We discus methods for fabrication of silica and composite nanoparticles, which can be used in various biomedical applications. The most promising types of such nanostructures are hollow silica nanosheres, sil-ica coated plasmon-resonant nanoparticles (gold nanorods and gold-silver nanocages) and nanorattles. Mesoporous silica shell can be doped by desirable targeting molecules. Here we present the results of for-mation of nanocomposites composed of gold nanorods and double-layer silica shell. The secondary mesopo-rous silica shell is doped with a photosensitizer (hematoporphyrine in our case). We demonstate some of promising theranostics applications of these nanocomposites for bioimaging and in vivo therapy of tumors.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/3548

Bashkatov, A.N.

Basko, M.V.

Bucharskaya, A.B.

Chumakov, D.S.

Genina, E.A.

Khanadeev, V.A.

Khlebtsov, B.N.

Khlebtsov, N.G.

Terentyuk, G.S.

English

SocioEconomic Challenges Journal (Sumy State University)

PROCEEDINGS OF THE INTERNATIONAL CONFERENCE  
NANOMATERIALS: APPLICATIONS AND PROPERTIES 
Vol. 2 No 4, 04NABM25(3pp) (2013) 
 
 
2304-1862/2013/2(4)04NABM25(3) 04NABM25-1  2013 Sumy State University 
Mesoporous Silica and Composite Nanostructures for Theranostics 
 
V.A. Khanadeev1, B.N. Khlebtsov1, G.S. Terentyuk2, D.S. Chumakov2, M.V. Basko3, 
A.B. Bucharskaya3, E.A. Genina2, A.N. Bashkatov2, N.G. Khlebtsov1,2,* 
 
1 Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, 13 Prospekt 
Entuziastov, 410049 Saratov, Russia 
2 Saratov State University, 83 Ulitsa Astrakhanskaya, 410012 Saratov, Russia 
3 Saratov State Medical University, 112 Ulitsa Bol’shaya Kazachia, 410012 Saratov, Russia 
 
(Received 14 June 2013; published online 01 September 2013) 
 
We discus methods for fabrication of silica and composite nanoparticles, which can be used in various 
biomedical applications. The most promising types of such nanostructures are hollow silica nanosheres, sil-
ica coated plasmon-resonant nanoparticles (gold nanorods and gold-silver nanocages) and nanorattles. 
Mesoporous silica shell can be doped by desirable targeting molecules. Here we present the results of for-
mation of nanocomposites composed of gold nanorods and double-layer silica shell. The secondary mesopo-
rous silica shell is doped with a photosensitizer (hematoporphyrine in our case). We demonstate some of 
promising theranostics applications of these nanocomposites for bioimaging and in vivo therapy of tumors. 
 
Keywords: Mesoporous silica, Nanoparticles, Nanocomposites, Theranostics, Photodynamic therapy 
 
 PACS numbers: 61.46.Df, 62.23.St, 87.50.wp 
 
 
                                                          
* khlebtsov@ibppm.sgu.ru 
1. INTRODUCTION 
 
Multifunctional nanocomposites that combine ther-
apeutic, diagnostic, and sensing modalities in a single 
nanostructure are widely used in a new field of nanobi-
otechnology called theranostics [1-4]. Although the 
term “theranostics” has been employed for the first 
time quite recently [5], it is now rapidly growing and 
promising field at the crossroads of plasmonics and 
nanomedicine [6,7]. 
Silica is widely used for synthesis of nanoparticles 
and multifunctional nanocomposites owing to its bio-
compatibility and facility of preparation [8]. Amor-
phous silica is used, for example, as a core for 
nanoshells [9], whereas its mesoporous counterpart is 
also widely used owing to high volume of pores, which 
can serve as effective carriers in drug delivery applica-
tions. Nowadays mesoporous silica nanoparticles are 
replaced by more complex structures like hollow silica 
nanoparticles and nanocomposites, which can support 
several modalities in one nanoparticle. For example, 
such modalities can include plasmonic heat generation, 
visible and IR luminescence, and photodynamic gener-
ation of singlet oxygen [10]. Here we describe several 
types of silica-based nanostructures composed of plas-
monic particles and double-layer silica shell. Such mul-
tifunctional nanocomposites can be used in promising 
theranostics applications [11] including bioimaging [12] 
and combined photodynamic (PD) and photothermal 
(PT) therapy of tumors [13].  
 
