- Open Access
Gold nanorods-conjugated TiO2 nanoclusters for the synergistic combination of phototherapeutic treatments of cancer cells
© The Author(s) 2018
- Received: 7 September 2018
- Accepted: 10 December 2018
- Published: 20 December 2018
Recently, a combination of photodynamic therapy (PDT) and photothermal therapy (PTT) to generate reactive oxygen species (ROS) and heat to kill cancer cells, respectively has attracted considerable attention because it gives synergistic effects on the cancer treatment by utilizing the radiation of nontoxic low-energy photons such as long wavelength visible light and near IR (NIR) penetrating into subcutaneous region. For the effective combination of the phototherapies, various organic photosensitizer-conjugated gold nanocomplexes have been developed, but they have still some disadvantages due to photobleaching and unnecessary energy transfer of the organic photosensitizers.
In this study, we fabricated novel inorganic phototherapeutic nanocomplexes (Au NR–TiO2 NCs) by conjugating gold nanorods (Au NRs) with defective TiO2 nanoparticle clusters (d-TiO2 NP clusters) and characterized their optical and photothermal properties. They were observed to absorb a broad range of visible light and near IR (NIR) from 500 to 1000 nm, exhibiting the generation of ROS as well as the photothermal effect for the simultaneous application of PDT and PTT. The resultant combination of PDT and PTT treatments of HeLa cells incubated with the nanocomplexes caused a synergistic increase in the cell death compared to the single treatment.
The higher efficacy of cell death by the combination of PDT and PTT treatments with the nanocomplexes is likely attributed to the increases of ROS generation from the TiO2 NCs with the aid of local surface plasma resonance (LSPR)-induced hot electrons and heat generation from Au NRs, suggesting that Au NR–TiO2 NCs are promising nanomaterials for the in vivo combinatorial phototherapy of cancer.
- Phototherapeutic nanocomplexes
- TiO2 nanoclusters
- Gold nanorods
- HeLa cells
- Cancer therapy
- Photodynamic therapy
- Photothermal therapy
The most common types of cancer treatments [1–4] are chemotherapy, radiation therapy and/or surgery. However, such treatments have many well-known disadvantages, including relatively poor specificity toward malignant tissues, drug resistance and side effects [5, 6]. Therefore, there has been a demand for the development of the new treatment that can selectively eliminate only cancer cells/tissues without damage and side effects to normal cells/tissues. Recently, phototherapies including photodynamic therapy (PDT) and photothermal therapy (PTT) have received considerable attention as potential cancer therapies due to their advantages such as remote controllability, few complications, improved selectivity and rapid recovery [5, 7]. The phototherapy employs the photosensitizer (PS) or photothermal agent (PTA) that are nontoxic in the dark but able to selectively kill cancer cells by reactive oxygen species (ROS) or heat generated under the light irradiation without damage to normal tissues, respectively [8–11]. These photoreactions occur in the immediate locale of the light-absorbing PS or PTA which can be activated only in the particular areas of cancer cells/tissues that have been exposed to light. The most of the PSs used in cancer therapy are organic dyes such as porphyrin derivatives [7, 12–15], boron-dipyrromethene (BODIPY) conjugates  and methylene blue . However, the PDT using the organic PSs gives unsatisfactory results because the PS’s absorb visible light mostly  with little absorption of near IR (NIR) (650–900 nm) penetrating deeply into biological tissue, and the PDT alone is not suitable for subcutaneous treatment. Thus, for the subcutaneous treatment, PTT using gold nanoparticles has been attracting interests because gold nanoparticles can absorb NIR radiation to generate heat killing cancer cells [11, 19–22]. Nevertheless, the efficacy of PTT is not so high as compared to that of PDT. Therefore, many researchers have attempted to apply the combination of PDT and PTT to enhance the therapeutic efficiency synergistically against malignant carcinomas as compared to PDT or PTT alone [10, 23–25].
