Plasmon-Resonant Gold Nanoparticles with Variable ...

Plasmon-Resonant Gold Nanoparticles with Variable Morphology as Optical Labels and Drug Carriers for Cytological Research Olga Bibikova*a,b, Alexey Popova, Ilya Skovorodkinc, Artur Prilepskyid, Timofey Pylaevd, Alexander Bykova, Sergey Staroverovd, Vladimir Bogatyrevb,d, Valery Tuchina,e,f, Matti Kinnunena, SeppoVainioc, Krizstian Kordasg, Nikolai Khlebtsovd a

Optoelectronics and Measurement Techniques Laboratory, Department of Electrical Engineering, P.O. Box 4500, 90014 University of Oulu, Finland b Department of Nonlinear Processes, Saratov State University, 410012, Saratov, Russian Federation c Laboratory of Developmental Biology, Oulu Center for Cell-Matrix Research, Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, Faculty of Medicine, P.O. Box 5000, 90014 University of Oulu, Finland d Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, 410049, Saratov, Russian Federation e Research-Educational Institute of Optics and Biophotonics, Saratov State University, Saratov, 410012, Russian Federation f Laboratory of Laser Diagnostics of Technical and Living Systems of Precision Mechanics and Control Institute, Russian Academy of Sciences, 410028 Saratov, Russian Federation g Microelectronics and Materials Physics Laboratories, Department of Electrical Engineering, Faculty of Technology, P.O. Box 4500, 90014 University of Oulu, Finland

ABSTRACT In this work, two types of nanocomposites, silica-coated nano-sea-urchins and silica-coated gold nanostars, were fabricated. CTAB-coated nano-sea-urchins with an average size of about 100 nm demonstrate an absorption peak near 600-700 nm and stability in aqueous suspension. CTAB was exchanged with m-PEG-SH by an intermediate PEG layer. A layer of silica was synthesized on the nano-sea-urchins surface with thickness of about 20 nm. Nanostars with an average size of about 60 nm with a number of thin sharp branches were fabricated and functionalized by PVP to improve their stability. PVP-coated nanostars were used in optical coherence tomography experiments to show their contrasting properties. After silica-coating, stable and monodispersed nanoparticles with silica shell thickness about 60 nm were obtained. Nontoxicity of the silica-coated nanostars at least until the concentration of nanoparticles about 400 μg/mL was showed by fluorescent cell viability assay using propidium iodide. Extinction coefficient of the gold nanostars and nanocomposites was estimated by a spectrophotometer system in collimated transmission regime. Keywords: plasmonic nanoparticles, nanocomposites, nanostars, nano-sea-urchins, HeLa cells, toxicity, optical properties, imaging, optical coherence tomography

1. INTRODUCTION Plasmon-resonant gold nanoparticles have attracted particular interest as a novel platform for nanotechnology and medicine [1,2] because of their unique optical properties, related to the localized plasmon resonance resulting in an enhanced electromagnetic field at the metal nanoparticle surface, low toxicity, convenient surface bioconjugation with molecular probes, stability in solvents and ideal size for delivery within the body [3]. Gold nanoparticles of various morphology successfully used in genomics [4], biosensorics [5], immunoassays [6], cancer cell photothermolysis [7], targeted delivery of drugs or other substances [8], optical coherence tomography [9], two-photon luminescence [10], or photoacoustic [11] techniques. Novel Biophotonic Techniques and Applications II, edited by I. Alex Vitkin, Arjen Amelink, Proc. of SPIE-OSA Biomedical Optics, SPIE Vol. 8801, 880102 · © 2013 SPIE · CCC code: 1605-7422/13/$18 doi: 10.1117/12.2032547 Proc. of SPIE-OSA/ Vol. 8801 880102-1 Downloaded From: http://proceedings.spiedigitallibrary.org/ on 06/22/2013 Terms of Use: http://spiedl.org/terms