2. FABRICATION OF HOLLOW SILICA 
SPHERES AND NANOCOMPOSITES 
 
2.1 Hollow Silica Nanoparticles 
 
The first step in fabrication of hollow silica nano-
particles is a formation of silica nanospheres using 
Stober method [14] (Fig. 1, a). According to the protocol 
by Fang et al. [15], silica nanoparticles were coated by 
cetyltrimethylammonium bromide (CTAB) and etched 
in alkaline conditions (Fig. 1, b, с). Two strategies of 
etching [15] lead to formation of various types of struc-
tures with worm-like (Fig. 1, b) and oriented pores in a 
silica shell (Fig. 1, с). Typically, the outer diameter of 
particles can be tuned within the range from 50 nm to 
1200 nm. The shell thickness also can be varied from 
15 nm to 70 nm. 
 
 
 
Fig. 1 – (a) Silica nanospheres formed by Stober method.(b) 
Hollow silica spheres obtained by alkaline etching using 
CTAB surface protection (c) Hollow silica spheres obtained by 
two-stages protocol including secondary mesoporous shell 
synthesis and alkaline etching. All scale bars are 200 nm 
 
2.2 Nanocomposites Containing Plasmonic  
Nanoparticles Within Silica Shell 
As a core of nanocomposites we used gold nanorods 
(NRs) and gold-silver nanocages (NCGs), which were 
coated by amorphous silica shell using modified Stober 
method [16]. The next step was coating of these nano-
particles by a mesoporous silica shell, containing fluo-
rescent dye and photosensitizer hematoporphyrine [17] 
(Fig. 2 a). Incorporation of hematoporphyrine (HP) into 
silica shell was achieved by preliminary formation of 
HP-containing silane precursor, which was then added 
to the reaction medium. Amorphous transitional silica 
 V.A. KHANADEEV, B.N. KHLEBTSOV, G.S. TERENTYUK, ET AL. PROC. NAP 2, 04NABM25 (2013) 
 
 
04NABM25-2 
layer was necessary for prevention of electron transfer 
between dye molecules and metal surface, which could 
result in the fluorescence quenching. 
In short, gold nanorods were synthesized by a seed-
mediated growth method [18] with an original modifi-
cations described in our paper [19]. Gold-silver 
nanocages were synthesized by a two step protocol [20] 
modified in our paper [21]. The first step is a synthesis 
of siver nanocubes and the second step is a synthesis of 
gold-silver nanocages by the galvanic replacement re-
action [22]. 
In a typical synthesis, AuNRs had an average 
length of 44  7 nm and an average width of 11  1 nm. 
The plasmon resonance wavelength was located near 
810 nm. The fabricated Au-Ag NCGs had an average 
edge length of about 50  5 nm and a plasmon reso-
nance peak near 750-800 nm, depending on the Ag/Au 
conversion ratio. 
 
 
 
Fig. 2 – (a) Nanocomposites containing gold nanorods. White 
dotted line showed the boundary between primary amorphous 
silica shell and secondary mesoporous shell containing hema-
toporphyrine. (b) Gold-silver nanocages coated by amorphous 
silica shells. (с) Nanorattles, obtained by etching of thick silica 
shells fabricated on small gold-silver nanocages 
 
2.3 Nanorattles 
 
One of recently developed types of silica-based com-
posite nanoparticles is so-called “nanorattles” [23], 
comprising a metal core, which can freely move inside 
the hollow silica shells. The strategy of their formation 
is similar to the method of fabrication of hollow silica 
nanoparticles.  
In this work we fabricated nanorattles comprising 
gold-silver nanocages (Fig. 2, c). Silica etching was per-
formed in alkaline conditions with poly(vinyl pyrroli-
done) (PVP) for surface protection [23]. 
 
