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26 1219
2010 The Japan Society for Analytical Chemistry


Polymer-functionalized Gold Nanoparticles as Versatile Sensing


Department of Applied Chemistry, Graduate School of Engineering, Utsunomiya University,

7-1-2 Yoto, Utsunomiya, Tochigi 3218585, Japan

In this brief review, gold nanoparticles conjugated with functional polymers are described from the viewpoint of application
to sensing materials. The optical properties of gold nanoparticles, the synthesis of polymer-functionalized gold
nanoparticles, and their analytical applications are discussed. Polymer-functionalized gold nanoparticles are categorized
into two classes: biopolymer-conjugated gold nanoparticles and artificial-polymer conjugated gold nanoparticles.
Fluorometric and colorimetric sensing using gold nanoparticles are focused; fluorometric detection enables us to exploit
sensitive assays for practical use. Furthermore, chemical amplification using gold nanoparticles is also discussed for the
sensitive probing.

(Received October 9, 2010; Accepted October 25, 2010; Published December 10, 2010)

1 Introduction 1219 41 Sensors based on bridging structures

2 Optical Properties of Gold Nanoparticles 1220 42 Sensors based on spontaneous aggregation
21 Surface plasmon resonance 43 Chemical amplification
22 Luminescence 5 Analytical Application of Gold Nanoparticles
3 Fabrication of Gold Nanoparticles Functionalized with Synthetic Polymers 1224
Functionalized with Polymers 1221 6 Fluorometric Nano-sensors with Polymer-
31 Grafting from fabrication functionalized Gold Nanoparticles 1224
32 Grafting to fabrication 61 Quenching control
33 Post modification 62 Molecular beacon
4 Analytical Application of Gold Nanoparticles 7 Perspective 1226
Functionalized with Biopolymers 1222 8 References 1226

include chemical inertness, easy preparation, easy modification,

1 Introduction and easy control of particle size. These properties have
facilitated the use of AuNPs as key materials for nanoscientific
Gold nanoparticles (AuNPs) are colloidal gold particles ranging and nanotechnological applications.2,3 Moreover, AuNPs are
from ca. 1 nm to ca. 100 nm in size. AuNPs have several commonly used in everyday life, e.g., in red stained glass and as
distinctive physical and chemical attributes; their optical and a red marker in diagnostic tests for influenza.
electrochemical properties and catalytic activity are not The dispersion of AuNPs affects their practical applications.
characteristic of bulk gold.1 Other versatile features of AuNPs Dispersed AuNPs are thermodynamically unstable because of
their high surface energy, and they tend to spontaneously form a
Nobuo UEHARA received his bachelor and
precipitate under external stimuli. The conjugation of AuNPs
master degrees, and a D.Sc. degree in with water-soluble polymers is an effective way to prevent the
Material Chemistry from Tohoku University. assembly of AuNPs because it decreases the high surface energy
He joined as a lecturer in the Department of the AuNPs, and it inhibits the contact between individual
of Applied Chemistry, Utsunomiya
AuNPs. Indeed, the first AuNP solution prepared by Faraday
University in 1988 and is presently
Associate Professor since 1998. His main was stabilized using gelatin, a water-soluble biopolymer, and it
area of research involves the fabrication, has retained its reddish color.4 Thus, water-soluble polymers
characterization and application of new have been used as effective stabilizers for disassembled AuNPs.
analytical systems for trace metal analysis. Water-soluble polymers often exhibit versatile analytical
He is currently, engaged in the development
of versatile and novel chemical sensing
properties. For example, water-soluble biopolymers such as
systems using stimuli-sensitive polymers polypeptides, nucleic acids, and polysaccharides play important
and colloidal gold for biological analysis. roles in specific recognition in homeostasis processes. Artificial
water-soluble polymers have also been used as functional
E-mail: materials in chemical analyses, e.g., typical thermoresponsive

Fig. 1Conjugation of gold nanoparticles with functional polymers.

