure 2a) is dominated by the ring stretching (1553, 1503,
and 1368 cm?1), CH bending (1197 cm?1), ring breathing (968
and 822 cm?1), ring deformation (792, 664, 539, and 517 cm?1),
and CS stretching (389 cm?1). The most interesting property
of pNIPAM microgels is aphase transition froma hydrophilic,
water-swollen state into a hydrophobic, globular state when
heated above their lower critical solution temperature
(LCST) which is about 328 8C, in water. Gel compression is
related to dehydration, and gives rise to final collapsed
volumes of less than 50% the swollen microgel volume,this
transition is completely reversible.Thus, when 1NAT is
added to the swollen Au@pNIPAM colloid (Figure 2b), the
analyte can easily diffuse through the polymer network until
reaching the gold-core surface, to which it readily chemisorbs.
This is reflected in the high SERS intensity recorded at 48 8C,
which remains high after gradually heating up to 608 8C and
Scheme 1. Schematic representation of the fabrication (a), and the
application of thermoresponsive Au@pNIPAM microgels for surface-
enhanced fluorescence (SEF) and surface-enhanced resonance Raman
scattering (SERRS) (b), and as molecular traps for surface-enhanced
Raman scattering (SERS) of non-interacting molecular probes (c).
Figure 1. Representative TEM images of Au@pNIPAM core–shell par-
ticles, with Au cores of a) 67 nm and b) 116 nm diameter. Insets:
magnifications of a single core–shell particle (scale bars: 100 nm).
c) UV/Vis spectra of aqueous suspensions of both Au@pNIPAM
microgel colloids, measured at 48 8C (solid lines) and 608 8C (broken
Figure 2. a) SERS spectrum of 1-napthalenethiol (lex=785 nm) in Au@pNIPAM
aqueous dispersions. Variation of the intensity of the band at 1368 cm?1(ring
stretching; highlighted in yellow), as a function of gold-core size and solution
temperature in two different cooling-heating cycles: b) from 4 to 60 to 48 8C; and,
c) from 60 to 4 to 608 8C. The intensity scale is common for (b) and (c). Acquisition
time was 2 s in all cases.
Angew. Chem. Int. Ed. 2009, 48, 138–143? 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
cooling down back to 48 8C. However, when
1NAT is added to a dispersion of the
collapsed microgel (608 8C), the measured
SERS signal is substantially lower (Fig-
ure 2c). Cooling this suspension down to
48 8C leads to an increase of the signal to an
intensity that is comparable to that of the
previous cycle. The signal remains stable
during subsequent temperature changes.
From these results we can conclude that,
when the gel is swollen, 1NAT can indeed
diffuse freely through the network, but
when the microgel is collapsed, diffusion
of the analyte is hindered and the gold
surface cannot be reached. However, once
1NAT has been adsorbed, it stays retained
regardless of the swollen or collapsed state
of the microgel. This result is consistent
with the formation of a covalent Au?S
bond, which has been oftenreported and is
additionally confirmed by the disappear-
ance of the SH stretching peak in the
SERS spectra(Figure S2,
Information).It is interesting to note
that precisely the same trend was observed
for core–shell colloids with different par-
ticle sizes, but the enhancement provided
by the larger, 116 nm Au cores is consid-
erable higher than that from the 67 nm
particles, partly because of the better
(785 nm) with the plasmon band (see
Figure 1).Therefore, in all the experi-
ments described below for the design of
other analytical applications of these
materials, only the Au@pNIPAM particles
with 116 nm Au cores were employed. A
final, interesting observationfrom this first
enhancement factor (EF) of 5.16?105
(see Experimental Section and Supporting
Information for details on EF calculation).
Since pure 1NAT (as all aromatic thiols)
does not present substantial charge-trans-
fer-related enhancement (the so-called
chemical effect),the calculated EF is
rather high, in particular considering that
the microgel shell surrounding the Au
particles prevents electromagnetic cou-
pling, and consequently the formation of hot spots.
A second demonstration of the trapping properties of the
Au@pNIPAM system (Scheme 1b) is provided in Figure 3,
which shows results for the heating–cooling cycles, using a
common dye, Nile Blue A (NBA) as a molecular probe. The
NBA molecule is slightly larger than 1NATand, in addition, it
contains an amine functional group, so that its affinity for gold
is lower than that of 1NAT.Another interesting property of
NBA is that it gives different spectra (either SERS or SEF/
SERRS) depending on the excitation wavelength. Upon
excitation with a near-IR (NIR, 785 nm) laser line, far away
from the electronic absorption band (Figure S3, Supporting
Information), NBA supported onto an optical enhancer will
produce a normal SERS signal. On the contrary, if NBA is
excited with a red laser (633 nm) perfectly matching its
absorption band (Figure S3, Supporting Information) either
SERRS or SEF will be produced, depending on the distance
to the metal nanostructure. If the molecule is close enough to
the metal, the fluorescence will be quenched, whereas if the
molecule is close but not next to the metal, it will feel the
Figure 3. Variation of the SERS (lex=785 nm; blue trace) and SEF/SERRS (lex=633 nm; red
trace) intensity of Nile Blue A, as a function of solution temperature in two different
cooling–heating cycles: a) from 4 to 60 to 48 8C; and, b) from 60 to 4 to 608 8C. The intensity
scale is common for (a) and (b). Acquisition time 2 s.