3. SILICA AND COMPOSITE NANOPARTICLES 
IN THERANOSTIC APPLICATIONS 
 
Nanocomposites containing gold nanorods and hema-
toporphyrine in the secondary silica shell (Fig. 2a) can 
be used in bioimaging due to intense fluorescence of 
hematoporphyrine molecules. (Fig. 3b).  
Straigtforward evidence for the successful function-
alization of composite particles with HP is provided by 
the photo in the figure 3. Shown here are the cuvettes 
containing composite particles with attached HP (NCs), 
gold nanorods without HP (NRs) and free HP solution 
(HP). Under white light illumination, the first two cu-
vettes demonstrate a red color because of selective ab-
sorption of visible light near 515 nm and a third cuvette 
with HP solution is transparent. When irradiated with 
a UV lamp, the second and third cuvettes exhibit in-
tense pink fluorescent emission, whereas the first cu-
vette retains nonfluorescent.  
Such nanocomposites combine the PT and PD modal-
ities can be used not only for antimicrobial treatment 
[17], but also for a combined therapy of cancer. We suc-
cessively used these nanocomposites for in vivo thera-
peutics of cancer tumors transplanted into rats. 
 
 
 
Fig. 3 – Suspensions of gold nanorods (NRs), nanocomosites 
containing gold nanorods, amorphous silica shell, and mesopo-
rous silica shell with hematoporphyrine (NCs), and free hema-
toporphyrine solution (HP), irradiated by white light (a) and 
UV-light (b) 
 
 
 
Fig. 4 – Images of (a) a tumor with volume of about 10 cm3 
before irradiation, (b) after 30 min of irradiation, and (c) after 3 
h of irradiation. Combined PDT and PTT under 630 nm (0,86 
mW/cm2) and 810 nm (2,3 W/cm2) irradiation 
 
The rat liver cancer cells PC-1 (kindly provided by 
Blokhin Cancer Research Center, Moscow) were intra-
muscularly injected in rats, and tumors were allowed 
to grow up to volume of 10 cm3. After intratumoral in-
jection of suspension of nanocomposites into tumors, 
they we treated for skin clearance [24] followed by ir-
radiation simultaneously by two lasers with wave-
lengths of 808 nm (2.3 W/cm2, for photothermal thera-
py) and 630 nm (0.86 mW/cm2, for photodynamic ther-
apy). 
Our results showed that combined usage of photo-
dynamic and photothermal therapy is much more effec-
 MESOPOROUS SILICA AND COMPOSITE NANOSTRUCTURES FOR THERANOSTICS PROC. NAP 2, 04NABM25 (2013) 
 
 
04NABM25-3 
tive than only one of them. Figure 4 shows images of a 
tumor with volume of about 10 cm3 grafted on the back 
of the rat before irradiation (Fig.4, a) and 30 min 
(Fig. 4b) and 3 h (Fig. 4c) after. 
 
4. CONCLUSIONS 
 
In this work we have demonstrated the capability of 
synthesis of silica-based nanoparticles with various 
structures, such as amorphous, mesoporous and hollow. 
We have also synthesized nanocomposites with core-
shell, core-double layered shell, and rattle-type struc-
tures.  
Nanocomposites with a gold nanorod core and a 
photosensitizer HP-doped silica shell have been suc-
cessfully fabricated. The visible fluorescence of bound 
HP molecules was not quenched due to metal-PS inter-
action because of separation from the nanorod core by 
amorphous silica shell. Under UV excitation, the nano-
composites reveal quite intense fluorescent emission of 
light that is visible by naked eye. These nanocompo-
sites have been successively used in combined PT and 
PD therapy of grafted cancer tumors in rats in vivo. 
Thus, fabricated composites may be effectively used for 
theranostics of cancer deceases. 
 
AKNOWLEDGEMENTS 
 
This research was supported by grants from the 
Russian Foundation for Basic Research, the Programs 
of the Presidium of the Russian Academy of Sciences 
“Basic Sciences for Medicine” and “Basic Technologies 
for Nanostructures and Nanomaterials”, and the Gov-
ernment of the Russian Federation (a grant to support 
scientific research projects implemented under the su-
pervision of leading scientists at Russian institutions of 
higher education). VK was supported by a scholarship 
from the President of the Russian Federation and a 
grant of OPTEC company for the support of young sci-
entists of leading higher educational establishments 
and research centers. 
 