polymers such as poly(n-isopropylacrylamide) and poly- The undulation of electrons existing on the surface of metal
(methylvinylether). They exhibit a change in conformation at nanoparticles causes a decrease in the radii of the nanoparticles
different solution temperatures. The thermoresponsive property from bulk (e.g., milli meter order) size to nano size. The
has facilitated the use of such polymers as key materials in undulation of electrons interacts with the incident light to
actuators,57 micro-TAS,8 and drug delivery systems.9,10 decrease the intensity of the light as a result of the energy
A combination of two different types of functional materials transferred from the light to the plasmon, resulting in extinction
results in the inadvertent development of new functions that are of the incident light.
not characteristic of the individual materials. A typical example The surface plasmon resonance of AuNPs is influenced by
is the conjugation of AuNPs with functional polymers, as shown their morphology (shape, size, and degree of aggregation).
in Fig. 1. The recognition of analytes by the functional polymers Spherical AuNPs whose particle sizes are above ca. 10 nm
in the resulting AuNP results in a morphological change in the exhibit an extinction band around 520 nm due to their inherent
gold cores, which is indicated a colorimetric change. In this surface plasmon band when disassembled in a solution.1517 The
review, the optical properties of AuNPs and conjugation of maximum wavelength of the extinction spectra of AuNPs is
AuNPs are focused, first. Next, the applications of correlated to the morphology of AuNPs by Mie theory.18,19 The
polymer-functionalized AuNPs to analytical systems are addition of ionic substances or other external stimuli causes the
discussed. Furthermore, homogeneous sensing systems using assembly of AuNPs because of the instability of disassembled
polymer-functionalized AuNPs are emphasize; hence, AuNPs. Once the AuNPs assemble, their surface plasmons are
heterogeneous sensors based on electrochemical sensing using coupled to generate a new extinction band at a longer wavelength,
electrodes modified with AuNPs are ruled out. Readers may resulting in a bluish color. This is the principle of colorimetric
refer to various informative reviews of electrochemical sensors sensors of AuNPs, which will be discussed in later sections (41
based on AuNPs.11,12 and 42).

22 Luminescence
2 Optical Properties of Gold Nanoparticles Unlike conventional size AuNPs (above several nanometers),
AuNPs with particle sizes below ca. 2 nm, which are referred to
21 Surface plasmon resonance as gold nanoclusters, luminesce, as quantum dots do.2022 The
Surface plasmon is the coherent oscillation of the surface luminescence of inorganic nanoparticles provides new
electrons of metal nanoparticles; it propagates at the surface of possibilities for cell staining. Although common organic
the metal nanoparticles along with an evanescent wave. When fluorescent dyes are expected to stain cells with high sensitivity,
an incident electromagnetic wave whose frequency is identical easy decomposition with an excitation light and interference
to that of the metal nanoparticle surface plasmon passes near the from the background of coexisting organic substances should be
surface of the metal nanoparticles, the resonance between the overcome for the practical cell staining with high sensitivity.
electromagnetic wave and the surface plasmon occurs to The fluorescent staining with inorganic nanoparticles, on the
decrease the intensity of the incident electromagnetic wave.13,14 other hand, can overcome the drawbacks because of the
Although the following model may be a quantitative expression, resistance of photo degradation by UV-irradiation.23 Because
it is a convenient representation of the surface plasmon band. irradiation of strong UV light decomposes organic fluorescent

Fig. 2Scheme of functionalization of gold nanoparticle through grafting from (A), grafting to
(B), and post modification (C) techniques.

substances, the irradiation prior to fluorescent detection of L-glutamate-co-L-glutamic acid)s grafted onto AuNPs to form
stained cells enables us to reduce background noise from the bio-conjugating gold nanocomposites. The molecular weight of
coexisting substances and improve S/N ration (i.e., sensitivity). the grafted peptides was ca. 73 kDa and the morphology of the
peptides was an -helix structure in an aqueous solution.

