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CRITICAL REVIEW
1. Introduction
Gold was one of the rst metals discovered by humans, and
the history of its study and application is estimated to be a
minimum of several thousand years old. The rst information
a
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2. GNPs in diagnostics
2.1 Visualization and bioimaging methods
GNPs have been actively used in various visualization and
bioimaging methods to identify chemical and biological
agents.33,34 Historically, electron microscopy (mainly its transmission variant, TEM) has for a long time (starting in 197111)
been the principal method to detect biospecic interactions
with the help of colloidal gold particles (owing to their high
electron density). Although GNPs can intensely scatter and
emit secondary electrons, they have not received equally wide
acceptance in scanning electron microscopy.35 It is no mere
chance that the rst three-volume book on the use of colloidal
gold36 was devoted mostly to the application of GNPs in
TEM. A peculiarity of current use of the electron microscopic
technique is the application of high-resolution transmission
electron microscopes and systems for the digital recording and
processing of images.37 The major application of immunoelectron
microscopy in present-day medical and biological research is
the identication of infectious agents and their surface antigens3840
(Fig. 1a). The techniques often employed for the same purposes
include scanning atomic-force41 (Fig. 1b), scanning electron,42
and uorescence43 microscopies.
Alongside the use of classic colloidal gold with quasispherical particles (nanospheres) as labels for microscopic
studies, the past few years have seen the application of
nonspherical cylindrical particles (nanorods), nanoshells, nanocages, nanostars, and other types of particles, referred to by
Chem. Soc. Rev., 2012, 41, 22562282
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Fig. 2 Various types of plasmon-resonant nanoparticles: 16 nm nanospheres (a);25 gold nanorods (b);44 gold bipyramids (c);45 gold nanorods
surrounded by silver nanoshells (d);25 nanorice (gold-coated Fe2O3 nanorods) (e);46 SiO2/Au nanoshells (f)25 (the inset shows a hollow
nanoshell47); nanobowls with bottom cores (g);48 spiky SiO2/Au nanoshells (h)49 (the inset shows a gold nanostar50); gold tetrahedra, octahedra,
and cubooctahedra (i);51,52 gold nanocubes (j);51 silver nanocubes and goldsilver nanocages obtained from them (in the insets) (k);53 and gold
nanocrescents (l).54 Adapted from the data of the cited papers by permission from The Royal Society of Chemistry, Elsevier, IOP Publishing,
Springer, Wiley Interscience, and The American Chemical Society.
Table 1
Particle
Major resonances/nm
Plasmonic shift/RIU/nm
510570
6501200
6501100
5501000
11001300
6001100
4590
150290
150540
790810
160b
315c
125
240665
83
410620
240880
Hollow Au shell
Nanobowls
Spiky SiO2 nanoshells and Au nanostars
Au polyhedralsd
Au cubes
AuAg nanocages
Au nanocrescentse
5601000
600850,
675770
550750
550700
4501000
9802600
Designations: RIUrefractive index unit, EMelectron microscopy, OIoptical imaging, HAhomogeneous assays, SAsolid phase assays,
PPTplasmonic photothermal therapy, DCdrug carriers, OAoptoacoustical applications, BSbiosensing, SERSsurface enhanced Raman
scattering. a PPT applications of clusterized Au nanospheres. b Monolayer data. c Suspension data. d Tetrahedra, octahedra, and cubooctahedra.
e
Nanolithography array.
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Fig. 3 Confocal image of HeLa cells in the presence of GNPs (a). Blue, the nuclei stained with Hoechst 33258; red, the actin cytoskeleton labeled
with Alexa Fluor 488 phalloidin; green, unlabeled GNPs. The image was taken by two-photon microscopy.63 Dark-eld microscopy of cancerous
(b) and healthy (c) cells by using GNPs conjugated with antibodies to epidermal growth factor.66 Adapted from the data of the cited papers by
permission from The American Chemical Society.
2.2
Table 2
Particles
Probe
Target
Detection method
Detection limit
Ref.
ssDNA
Cross-linking aggregation,
UVAS, spot test
10 fmol
125, 1997
5 0 -SH(dT)10-3 0
Biotinylated PCR
product
126, 2003
5 0 -N15(CH2)10SH-3 0 a;
5 0 -SH(CH2)10N15-3 0 b
5 0 -N15C-3 0 (CH2)3SH;
HS(CH2)65 0 -N18-3 0
5 0 -HSN16-3 0
ssDNA
127, 2004
1-round PCR
product
ssDNA
128, 2006;
140, 2005
129, 2006
5 pM
130, 2008
ssDNA
SERS
10 zM
136, 2010
ssDNA
Fluorescence quenching/retaining
with nontarget/target ssDNA
Stabilization/aggregation with
nontarget/target ssDNA, UVAS
Aggregation in the case of nontarget
molecules, VE, UVAS
0.5 pM
133, 2004
2 pM
134, 2004
1 pM (DNA);
10 nM (thrombin);
10 mM (cocaine);
50 mM (Hg)
10 pM
144, 2010
1.7 nM
135, 2008
0.1 pM
145, 2010
5 -HS(CH2)6N13N15-3
Modied
GNSs
(GNSs with
chemically
attached
probes)
5 0 -N12C3SS-3 0 ;
5 0 -SSC6N15-3 0
5 0 -SH(CH2)6N15-3 0 ;
5 0 -RoxN15(CH2)3SH-3 0
Rhodamine red5 0 -N15-3 0
Unmodied
GNSs
5 -N15-3
ssDNA, aptamers +
conjugated polyelectrolytec
ssDNA, PCR
product
ssDNA, thrombin,
cocaine, Hg
5 0 -N21-3 0 , 5 0 -N23-3 0
ssDNA
ssDNA
5 0 -N30-3 0
ssDNA
5 -N21-3
Unmodied
GNRs
PCR product
44, 2011
Designations: Nmm-bases oligonucleotide; GNSsgold nanospheres (colloidal gold nanoparticles with a roughly spherical shape); UVASUVvis
absorption spectroscopy; VEvisual evaluation; UVLSUVvis light scattering spectroscopy; PSAprostate-specic antigen; DLSdynamic light
scattering; GNRsgold nanorods. a Particle probe. b Substrate probe. c Poly [(9,9-bis (60 -N,N,N-trimethylammonium)hexyl)uorene-alt-1,4-phenylene]
bromide.