There are many subtypes of gold nanoparticles with well-controlled size distribution and optical properties. Plasmon resonance of the nanoparticles can be tuned to the near-infrared (NIR) spectral region of the “diagnostic/therapeutic window” (700-1300 nm) with enhanced light penetration into biotissue [12]. Recently, branched and star-shaped gold nanoparticles have received considerable attention for their unique optical and electronic properties, specifically, strong absorptions in the NIR wavelength range and tremendously high electric field intensities at their branches, which, in turn, can result in extremely high activity in surface-enhanced Raman spectroscopy (SERS) [13]. Additionally to the SERS application, star-shaped nanoparticles have other applications in the biomedical field, such as drug delivery and optical imaging [14]. Outstanding brightness of the nanostars allows tracing the morphological changes in a cells population thereby determining the toxicity of the nanocomposites. A new tendency in nanotechnology is fabrication of multifunctional nanoparticles, which combine therapeutic and diagnostic modalities in a single nanostructure. In these nanocomposites gold nanoparticles simultaneously exhibit properties of optical labels and therapeutic agents (for drug or gene delivery, photothermolysis and photodynamic therapy). Multifunctional nanoparticles hold considerable promise as a next generation of medicines enabling detection of diseases at early stage, simultaneous monitoring and treatment and targeted therapy with low damage of healthy tissues and organs. Particles toxicity and their localization within cells play a crucial role in developing novel nanostructures for biomedical applications [15]. *[email protected]; phone +7 927 150-3494; +358 40 445-1954; fax +358 8 553 2774; http://www.oulu.fi/eeng

In multifunctional nanoparticles for theranostics a silica shell is used to enhance cargo volume and surface area to increase colloidal stability of nanoparticles, provide tunable solubility in various solvents, and size- and shape-dependent optical properties [16]. Here we report about fabrication and characterization of gold nano-sea-urchins and nanostars, intact and coated with silica shells, examine their cytotoxic properties and show imaging capabilities.

2. METHODOLOGY Chemicals Gold(III) chloride trihydrate (HAuCl4 3 3H2O), trisodium citrate dihydrate (C6H5O7Na3 3 2H2O), 1 N HCl, L(+)ascorbic acid (AA), tetraethyl orthosilicate (TEOS), propidium iodide (PI); sodium borohydride (NaBH4), 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), hexadecyltrimethylammonium bromide (CTAB), poly(vinyl pyrrolidone) (PVP; Mw = 55000), silver nitrate (AgNO 3), potassium carbonate (K2CO3) were purchased from Sigma-Aldrich (USA) at the highest purity grade available. Absolute isopropyl alcohol (IPA; 99.99%),), absolute ethanol (99.99%), ammonia NH4OH (29.5%), Dulbecco’s Modified Eagle’s Medium (DMEM), penicillin-streptomycin solution were purchased from Sigma-Aldrich (USA). DMSO (ACS grade) was purchased from Amresco, mPEG-SH (MW, 5000) was purchased from Creative PEGWorks, polyethylenglycol (PEG, MW, 20000) was from Ferax (Germany). Milli-Q water (18 MOhm- cm; Millipore) was used in all preparations. Nano-sea-urchins synthesis CTAB-coated nano-sea-urchins were prepared by seed-mediated process described by Yu [17], with modifications. Gold seeds were prepared by adding 0.1 mL of an ice-cold 30 mM NaBH4 aqueous solution into a 10 mL aqueous solution with 250 μM HAuCl4 and 250 μM trisodium citrate during gentle shaking. The seed suspension was allowed to stand for 4 h. Growth solutions are prepared as follows: 300 μL of seeds, 30 μL 20 mM of freshly prepared AgNO 3 aqueous solution were added into 50 mL of aqueous solution containing 82.3 mМ CTAB and 240 μM HAuCl4 were added, 2.5 mL of 100 mM freshly prepared AA aqueous solution. The suspension was allowed to proceed for 3 h, while its color gradually changed to dark-gray. The solution was washed at 8000 rcf for 10 min once and redispersed in 50 mL of water. Then, the CTAB molecules on nano-sea-urchin surfaces were replaced by mPEG-SH by modified Thierry method [18]. 1 mL 1% aqueous solution of PEG was added to 49 mL nano-sea-urchins and the reaction was left to proceed for 15 min. Then 0.2 mL of 0.2 M K2CO3 and 0.67 mL of 1 mM mPEG-SH were added into the solution. The mixture was allowed to react overnight. Excess mPEG-SH molecules were removed by double centrifugation and redispersion in 50 mL of water.