3 Fabrication of Gold Nanoparticles 32 Grafting to fabrication

Functionalized with Polymers The evolution of gold cores in polymer aggregates, which is
referred to as grafting to fabrication, is another potential
The conjugation of AuNPs with functional polymers is the first method for producing polymer-modified gold nanoparticles.
step toward fabricating functional gold nanocomposites. Many Advantages of this method are the availability of many kinds of
investigations involving with the fabrication of gold nanoparticles polymers and the easy synthesis (one-pot synthesis). The
functionalized with polymers have been reported. The reported one-pot synthesis enables us to reduce laborious steps that
fabrication methods can be classified into the following three grafting-from modification requires.
representative categories illustrated in Fig. 2. Polymers to be used for the grafting to modification are
categorized into two types: one is a polymer terminated with a
31 Grafting from fabrication sulfur-containing group and the other is a polymer terminated
Grafting from fabrication is a technique in which polymer with a sulfur-free group. Polymers terminated with a sulfur
chains extend from scaffolds attached to the surface of AuNPs containing group (dithioester, trithioester, thiol, thioether and
(Fig. 2(A)).2428 This technique provides the following disulfide) provide chemical-bonded shell layers around the gold
advantages: precise control of the molecular weight (i.e., cores, which also occurs in the grafting from method.29,30 The
polymer layer thickness) of introduced polymers, versatile polymers terminated with sulfur containing groups can be
structural design of a polymer layer, and effective introduction synthesized by a radical polymerization using chain transfer
of polymer chains with high density. Chemically-bonded reagents containing sulfur atoms.31
scaffolds are superior to physically-adsorbed ones in terms of The evolution of gold cores in aggregates composed of
robustness of the resulting gold nanocomposites. conventional polymers without sulfur atoms results in gold
Although most polymers introduced by the grafting from nanocomposites in which the polymers interact with gold cores
method are artificial polymers,2426 representative biopolymers through multi-point physical adsorption.32 Not only artificial
such as oligonucleotides and peptides can also be introduced. polymers, such as poly(N-vinylpyrrolidine),33 poly(vinylpyridine),34
To introduce single-strand oligonucleotide chains, primers poly(ethyleneglycol),35 poly(vinyl alcohol),36 poly(vinyl
having thiol groups were attached to the AuNPs surface methylether),37 poly(ethyleneimine),38 poly(dialyl dimethyl-
followed by the extension of single-stranded DNA (ssDNA) ammonium),39 but also biopolymers, were examined for the
chains conducted by rolling circle polymerization using DNA grafting to fabrication. The drawback of using the polymer
polymerase.27 Since the molecular size of the primer is small, terminated with a sulfur-free group is instability of the resulting
effective introduction of ssDNA chains can be achieved. To gold nanocomposites. The polymer-coated AuNPs are prone to
graft peptides onto AuNPs, sulfhydryl amines are introduced being detached because of a lack of chemical bonds, resulting in
onto AuNPs surface followed by elongation of peptide chains assembly of the AuNPs when the polymer micelles that surround
with a ring opening polymerization. Higuchi and coworkers28 the AuNPs collapse. Crosslinking between the polymer
demonstrated the introduction of poly(gamma-methyl networks in the polymer layer is an effective way to suppress

Fig. 3Aggregation of AuNPs through ridging structure via (A) hybridized DNA, (B) chelating bond,
(C) supermolecule, (D) biological interaction, and (E) covalent bond.

the instability of the resulting gold nanocomposites. The use of for the last decade.42,43 Based on the recognition abilities of the
unimolecular micelles40 or stabilized micelles with crosslinking biopolymers, cell staining has been investigated with the
networks provides another promising strategy for overcoming biopolymer-functionalized AuNPs discussed earlier (Sect. 22).
the instability because the morphology of these micelles is not
influenced by solution conditions.41 41 Sensors based on bridging structures
As mentioned in Sect. 21, disassembled and assembled
33 Post modification AuNPs, which develop a reddish and bluish-purple solution
Conjugation of as-prepared AuNPs with as-prepared polymers color, respectively, due to their surface plasmon bands of the
is the most common and the simplest method for preparing gold corresponding morphology, have been utilized for fabrication of
nanocomposites because mixing both of the as-prepared colorimetric sensors. The formation of bridging structures
materials can eliminate uncertain factors in fabricating gold between AuNPs facilitates a linkage for assembling the AuNPs,
nanocomposites, such as the dispersion of AuNP size and resulting in a change in solution color from red to blue-purple.
molecular weight. Drawbacks of the post modification Figure 3 depicts representative bridging structures for linking
method, however, are low efficiency of polymer introduction of AuNPs.44 After Mirkin and coworkers first reported the
due to the steric hindrance of the conjugated polymers and assembly of AuNPs linked through double-stranded DNAs,45
unintended adsorption through functional groups in the related bridging structures have been developed for colorimetric
polymers. As well as the other modifications reviewed in this sensors of DNAs with AuNPs.46,47 In addition to DNA
section, conjugation of AuNPs with the polymers having hybridization,4547 interactions such as antigen-antibody,48,49
SH-terminated groups form covalent-bonded type gold avidin-biotin,50,51 lectin-sugar,5254 and generation of a chemical
nanocomposites while the conjugation with other polymers bond55 have been investigated for the formation of bridging
without thiol groups form physically-adsorbed gold structures. Chelation56 and the formation of supermolecular
nanocomposites. structure57,58 have been also studied.