? 2009 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimAngew. Chem. Int. Ed. 2009, 48, 138–143
electromagnetic field enhancement generated by the nano-
structure. Though SERRS and SERS spectra fit band to band,
the relative intensities are different because in SERRS not
only the surface selection rulesbut also the resonance
effectsare to be considered. Briefly, both the SERS and
SERRS spectra are characterized by ring stretching (1643,
1492, 1440, 1387, 1351, and 1325 cm?1), CH bending (1258,
1185 cm?1), and the in-plane CCC and NCC (673 cm?1), CCC
and CNC (595 cm?1), and CCC (499 cm?1) deformations.
The bands at 673 and 595 cm?1are significantly more
enhanced in SERRS than in SERS, indicating that they
correspond tothe chromophore(inthis casethe phenoxazine)
and the electronic resonance tends to enhance scattering
bands from chemical groups that absorb the excitation laser
line. On the other hand, enhanced fluorescence (SEF)
spectra are very similar to those for standard fluorescence,
with a maximum emission at 668 nm.
When NBA was added to the swollen colloid (48 8C,
Figure 3a), and excited with the NIR laser line, the recorded
SERS intensity was very weak. However, the intensity
notably increased with temperature and gel collapse, decreas-
ing again after cooling. When the same samples were excited
with the red line, the spectrum of the initial, swollen sample
showed intense fluorescence, which can be readily described
as SEF, as the intensity was 16-fold that of normal
fluorescence. However, when the temperature
was increased to 608 8C (gel collapse), the fluores-
cence was completely quenched, and the SERRS
spectrum was obtained. After subsequent cooling
to 48 8C, a less-intense SERRS spectrum could still
be identified on top of a strong SEF background.
Because of the difference in the affinity of amines
and thiols for gold, the retention of NBA is not as
stable as that of 1NAT, as reflected in the
decrease in SERS and SERRS, along with the
increase in SEF, when the sample was swollen
again, indicating partial release of NBA mole-
cules. Interestingly, when the inverse cycle (60–4–
608 8C, Figure 3b) was applied, strong SEF inten-
sity was recorded at 608 8C, which turned upon gel
expansion into a weak SERRS signal (48 8C), with
complete fluorescence quenching, and then to an
intense SERRS signal after final heating, back to
608 8C. Interpretation of these results is as follows.
Swollen pNIPAM does not allow the adsorption
of NBA onto the gold cores (as indicated by a
very weak SERS signal at 48 8C), but it does trap
the analyte molecules within the polymer gel
network (strong SEF completely screening the
SERRS signal). When the temperature is raised
up to 608 8C, the shell is collapsed and NBA
molecules are trapped closer to the cores, as
indicated by notable increases of SERS and
SERRS, while SEF is quenched. Temperature
sensitivity of fluorescence enhancement has been
reported by Kotov and co-workers for Au nano-
particles linked to quantum dots through a
thermoresponsive molecule.In the second
cycle (60–4–608 8C),a similar behavior was
observed. For the original, collapsed microgel, only SEF is
recorded, but upon swelling and subsequent collapse, NBA is
retained in close contact with the gold core surface. This
trapping effect is very likely related to the hydrophilic–
hydrophobic transition, as well as dehydration and micro-
capillarity effects during microgel collapse.Thus, these
Au@pNIPAM microgels can provide a fine control on the
nature of the measured signal by simply controlling the
Finally, and probably most remarkably, the described
trapping effect can be applied to the SERS identification of
molecules such as 1-napthol, which had not been possible to
date becauseit doesnot easilyadsorb ontoconventionalsilver
or gold surfaces (Scheme 1c). Thus, the 1-napthol SERS
spectrum could be recorded for the first time (Figure 4), and
found to be characterized by CH bending (1447 cm?1), ring
stretching(1390 cm?1), CCC
(842 cm?1), CH out-of-plane deformation, ring breathing
(716 cm?1), ring deformation (655 and 584 cm?1) and, ring
twisting (477 cm?1), in close agreement with the Raman
assignment reported by Lakshminarayan and Knee.As
shown in Figure 4, the SERS signal can only be properly
identified after a swell–collapse transition, so that 1-napthol
can first be retained within the polymer networks and then
Figure 4. Variation of the SERS (lex=785 nm) intensity of 1-naphthol as a function
of the solution temperature in two different cooling-heating cycles: b) from 4 to 60
to 48 8C; and, b) from 60 to 4 to 608 8C. The intensity scale is common for (a) and (b).
Acquisition time 2 s.