Proc. of SPIE-OSA/ Vol. 8801 880102-2 Downloaded From: http://proceedings.spiedigitallibrary.org/ on 06/22/2013 Terms of Use: http://spiedl.org/terms

Silica-coating of nano-sea-urchins Silica coating of nano-sea-urchins were carried out by the modified Stöber method [19] 5 mL of PEGylated nano-seaurchins was added under stirring to 7.5 mL of IPA, then 400 μL of an 3% ammonia solution in IPA and 450 mL of a 100 μM TEOS solution in IPA were added. The reaction took place overnight at room temperature. The suspension was washed by water by centrifugation at 7000 rcf for 10 min three times and finally redispersed in 30 mL of water. Nanostars synthesis Nanostars were fabricated by seed-mediated growth method with small modifications as described by Yuan et al [20].The seed solution was prepared by reduction of HAuCl 4 with sodium citrate by Grabar method [21]. Briefly, 10 mL of 38.8 mM sodium citrate was added quickly to boiled 100 mL of 1 mM water solution HAuCl 4, which resulted in a change in solution color from pale yellow to deep red. Further 10 μL of 1 N HCl and 100 μl of the seed solution were added to 10 ml of 0.25 mM of HAuCl4 water solution at room temperature under vigorous stirring. Quickly, 100 μL of 2 mM AgNO3 and 50 μL of 0.1M AA were added simultaneously. The solution was stirred for 30 s and turned from lightred to a dark-gray. Immediately afterwards 250 μL of 0.36 mM PVP was added under gentle stirring. The solution was stirred for 15 min and washed at 7500 rcf for 10 min once. The solution was redispersed in 0.5 mL of water. Silica-coating of nanostars A method from elsewhere [22] was used for formation of the silica shell on PVP-covered nanostars. Under gentle stirring, 0.5 mL of the nanostars was added to 2.25 mL of IPA. 90 μL of a 30% aqueous ammonia solution and 6.25 μL of TEOS were added to the solution under continuous stirring. The reaction was allowed to proceed for 30 min at room temperature under gentle stirring. The resulting solution was washed three times by centrifugation at 6000 rcf and finally the colloids were redispersed in 2 mL of water. Characterization of the particles Microscopy images were taken on LEO 912 OMEGA Energy filtered transmission electron microscope (TEM) operating at 120 kV. To prepare samples for TEM observations, one drop of water suspension was deposited onto carbon-coated copper grid. The optical properties of the products was characterized by Spectrophotometer system (Optronic Laboratories, USA) with integrating spheres in collimated transmittance regime. The attenuation coefficient was retrieved from the measurements and applying Beer’s law. Cell viability test Viability of cells was examined by fluorescent cell viability assay using propidium iodide (PI). HeLa cells (Biocenter Oulu, Finland) were maintained at 37 C and 5% CO2 in complete DMEM medium supplemented with 10% bovine serum, 1 % penicillin-streptomycin. For the fluorescent assay, the cells in concentration 106 mL-1 were maintained in 6-well culture plates in 1 mL of medium and incubated overnight with silica-coated gold nanostars at concentrations of 25 μg/mL, 50 μg/mL, 100 μg/mL, 200 μg/mL and 400 μg/mL. After incubation, PI solution was added to the cells to form the final concentration of 3 µg/mL. Cells were stained for 20 min in the dark at 37 C. Each experiment was repeated 3 times. Fluorescence of cells with compromised membranes (and thus considered as dead) was registered by Olympus IX81 epifluorescent inverted microscope equipped with a filter cube TRITC 41002c (Chroma). Ratio of fluorescing cells to the total number of cells in a field of view was calculated. For investigation of the nanoparticles localization the cells were maintained in sterile microscopic cover-glass and incubated overnight with silica-coated gold nanostars at concentration of 400 μg/mL. The samples were examined by laser scanning microscope Zeiss LSM 780 with EC Plan-Neofluar 10x /0.3 objective in transmission PMT regime. Optical coherence tomography experiments A spectral-domain optical coherence tomograph Hyperion (Thorlabs, USA) operating at 930-nm central wavelength with axial (along Z-axis) resolution of 5.8 μm and lateral resolution of 8 μm was used for imaging of gold nanostar (OD=10,  = 930 nm) and Intralipid aqueous suspensions. Intralipid is a commercially-available fat-containing emulsion (Fresenius Kabi, Sweden) usually used for intravenal feeding of patients in hospitals. In biomedical optics research, it is often


applied for imaging and sensing experiments due to its tissue-mimicking properties in NIR range (4% suspension). We used ready Intralipid-20% to prepare Intralipid-4% suspensions in 200-μm-thick capillaries plane glass capillaries.