42 Sensors based on spontaneous aggregation

4 Analytical Application of Gold Nanoparticles Non-crosslinking aggregation based on the enthalpic
Functionalized with Biopolymers destabilization of gold nanocomposites is another potential
approach for developing the colorimetric sensors. Since
In this section, an overview of the analytical applications of negative charges on the surface of AuNPs stabilize the AuNPs,
biopolymer-functionalized gold nanoparticles to chemical cancellation of negative charges or shrinkage of the electric
sensing and chemical magnification is provided. The chemical double layers surrounding gold nanoparticles cause the
inertness of AuNPs provides them with low bio-toxicity, which spontaneous non-crosslinking aggregation. Although the
is an advantage in biological and medical applications. In cancellation of the negative charges on gold nanocomposites is
addition to the inherent inertness of AuNPs, the conjugation of easy to achieve by adding counter ionic, i.e., cationic substances,
biopolymers further increases the biocompatibility of the the control of the selectivity is difficult in practice.59
resulting gold nanocomposites. Since the conjugation of The shrinkage of electric double layers surrounding AuNPs is
biopolymer confers recognizing functions to the resulting another potential approach to serve a platform of colorimetric
polymer-functionalized AuNPs, the resulting gold sensors. Increasing the ionic strength of a solution by adding of
nanocomposites have been investigated as bio-sensing probes an inorganic salt compresses the electric double layers of gold

Fig. 4Spontaneous aggregation of gold nanocomposites based on salting out assisted with
destabilization. A) Hybridization with complement, B) disruption of bonded polymer.

nanocomposites to destabilize the nanocomposites, resulting in amplification magnifies the background noise as well as signals
spontaneous aggregation.60,61 Introduction of the mechanisms of analytes, it does not practically improve the signal-to-noise
that can be manipulated externally allows us to develop selective ratio. On the contrary, the chemical amplification has the
colorimetric assays with the gold nanocomposites. Typical potential to amplify only signals of analytes to improve the
mechanisms for spontaneous aggregation based on salting out sensitivity of the whole analytical system. One of the most
are shown in Fig. 4. Single-stranded oligonucleotides, acting as effective chemical amplification systems utilizing gold
anionic and flexible biopolymers, were examined to verify the nanoparticles is a bio-barcode method, in which magnetic
spontaneous aggregation. The single-stranded oligonucleotides particles play an important role along with the gold
stabilize AuNPs even under saline conditions. Hybridization nano-composites. The bio-barcode method is based on the
with the complementary single-stranded oligonucleotides forms formation of linkages composed of analytes between the
rigid double-stranded oligonucleotides with reduced the magnetic nanocomposites and gold nanocomposites that hold
flexibility, causing the gold nanocomposites to assemble due to barcode DNAs on their surface, as shown in Fig. 5.66 The
entropic instability with the aid of salting out. Single nucleotide resulting sandwich-type magnetic conjugates are separated and
polymorphisms (SNPs) form imperfect double strands, which isolated from a solution with an external magnetic field. After
do not cause the assembly of the oligonucleotides and hence the isolation of the conjugates with the magnetic field, the
stabilize AuNPs. Based on the different responses of the SNPs barcode DNAs from the gold nanocomposites are liberated by
and the complementary DNA, the SNPs could be discerned with heating the solution as a result of dehybridization. Since one
the naked eye (Fig. 4A).62 target molecule is converted to the liberated barcode DNAs
Cleavage of aptamers, engineered nucleotides, provides through the bio-barcode process, the number of barcode ssDNAs
another sensing platform for non-crosslinking. When specific in the gold nanocomposites corresponds to the amplification
substances cleave aptamers bonded onto AuNPs to generate ratio of the bio-barcode amplification, at least in principle. The
single-stranded fragments, the resulting AuNPs with cleaved amplification ratio of bio-barcodes is comparable to polymerase
aptamers become unstable and assemble with the addition of chain reaction (PCR) amplification.67 The principle of
salts. Thus, the specific substances can be quantified by the bio-barcodes worked on the amplification of proteins that
colorimetric change in the solution.63 Because the liberated act as specific and stable linkers through antigen-antibody
fragments of aptamers work as anionic soluble polymers which interactions.68 After the first investigation reported by Mirkins
coat and stabilize AuNPs through multi-point interaction to group,68 various modifications of bio-barcodes have been
prevent aggregation by the salting out effect, another sensing reported.66
system platform can be designed using the cleaved fragments.64,65 The bio-barcode amplification technique has been combined
Since the original aptamers are rigid, they do not stabilize the with a chip-based DNA detection. In the chip-based detection,
AuNPs, leading to the spontaneous aggregation by salting out. liberated barcode DNAs are hybridized to a microarray slide
Subsequently, the specific substances were assayed followed by capture of universal gold nanocomposites through
colorimetrically after the addition of sodium chloride. further hybridization. Catalytic deposition of silver ions on
AuNPs further enhances the sensitivity of the chip-based
43 Chemical amplification detection. The combination of PCR amplification and
Chemical amplification prior to assay is an important bio-barcodes also achieved high sensitivity for a protein with
technique for the sensitive assay. Because the electric the detection limit at the atto molar level.68

