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Biomedical Optics & Medical Imaging

Novel multifunctional nanocomposites for theranostics

Hybrid nanoparticles consisting of a gold-silver nanocage core and a mesoporous silica shell doped with a photodynamic sensitizer have been fabricated, characterized, and tested in vitro and ex vivo.
22 September 2011, SPIE Newsroom. DOI: 10.1117/2.1201109.003832

Multifunctional nanoparticles that combine therapeutic and diagnostic modalities are a new trend in nanobiotechnology. One attractive option for theranostic applications are systems that combine the unique optical properties of plasmonic nanoparticles1 and the advantages of mesoporous silica functionalized with an appropriate photosensitizer. However, there is limited data available on such materials.

Figure 1. Schematic illustration summarizing how fluorescent composite nanoparticles can be fabricated starting with silver nanocubes and ending with gold-silver (Au-Ag) nanocages coated with silica (SiO2) that is functionalized with ytterbium-hematoporphyrin (Yb-HP) molecules. The right, center photo shows visible fluorescence of the particles under UV excitation. The left, bottom plots show the absorbance spectra of silver nanocubes (black), Au-Ag nanocages (yellow-gold), silica-coated nanocages (blue circles), and final Au-Ag/SiO2/Yb-HP nanocomposites (red). The right, bottom image illustrates potential applications for in vivo imaging and photodynamic therapy—using IR-luminescence and singlet oxygen (1O2) generated by Yb-HP—and photothermal therapy (using the heat generated by plasmonic nanocages).

Recently, we suggested nanoparticles consisting of a gold-silver (Au-Ag) nanocage core and a mesoporous silica (SiO2) shell that is doped with the photodynamic sensitizer ytterbium-hematoporphyrin (Yb-HP).2 The synthesis of such composites includes four basic steps (see Figure 1). First, silver nanocubes are prepared by the sulfide-mediated polyol method.3 Then, these cubes serve as templates to create partly hollow Au-Ag alloyed structures called nanocages, whose formation is accompanied by controllable red shift of the plasmon resonance from 435nm to 650–900nm. Finally, the third and fourth steps involve fabricating a mesoporous silica shell (20–120nm) doped with Yb-HP molecules.

Figure 2. Transmission electron microscope images of (a) silver nanocubes, (b) Au-Ag nanocages, and (c) composite silica-coated nanocages. The insets in (b) show the box and cage particle morphologies. Images (d) and (e) show cuvettes with 1: final nanocomposites Au-Ag/SiO2/Yb-HP; 2: silica-coated particles Au-Ag/SiO2; and 3: free Yb-HP solution under white and UV light excitation respectively. The scale bars in the insets are 50nm.

Figure 3. (a) The average integral luminescence intensities over the 900–1060nm spectral band recorded with 405nm excitation for five mice organs taken 20h after intravenous injection of Yb-HP and Au-Ag/SiO2/Yb-HP nanocomposites (NC). The numbers designate 1: tumor, 2: liver, 3: spleen, 4: muscle, and 5: skin. (b) Cell viability as determined by the MTT in vitro nanotoxicity assay for HeLa cells under various treatment conditions. Bars designate standard deviation (n=4).

Figure 2 shows images of cuvettes with silver nanocubes, Au-Ag nanocages, and silica-coated nanocages. Straightforward evidence for the successful functionalization of the composite particles with Yb-HP is provided by the photo on the right, bottom, which shows cuvettes containing the nanocomposites with and without attached Yb-HP, and with free Yb-HP molecules. Under white light illumination, cuvettes 1 and 2 show a blue-green color while 3 looks faint pink because of selective absorption near 400nm. When irradiated with a UV lamp, cuvettes 1 and 3 exhibit intense pink fluorescent emission whereas 2 remains blue. Additional evidence for the successful functionalization of the particles was obtained from measurements of singlet oxygen (1O2) generation.

We used IR luminescence for the ex vivo detection of Au-Ag/SiO2/Yb–HP nanoparticles in different organs taken from tumor-bearing mice: see Figure 3(a). To assess the potential of the particles as theranostic agents, we examined the viability of HeLa cells in the presence of free Yb-HP and nanocomposites with and without light treatment: see Figure 3(b). We observed enhanced killing of HeLa cells incubated with the particles and irradiated with a 625nm LED.

The hybrid nanoparticles combine several promising theranostic modalities: an easily tunable plasmon resonance across the 650–950nm spectral band with possible use in photothermolysis; a mesoporous silica shell that preserves the plasmon resonance from an aggregation shift and provides a convenient possibility of surface or volume functionalization with various molecular probes; and a combination of singlet oxygen generation with IR-luminescence band of Yb-HP, which can be used for optically controlled photodynamic therapy.

We are now attempting to fabricate silica-coated Au-Ag nanocages and Au nanorods functionalized with hematoporphyrin, which we plan to characterize using transmission electron microscopy, absorption and fluorescent spectroscopy, and other methods. These nanocomposites will be tested as potential antimicrobial agents against several pathogenic bacteria.

This research was supported by grants from the Russian Foundation for Basic Research and from the President and the Ministry of Education and Science of the Russian Federation. We thank Dr. I. Shilov for NIR-luminescence measurements and Dr. A. Ryabova for singlet oxygen measurements.

Nikolai Khlebtsov, Boris Khlebtsov, Elizaveta Panfilova, Vitaly Khanadeev, Olga Bibikova, Sergey Staroverov
Laboratory of Nanobiotechnology
Institute of Biochemistry and Physiology of Plants and Microorganisms
Russian Academy of Sciences (IBPPM RAS)
Saratov, Russia

Nikolai Khlebtsov is the head of the Nanobiotechnology Lab at IBPPM RAS and a biophysics chair at Saratov State University. His scientific interests include biophotonics and nanobiotechnology of plasmon-resonant particles and their biomedical applications.

Georgy Terentyuk
Saratov State University
Saratov, Russia
Valentina Rumyantseva
Lomonosov Moscow State Academy of Fine Chemical Technology
Moscow, Russia
Andrei Ivanov
Blokhin Russian Cancer Research Center
Moscow, Russia

1. N. G. Khlebtsov, L. A. Dykman, Optical properties and biomedical applications of plasmonic nanoparticles, J. Quant. Spectrosc. Radiat. Transf. 111, pp. 1-35, 2010.
2. B. Khlebtsov, E. Panfilova, V. Khanadeev, O. Bibikova, G. Terentyuk, A. Ivanov, V. Rumyantseva, I. Shilov, A. Ryabova, V. Loshchenov, N. Khlebtsov, Nanocomposites containing silica-coated gold-silver nanocages and Yb-2,4-dimethoxyhematoporphyrin: Multifunctional capability of IR-luminescence detection, photosensitization, and photothermolysis, ACS Nano 5, 2011. doi:10.1021/nn2017974
3. S. E. Skrabalak, L. Au, X. Li, Y. Xia, Facile synthesis of Ag nanocubes and Au nanocages, Nat. Protoc. 2, pp. 2182-2190, 2007.