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Sensitivity limit
(pg of protein per fraction)
125
I
Horseradish peroxidase
Alkaline phosphatase
Colloidal gold
Colloidal gold + silver
Fluorescein isothiocyanate
5
10
1
1
0.1
1000
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2263
2264
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3. GNPs in therapy
3.1
Fig. 10 Scheme and the results of an experiment on the photothermal destruction of an implanted tumor in a mouse (23 weeks after injection of
MDA-MB-435 human cancer cells). Laser irradiation (a, b; 810 nm, 2 W cm2, 5 min) was performed at 72 h after injection of gold nanorods
functionalized with poly(ethylene glycol) (PEG) (a, c; 20 mg Au per kg) or of buer (b, d). It can be seen that the tumor continued developing after
particle-free irradiation (control b), as it did after particle or buer administration without irradiation (controls a and d), and that complete
destruction was obtained only in the experiment (a). Designations: NIR, near-IR region; NRs, nanorods. Adapted in part from ref. 304 by
permission from The American Association for Cancer Research.
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Table 4
Drugs
Particles
Methods of
functionalization
Auxiliary substances
Paclitaxel
GNSs, 26 nm
PaclitaxelSH
PEGSH, TNF
Methotrexate
GNSs, 13 nm
Physical adsorption
Daunorubicin
GNSs, 5 nm,
16 nm
GNSs, 5 nm
3-Mercaptopropionic
acid as a linker
Physical adsorption
Gemcitabine
Ref.
GNSs, 5 nm
GNSs,
36 nm
5-Fluorouracil
GNSs, 2 nm
c,c,t-[Pt(NH3)2Cl2(OH) GNSs, 13 nm
(O2CCH2CH2CO2H)]
Cisplatin
GNSs, 5 nm
Physical adsorption
Physical adsorption
Cetuximab
(monoclonal
antibodies)
Thiol ligand
Amide linkages
DNA
MCF-7
HeLa, U2OS, PC3
402, 2009
403, 2009
PEGSH as a linker
404, 2010
Oxaliplatin
GNSs, 30 nm
PEGSH as a linker
PEGSH
Kahalalide F
406, 2009
PEGSH
407, 2009
408, 2009
b-Lapachon
GNSs, 20,
Physical adsorption
40 nm
GNSs, 25 nm
PEGSH as a linker
GNRs, lmax=760 nm 11-Mercaptoundecanoic
acid as a linker
GNSs, 25 nm
Physical adsorption
OV-167, OVCAR-5,
HUVEC, OSE
A549, HCT116, HCT15,
HT29, RKO
HeLa
Doxorubicin
Prospidin
GNSs, 12 nm
GNSs, 50 nm
6-Mercaptopurine
Dodecylcysteine
Tamoxifen
Herceptin
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Physical adsorption
Physical adsorption
399, 2008
K-562
EAC
400, 2008
401, 2008
HeLa
405, 2010
409, 2009
410, 2010
411, 2010
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Scheme 2
The antibody titers obtained during immunization of rabbits with Yersinia antigen
Preparation
1st immunization
2nd immunization
Boosting
1 : 32
1 : 32
1:2
1 : 256
1 : 256
1 : 16
1 : 10 240
1 : 10 240
1 : 512
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6. Conclusions
Owing to the success of the rapid development of technologies
for the chemical synthesis of GNPs during the past decade,
investigators currently have at their disposal an enormous
diversity of available particles with required parameters in
respect of size, shape, structure, and optical properties. Moreover, the question that is now on the agenda is the primary
modeling of a nanoparticle with desired properties and the
subsequent development of a procedure for the synthesis of a
theoretically predicted nanostructure.
From the standpoint of medical applications, much signicance was held by the development of eective technologies
for the functionalization of GNPs with molecules belonging to
various classes, which ensure nanoparticle stabilization in vivo
and targeted interaction with biological targets. At this juncture,
the best stabilizers are thiolated derivatives of PEG and other
molecules. Specically, PEG-coated particles can circulate in
the blood stream for longer times and are less susceptible to
the attack of the cellular components of the immune system.
However, the creation of stealth conjugates, able to bind to
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Acronyms
CTAB
EGFR
GNP(s)
PEG
PDT
PPTT
SPIA
SPR
TEM
TNF
cetyltrimethylammonium bromide
epidermal growth factor receptor
gold nanoparticle(s)
poly(ethylene glycol)
photodynamic therapy
plasmonic photothermal therapy
sol particle immunoassay
surface plasmon resonance
transmission electron microscopy
tumor necrosis factor
Acknowledgements
We acknowledge support from the Russian Foundation for Basic
Research and from the Presidium of the Russian Academy of
Sciences within the program Basic Sciences for Medicine. We also
acknowledge support by grants from the Ministry of Education and
Science of the Russian Federation (no. MK-1057.2011.2, 2.1.1/
2950, 14.740.11.260, and 02.740.11.0484) and by a grant from the
Government of the Russian Federation designed to support
research projects supervised by leading scientists at Russian institutions of higher education. We thank D. N. Tychinin (IBPPM
RAS) for his help in preparation of the manuscript.
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