For the effective combination of the phototherapies, many PS-conjugated PTA nanocomplexes have been developed. However, ROS generation by PS is more or less inhibited due to the excitation energy transfer from PS to PTA in addition to oxygen, and the combination efficiency cannot be maximized as anticipated. In order to overcome this problem, modification of the PS–PTA nanocomplexes has been performed by leaving the space between PS and PTA [7, 26–28]. Very recently Chung et al.  have prepared the dendrimer porphyrin (DP)-coated gold nanoshell (DP-AuNS) in which dendritic wedges of DP play a role as a spacer between porphyrin and PTA to minimize the additional energy transfer, and they found that the DP-AuNS could be applied to synergistic combination of the PDT and PTT. In spite of such improvements of PS–PTA nanocomplexes, they can’t be used for a long time because of photobleaching of organic photosensitizers. Thus, inorganic semiconductor nanomaterials would be rather useful as an alternative PS if they generate ROS. Among the semiconductor nanomaterials, TiO2 NPs are attracting much attention because of strong photocatalytic activity, non-toxicity, high photostability and inexpensiveness . However, most of the pristine TiO2 NPs are active under UV light excitation which induces damage to biological components and its penetration into biological tissue is very limited to reach the cancer cells situated far away from the tissue surface. Thus, TiO2 NPs for in vivo treatment of subcutaneous cancers need to be modified to absorb long-wavelength visible light or NIR. Previously, we had synthesized defective TiO2 NPs (d-TiO2 NPs) which absorb a broad range of light from visible to NIR. The resultant d-TiO2 NPs were found to generate ROS including singlet oxygen (1O2) by a different mechanism other than the excitation energy transfer under the long wavelength visible light irradiation , leading to killing cancer cells by PDT pathway.
Hereby, as a new nanocomplex for the effective combination of PDT and PTT, we fabricated gold nanorods (Au NRs) conjugated with d-TiO2 NP clusters (Au NR–TiO2 NCs) by functionalizing with (3-aminopropyl) triethoxysilane (APTES) [30, 31] and polyethylene glycol (PEG) [32–36]. Their optical and photothermal properties were characterized, supporting that they generate ROS and heat upon irradiation of long wavelength visible light and NIR, respectively. Thus, the simultaneous application of PDT and PTT of cancer cells (HeLa cells) incubated with the nanocomplexes exhibited a synergistic increase of cell death by the enhanced generation of ROS from TiO2 NPs with the aid of the NIR-induced heat from the Au NRs.
Preparation and characterization of Au NR–TiO2 NCs
Intracellular generation of ROS from nanoparticles
The intracellular ROS generation was examined by monitoring green fluorescence from a standard ROS probe , H2DCFDA upon visible light irradiation. A strong green fluorescence was observed in the cytoplasm of Hela cells treated with APTES–TiO2 NPs and Au NR–TiO2 NCs while not observed in untreated cells, indicating that the nanoparticles were taken up and internalized to generate ROS upon irradiation. Quantification of ROS based on fluorescence intensities (Fig. 4b) revealed that the significantly high level of ROS was produced by APTES–TiO2 NPs and Au NR–TiO2 NCs as compared with negligible level generated by PEG–Au NRs. It is noteworthy that such green fluorescence was not observed from any nanoparticles-treated cells upon irradiation with NIR at 808 nm [Additional file 1: Figure S3 (B)]. These results demonstrate that the observed ROS generation in the cells was resulted from the absorption of the visible light by TiO2 NPs. Therefore, the relatively lower level of ROS produced from Au NR–TiO2 NCs is attributed to inhibition of directly visible light absorption of NPs by the LSPR of Au NRs or the LSPR-enhanced charge transfer quenching of the visible-light-induced electrons which are supposed to produce ROS . Anyhow, it is evident that Au NR–TiO2 NCs are able to not only generate the significant amount of ROS but also induce photothermal heating from Au NRs exposed to NIR light which is caused by electron energy loss due to its longitudinal LSPR oscillation . Thus, it would be worthwhile to attempt to combine both photodynamic and photothermal effects with Au NR–TiO2 NCs using visible light and NIR.
Photothermal properties of nanoparticles and nanocomplexes
In vitro cell viability under the dark and light irradiation conditions
Significant PDT and PTT effects were observed from HeLa cells treated with d-TiO2 NPs or Au NRs upon visible light or NIR irradiation alone. Further synergistic enhancement of the phototherapeutic efficiency was achieved by simultaneous irradiation with visible light and NIR onto the cells incubated with inorganic nanocomplex such as Au NR–TiO2 NCs which were newly fabricated by coupling d-TiO2 NPs and Au NRs. It was found that visible light-induced ROS production from the Au NR–TiO2 NCs increased with the aid of LSPR-induced hot electrons and heat generation. Therefore the combination of PDT and PTT treatments with Au NR–TiO2 NCs has a great potential to be applied to improve the cancer therapy.