Fig. 5Bio-barcode amplification. Step 1, Formation of gold-magnetic conjugates; step 2, magnetic

separation; step 3, liberation of hybridized barcode DNA (e.g. heating).

close to the surface of AuNPs to enhance FRET, leading to

5 Analytical Application of Gold Nanoparticles suppression of the fluorescence, and vice versa.
Functionalized with Synthetic Polymers The phase transition of thermoresponsive polymers attached
to AuNPs alters not only the polymer configuration but also the
Synthetic polymers also provide versatile functions to gold morphology of gold cores in nanocomposites. The present
nanoparticles to be used as chemical sensors. authors group has developed a unique colorimetric sensor using
Poly(ethyleneglycol), which is a typical synthetic polymer gold nanocomposites conjugated with thermoresponsive
composed of a repeating oxyethylene unit, is one of the most copolymers possessing poly(ethyleneamine).76 Figure 6
promising candidates to be conjugated with AuNPs for the illustrates the schematic of the colorimetric sensor whose color
development of chemical sensors due to the high changes from blue-purple to red by thermal stimuli (heating
bio-compatibility and the stable dispersibility. AuNPs linked followed by cooling). Although the gold nanocomposites
with lactose through poly(ethyleneglycol) were examined as a aggregate initially due to the poly(ethyleneamine) groups, they
colorimetric sensor of lectin.6971 RCA120, a bivalent lectin that do not precipitate owing to the conjugated polymers. Heating a
recognizes the -D-galactose specifically, accumulates solution facilitates shrinkage of polymer chains on the AuNPs
lactose-linked AuNPs, resulting in the alteration of the solution surface to expand the inter-particle distance of the AuNPs like a
color from red to blue-purple. The addition of excess galactose wedge. After the solution is cooled, the aggregated gold
releases the lactose-linked AuNP from the aggregates of AuNPs nanoparticles become disassembled, leading to a change in the
and RCA120, leading to disassembly of the AuNPs. Based on the solution color to red. Cysteine, a sulfhydryl monopeptide,
lectin-sugar interaction, antimicrobial susceptibility,71 Cholera inhibits the disassembly through replacement of the polymer
toxin,72 and ConA52,73 were assayed with the sugar-bonded adsorbed on the gold nanocomposites. As the concentration of
AuNPs. cysteine added into the solutions increases, the resulting
Thermoresponsive polymers reveal a reversible phase solutions exhibit gradation from red to blue-purple. The
transition between hydration and dehydration in response gradation could be quantified with the L*a*b* color coordinates
to the solution temperature. Conjugation of AuNPs with to determine the concentration of cysteine. Further studies
poly(n-N-isopropylacrylamide), a typical thermoresponsive indicated that the addition of glutathione induced the spontaneous
polymers, produces a novel type of colorimetric sensing disassembly of the polymer-conjugated AuNPs without the
material. A layer of thermoresponsive polymer surrounding the thermal stimuli.77
AuNPs swells below the phase transition temperature and
shrinks above the phase transition temperature.74 The
temperature-controlled thickness of the polymer layer is applied 6 Fluorometric Nano-sensors with Polymer-
to the fabrication of a nano-sized thermometer based on functionalized Gold Nanoparticles
fluorometry.75 The nano-sized thermometer is composed of the
temperature-controlled polymer containing fluorophores and 61 Quenching control
gold nano-cores. Fluorescence of the fluorophores in the AuNPs whose particle sizes exceed ca. 10 nm work as an
polymer layer is influenced by energy transfer from excited effective fluorescence quencher.78,79 The quenching efficiency
fluorophers to AuNPs (referred to as florescence resonance of AuNPs is much larger than that of conventional organic
energy transfer, FRET) that can be controlled by thermal stimuli quenching substances. The quenching is caused by FRET,
externally. Fluorophores in the shrunken polymer layer come which occurs when a fluorophore and an AuNP locate closely