3. RESULTS AND DISCUSSIONS 3.1

Fabrication and characterization of silica-coated nano-sea-urchins

For our experiments, two types of gold nanoparticles were used: gold nano-sea-urchins [17] and gold nanostars [21]. A general scheme for the synthesis of nano-sea-urchins is the reduction of chloroauric acid with ascorbic acid and silver nitrate at room temperature, on pre-synthesized gold nanocrystal seeds and in the presence of a cationic surfactant CTAB[17]. Gold nano-sea-urchins should be functionalized with thiols in order to substitute surfactant bilayer at the particle surfaces to avoid cytotoxic side-effects of the CTAB. Among various polymers used for this purpose, m-PEGSH is one of the most effective in improving stability in aqueous or alcohol media [23] and one of the most popular precursor for silica-coating [24]. For successful functionalization of the nano-sea-urchins with m-PEG-SH, the intermediate PEG layer, which aims to provide efficient steric stabilization of the nanoparticles during the ligand exchange reaction with thiols was introduced [18]. Figure 1 shows the optical spectra of PEG-coated NSUs and PEGcoated nano-sea-urchins after silica-coating (Figure 1a) and TEM images of nanoparticles taken at two synthetic stages, the first of which consisted in fabricating a nanoparticles core (Figure 1b). It can be seen that the nano-sea-urchins had an average size of about 100 nm and consisted of a few thick branches. At the second stage, after PEGylation, a layer of silica was deposited on the nano-sea-urchins surface with thickness of about 20 nm. - -- nano -sea - urchins -peg

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Figure 1. Absorption spectrum of nano-sea-urchins and nanocomposites with silica (a), TEM images of PEG-coated nano-seaurchins (b).

Silica coating of nano-sea-urchins were carried out by the modified Stöber method. A layer of silica was formed on the particle surface and did not have a mesoporous structure according to TEM images (Figure 1c, d). Silica coating of the nanoparticles gives an expected red shift in the absorption spectrum about 30 nm due to an increase in the local refractive index around the nano-sea-urchins [25] (Figure 1a). . 3.2

Fabrication and characterization of silica-coated nanostars

The nano-sea-urchins are one of the most stable types of bumpy gold nanoparticles, but the synthesis of the particles is extremely long, and it is difficult to control the optical and plasmonic properties. Additionally, their use is limited by the potential toxicity of CTAB [26] and the particles show small amount of thick beams. Sharp beams interact more intensively with NIR laser excitation, and play a key role in determining the optical properties of the nanostars. For biological applications and optical imaging biocompatible surfactant-free synthesis of nanostars in aqueous media presented by Vo-Dinh’s research group [20] is more suitable. Nanostars of this type have a lot of thin sharp beams. The synthesis is simple and takes about 1 min, but fabricated in our lab, the nanostars were not stable enough, and irreversible aggregation was observed even after fictionalization by m-PEG-SH as described in Fales work [14].To avoid


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significant aggregation, PVP instead of PEG functionalization was performed with the nanostars. The PVP functionalization proceeds 15 min. The resulting nanostars after PVP-coating proved to be stable at least for 3 months and allowed multiple centrifugation-redispersion cycles in different media. Figure 2a demonstrates optical spectra of PVP-coated nanostars and PVP -coated nanostars after silica-coating and TEM images of nanocomposites taken at two synthetic stages as well. The nanostars had an average size of about 60 nm and possessed a number of thin sharp beams. A layer of silica was synthesized on the nanostars surface with thickness about 60 nm.

Figure 2. Absorption spectrum of nanostars and nanocomposites with silica (a), TEM images of PVP-coated nanostars (b).