Angew. Chem. Int. Ed. 2009, 48, 138–143 ? 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
brought into contact with the gold surface. Upon subsequent
cooling, the microgel shell swells again and the 1-napthol
molecules are totally released from the gold surface, resulting
in a dramatic loss of SERS signal (Figure 4a). The low affinity
of hydroxy groups for Au surfaces is very clearly reflected in
the reversibility of the SERS signal along the swell–collapse
In summary, we have designed, characterized, and applied
an advanced optical platform that allows for general, ultra-
sensitive analysis of a wide variety of molecules through
surface enhanced spectroscopy. The unique thermoresponsive
properties, high EF with no electromagnetic coupling, and the
colloidal stability of these materials should find application in
quantitative analysis through direct SERS/SERRS sensing,
fabrication of encoded particlesby using thiolated dyes,
or as solution fluorescence enhancersfor a variety of
biomedical applications,such as cellular uptake,imag-
Gold nanoparticles encapsulated in thermoresponsive pNIPAM
microgels were prepared as described elsewhere.Briefly, AuNPs
(average diameter (67?5) nm) were prepared through a seeded
growth methodby reduction of HAuCl4with ascorbic acid on
CTAB-stabilized Au seeds (ca. 15 nm), in the presence of 0.015m
CTAB. Initial polystyrene coating of AuNPs was carried out as
follows: as-prepared CTAB-stabilized AuNPs (150 mL) were centri-
fuged, the supernatant solution discarded, and the precipitate
redispersed in milli-Q water (150 mL). The solution was then
heated to 308 8C, followed by addition of styrene (10 mL) and
divinylbenzene (5 mL) under stirring. After 15 min the temperature
was furtherraised to 708 8C and polymerization was initiated by adding
20 mL, 0.1m in water), and allowed to proceed for 2 h. The colloid
was then washed by centrifugation and redispersion in milli-Q water
(15 mL). The pNIPAM shell was grown by addition of N-isopropyl-
acrylamide (NIPAM, 0.1698 g) and N,N-methylenebisacrylamide
(0.0234 g) under nitrogen. After 15 min, the nitrogen flow was
removed and the polymerization was initiated by adding AAPH
(150 mL 0.1m). The reaction was allowed to proceed for 3 h at 708 8C.
The reddish-white mixture was then allowed to cool to room
temperature under stirring. To remove small oligomers, residual
monomers as well as gold-free microgels, the dispersion was diluted
with water (15 mL), centrifuged, and redispersed in water three times.
Further in situ growth of the AuNP cores up to (116?11) nm
diameter was performed by adding CTAB (4.06 mL; 0.1m) containing
HAuCl4(0.125 mm) and ascorbic acid (0.25 mm) onto Au@pNIPAM
UV/Vis spectra were recorded using an Agilent 8453 UV/Vis
diode array spectrophotometer. Transmission electron microscopy
was carried out by using a JEOL JEM 1010 microscope operating at
an acceleration voltage of 100 kV.
Raman, SERS, SERRS, and SEF were measured on a LabRam
HR (Horiba-Jobin Yvon) Raman system. Microgel characterization
was performed under the microscope by centrifuging 1 mL of the
corresponding suspension and casting the residue on a glass slide,
SERS was recorded by exciting the sample with a 785 nm laser line.
SERS, SERRS and/or SEFof either, 1-naphtalenethiol (1NAT, Acros
Organics), Nile Blue A (NBA, Aldrich) or 1-naphthol (1NOH,
Aldrich) were recorded in suspension by using a macrosampling
accessory. Two different experiments were designed. First, 1 mL
aliquots of AuNP@pNIPAM (5?10?4m in gold) were stabilized at
48 8C. Then, 10 mL of analyte was added to each NP suspension
reaching final concentrations of 10?5m for 1NAT and 1NOH and
10?6m for NBA. After 2 h at 48 8C, time enough to reach thermody-
namic equilibrium, the samples were excited with a 785 nm laser line
to collect the SERS spectra. In the case of NBA, fluorescence
emission and SERRS were excited by illuminating the sample with a
633 nm laser. Thereafter, the samples were equilibrated at 608 8C for
2 h and again at 48 8C. After each equilibration step, spectra were
collected under the same conditions. In the second experiment,
equilibration steps were repeated, but starting at 608 8C, cooling down
to 48 8C and heating back to 608 8C. Again, spectra were collected after
each step under identical conditions.
Approximate enhancement factors (EF) of AuNP@pNIPAM for
SERS and SEF were estimated by applying Equation (1):
EF ¼ ðIAVA=IBVBÞf
Where VAand VBrepresentthe probed volumes, and IAand IBthe
intensities in SERS and Raman, respectively; f, is a correction factor
that considers the concentration ratio of the probed molecule in both
experiments under the same conditions. Since 1NAT is a liquid,
Raman spectra were collected directly, with no need for dissolution in
any solvent. The concentration of pure 1NAT (7.18m) was deter-
mined through its density (11NAT=1.15 kgl?1). In the case of NBA,
which is a solid, fluorescence was collected from a 10?5m solution.
Provided that VAand VBare similar, Equation (1) can be reduced to
EF=(IA/IB)f, were f is 7.18?105for 1NAT and 10 for NBA.
Received: August 16, 2008
Published online: November 27, 2008
Keywords: colloids · gold · nanoparticles · sensing · SERS
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