Fig. 6Thermal stimuli-induced disassembly of aggregated gold nanocomposites conjugated with

thermoresponsive polymer.



FL nanoparticle




Fig. 7Fluorometric sensing based on suppression of fluorescence resonance energy transfer (FRET).

(<2 nm). When analytes isolate fluorophores and AuNPs with same sequence (system A). Competition of complexation with
enough distance to suppress FRET, the fluorophores regain their a target metal ion releases a bound complex connecting with a
inherent fluorescence. Based on the recovery of the fluorescence, fluorophore (system B). A target substance disrupts a linkage
the fluorescent sensors attain high sensitivity because a blank between a fluorophore and an AuNP, leading to liberation
fluorescence can be suppressed effectively by AuNPs. of the fluorophore (system C). A target substance releases a
Figure 7 depicts the five representative assay systems of the fluorophore in a super-molecular structure bound with an AuNP
quenching control of fluorescence. A target single-stranded (system D). A target sulfhydryl compound releases a fluorophore
DNA replaces a fluorophore-connected DNA possessing the adsorbed on an AuNP through replacement (system E).

Fig. 8Molecular beacon probe (A) and its stemmed molecular probe (B).

62 Molecular beacon with biopolymers have provided potential bio-sensing materials

Molecular beacon (MB), a typical molecular switching for labeling, imaging, and assaying. Also, the conjugation of
method, is categorized as a fluorophore quenching control thermoresponsive polymers has introduced a thermoresponsive
method. Since MB methods for the detection of DNA were property in the resulting gold nanocomposites, allowing us to
originally developed by Klamer and coworkers,80 many related fabricate unique colorimetric sensors. The changes in the
methods have been developed to detect DNA. Therefore, we morphology of the thermoresponsive gold nanocomposites
briefly review MB independently. Figure 8 shows two between assembly and disassembly, which are read by
representatives of the molecular switching methods, which colorimetric changes, can be controlled externally by the
utilize changes in configuration and rigidity of hybridized solution temperature with reversibility. In this review, distinctive
DNA.81 A key material of MB is a single-stranded DNA that and versatile properties of polymer-functionalized gold
possesses complementary sequences at each terminal to form a nanoparticles have been discussed in terms of their analytical
hairpin-like configuration through hybridization. To prepare a uses. Because many kinds of metal nanoparticles and functional
MB probe, a quencher and a fluorophore are attached at each polymers are available at the present time, the number of
end of the single-stranded DNA followed by the formation of a possible combinations is immense. There are many more
hairpin. Energy is transferred from the fluorophore to the remain excellent and innovative polymer-functional gold
quencher in the MB probe due to their proximity, quenching the nanoparticles; a limited number of examples are highlighted
fluorescence. Hybridization of a fully complementary DNA here. The author hopes this brief review inspire readers to
with the probe conjugate opens the hairpin to alienate both the develop novel functional materials.
quencher and the fluorophore, resulting in inhibition of the
energy transfer to recover the fluorescence (Fig. 8A). The
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