 
REFERENCES 
 
1. F.J. Picard, M.G. Bergeron, Drug Discov Today 7, 1092 
(2002).  
2. X. Chen. Theranostics 1, 1 (2011). 
3. D.S. Wagner, N.A. Delk, E.Y. Lukianova-Hleb, 
J.H. Hafner, M.C. Farach-Carson, D.O. Lapotko, Bio-
materials 31, 7567 (2010). 
4. T. Lammers, S. Aime, W.E. Hennink, G. Storm, 
F. Kiessling, Acc Chem Res. 44, 1029 (2011). 
5. J. Funkhouser, Curr Drug Discov. 2, 17 (2002). 
6. S. Warner, Scientist 18, 38 (2004). 
7. S.S. Kelkar, T.M. Reineke, Bioconjug Chem. 22, 1879 
(2011). 
8. F. Tang, L. Li., D. Chen, Adv. Mater. 24, 1504 (2012). 
9. S. Oldenburg, R.D. Averitt, S. Westcott, N.J. Halas, Chem. 
Phys. Lett. 288, 243 (1998). 
10. B. Khlebtsov, E. Panfilova, V. Khanadeev, O. Bibikova, 
G. Terentyuk, A. Ivanov, ACS Nano 5, 7077 (2011). 
11. N. Khlebtsov, V. Bogatyrev, L. Dykman, B. Khlebtsov, 
S. Staroverov, A. Shirokov, L. Matora, V. Khanadeev, 
T. Pylaev, N. Tsyganova, G. Terentyuk, Theranostics 3, 
167 (2013). 
12. C.-C. Huang, W. Huang, C.-S. Yeh, Biomaterials 32, 556 
(2011). 
13. S. Wang, P. Huang, L. Nie, R. Xing, D. Liu, Z. Wang, 
J. Lin, S. Chen, G. Niu, G. Lu, X. Chen, Adv. Mater. (2013) 
doi: 10.1002/adma.201204623 
14. W. Stober, A. Fink, J. Bohn, J. Colloid Interface Sci. 26, 62 
(1968). 
15. X.Fang, C. Chen, Z. Liu, P. Liu, N. Zheng. Nanoscale 3, 
1632 (2011). 
16. Y.S. Chen, W. Frey, S. Kim, P. Kruiziga, K. Homan, 
S. Emelianov, Nano Lett. 11, 348 (2011). 
17. B. Khlebtsov, E. Tuchina, V. Khanadeev, E. Panfilova, 
P. Petrov, V. Tuchin, N. Khlebtsov, J. Biophotonics 6, 338 
(2013). 
18. B. Nikoobakht, M.A. El-Sayed, Chem. Mater. 15, 1957 
(2003).  
19. B.N. Khlebtsov, V.A. Khanadeev, N.G. Khlebtsov, J. Phys. 
Chem. C 112, 12760 (2008). 
20. S.E. Skrabalak, L. Au, X. Li, Y. Xia, Nat. Protoc. 2, 2182 
(2007). 
21. E.V. Panfilova, B.N. Khlebtsov, A.M. Burov, 
N.G. Khlebtsov, Colloid J. 74, 99 (2012). 
22. B.N. Khlebtsov, N.G. Khlebtsov, V.A. Khanadeev, 
I.L. Maksimova, G.S. Terentyuk, Nanotechnologies in 
Russia 5, 454 (2010). 
23. Q. Zhang, J. Ge, J. Goebl, Y. Hu, Z. Lu, Y. Yin, Nano Res. 
2, 583 (2009). 
24. A.N. Bashkatov, E.A. Genina, V.V. Tuchin, J. Innovative 
Optical Health Sci. 4, 9 (2011). 
 


Mesoporous Silica and Composite Nanostructures for Theranostics

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Mesoporous Silica and Composite Nanostructures for Theranostics

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