We have used the method of silica coating presented by Khlebtsov et al. [27]. A silica shell around a nanostar core is synthesized due to base-catalyzed hydrolysis of TEOS. The silica shell thickness can be simply varied by changing the reaction time and TEOS concentration. In our case, the reaction took 30 min. All together, the fabrication of silica coated gold nanostars took around 45 min. 3.3

Optical absorption and scattering of nanoparticles

Analysis of optical properties was performed by the UV-Vis spectrophotometer allows for calculation of the extinction coefficient of the fabricated nanoparticles suspensions, being their important optical property. 3.0

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Figure 3. Attenuation (a) coefficient of gold nanostar suspension retrieved from spectrophotometric measurements. The device comprises a light source, a monochromator, and an integrating sphere (transmittance mode) (b). Figure 3 shows, that due to different positions of the maximal scattering and absorption, nanocomposites are more beneficial for biotissue imaging and therapy due to weaker light attenuation (and thus deeper penetration) at 900 nm than at 700 nm. Scattering properties are utilized in purely light imaging and absorption properties are necessary for e.g. photoacoustic imaging and thermal therapy.


3.4

Cell viability test

For proving the potential usability of silica-coated gold nanostars, we investigated nanoparticles toxicity on the HeLa cell line by fluorescent cell viability assay using propidium iodide at various concentrations of silica-coated gold nanostars.

Reproportioning of live and dead cells, %

This cytotoxicity test is used to separate live and dead cells by staining only damaged cells with propidium iodide. Number of dead cells was counted for each nanoparticles concentration and then the percentage of live cells was calculated. Figure 4 demonstrates the concentration-dependent percentage of live cells. The result proves nontoxicity of the silica-coated nanostars.

Figure 4. Cytotoxicity of silica-coated gold nanostars of different concentrations evaluated by fluorescent cell viability assay with propidium iodide.

3.5

Optical coherence tomography experiments

PVP-coated nanostars were used for optical coherence tomography (OCT) glass capillary imaging. The use of the nanoparticles for OCT imaging significantly increases visibility of capillaries in tissue-mimicking phantoms and in laboratory animals in vivo rendering nanostars as a contrasting agent. Nanostars with plasmon resonance maximum at 700-900 nm corresponds to central emission wavelength of the light source (superluminescent diode) of the employed OCT system (Thorlabs, USA). The capillaries were filled in with gold nanostars (10 μL, OD = 10) or Intralipid-4%. Brighter color indicates higher scattering at 930 nm. Inner capillary thickness is 200 μm. All settings of the OCT device were kept the same to properly compare imaging capability of the used nanostars with Intralipid. It is seen that the nanostars are not as bright as Intralipid-4%. When mixed with Intralipid-4%, nanostars introduce both additional scattering and absorption (Figure 5). The effect should be much more pronounced when imaging such forward-scattering liquids as blood, since nanostars will increase backward-reflected light, making possible not only static blood capillary imaging but also reconstruction of blood velocity profile important for disease diagnostics.


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Figure 5. Optical coherence tomography (OCT) glass capillary imaging. The capillary (cross-section shown) is filled in with gold nanostars (10 μL, OD = 10) and Intralipid-4%. Brighter color indicates higher scattering at 930 nm. Inner capillary thickness is 200 μm.

4. CONCLUSIONS In summary, two types of nanocomposites: silica-coated nano-sea-urchins and silica-coated gold nanostars were fabricated. Silica-coated nano-sea-urchins demonstrate an absorbance peak near 500-550 nm and stability in aqueous suspension. Nevertheless the nano-sea-urchins used as a core are potentially toxic due to CTAB surfactant and show a small number of thick beams, while sharp beams are responsible for extremely high light scattering of nanostars. This was a reason to use Vo-Dinh's nanostars with a lot of thin and sharp beams as a core. They exhibited absorbance within the range of 790-830 nm. PVP functionalization was used for increasing stability of nanostars. PVP-coated nanostars were used for optical coherence tomography experiments and show promising imaging capabilities. After silica-coating stable and monodispersed nanoparticles with silica shell thickness about 60 nm were obtained. Nontoxicity of the silicacoated nanostars at least up to 400 μg/mL was assessed by fluorescent cell viability assay using propidium iodide.

ACKNOWLEDGMENT This research was supported by the program “U.M.N.I.K” № 10497р/16910 (Russian Federation), CIMO fellowship (# 24301281, Finland), Tauno Tönning Foundation (Finland) and Tekniikan Edistämissäätiö (Finland).

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