Materials and experimental methods
All of the chemicals used for the synthesis of AuNR–TiO2NPs, including P-25 (Degussa-Huls), egg lecithin (L-R-phosphatidylcholine, > 60%, Sigma-Aldrich), chloroform (> 99.8%, Samchun, Korea), sodium hydroxide (> 93%, Duksan, Korea), ethanol (200–proof, > 99.8%, Sigma-Aldrich), (3-aminopropyl)triethoxysilane (> 99%, Sigma-Aldrich), citrates-capped Au NRs (AC12-25-808-CIT-DIH-1, Nanopartz), HS–PEG–COOH (MW 10 k, Nanocs), EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, > 98%, Sigma-Aldrich) and NHS (N-hydroxysuccinimide, > 98%, Sigma-Aldrich) were of analytical grade and used as purchased without further purification.
Synthesis of Au NR–TiO2 NCs
Firstly, the surfaces of as-prepared d-TiO2 NPs were modified by binding with APTES as per the previous report . In the first step, APTES solution was prepared by dissolving 0.1% acetic acid, 4% deionized water and 2% APTES in ethanol. The d-TiO2 NPs were dispersed in a beaker containing 10 mL ethanol under constant ultrasonication for 30 min. Then, the APTES solution was added into the ethanol dispersed d-TiO2 NPs solution and stirred for 24 h. The solution was washed with ethanol and deionized water several times by repeated centrifugation. An aliquot of these particles was dried in an oven at 40 °C. Next, the purchased citrates-capped Au NRs were exchanged with HS–PEG–COOH to prepare the PEG–Au NRs. Finally, the preparation of the Au NR–TiO2 NCs was performed by coupling of the two surface-modified nanomaterials (APTES–TiO2 NPs and PEG–Au NRs) to lead to the formation of the amide bond between the amine group of APTES and the carboxyl group of PEG [37, 38].
Structural and optical characterization of nanoparticles
The morphology of the as-prepared d-TiO2 NPs, PEG–Au NRs and Au NR–TiO2 NCs were examined by transmission electron microscopy (TEM; Tecnai G2 F30). The TEM sample was prepared by dip-coating Formvar/carbon film-Cu grids with a nanocolloidal solution obtained by sonication of the synthesized nanoparticles in ethanol.
The particle sizes and ζ-potentials of the dispersed solution of the synthesized nanoparticles were measured respectively by dynamic light scattering (DLS) and laser Doppler velocimetry (LDV) using an electrophoretic light scattering spectrophotometer (Otsuka Electronics Co., Ltd; ELS-Z2).
For the optical properties, diffuse reflectance UV–VIS-NIR absorption spectra (DRS) were recorded using a Solid Spec-3700 double beam spectrophotometer equipped with an integrating sphere.
Cell culture and imaging
The human cervical carcinoma cells (HeLa) were grown in 89% Dulbecco’s modified Eagle’s medium with 10% fetal bovine serum and 1% antibiotic–antimycotic solution. The cells were routinely maintained in the plastic tissue culture dishes at 37 °C under a humidified 5% CO2—containing an atmosphere.
The cell images were obtained by observing differential interference contrast (DIC) and fluorescence of DAPI (4′,6-diamidino-2-phenylindole) or H2DCFDA using laser-scanning confocal microscopy (LSCM; LSM5 live configuration Vario Two VRGB).
Measurement of ROS generation under visible region
For the measurement of ROS generation, HeLa cells were seeded in a 15 μ-slide 8 well plate (Ibidi, Germany) at a density of 5 × 103 cells per well and incubated for 24 h at 37 °C under a 5% CO2 atmosphere followed by addition of 10 μg/mL of APTES–TiO2 NPs, PEG–Au NRs or Au NR–TiO2 NCs. After 24 h, the culture medium was replaced by the new medium contained 20 μg/mL carboxy-H2DCFDA (Sigma-Aldrich) for 30 min in the conventional incubator (37 °C, 5% CO2). Next, carboxy-H2DCFDA-containing medium was removed and added the fresh medium. Then, the 8 well plates were irradiated under broadband visible-light region (12 mW/cm2) with a xenon lamp (Asahi Spectra, MAX-302, Japan) for 30 min. Subsequently, the nucleus was stained with 10 μg/mL bisbenzimide trihydrochloride (Hoechest33342) for 10 min and washed with DPBS several times. Fluorescence images of the intracellular ROS generation detected by carboxy-H2DCFDA D were obtained with a confocal laser microscope (Zeiss LSM5 live configuration Vario two VRGB).
Photothermal properties of nanoparticles
To measure the photothermal conversion performance of APTES–TiO2 NPs, PEG–Au NRs and Au NR–TiO2 NCs, temperature of the nanoparticles-containing solutions were measured with infrared camera (640 × 512 cooled InSb IRFPA with 90 µm pixel pitch) after irradiation using a 808 nm NIR laser (1 W/cm2) or broadband visible light from a xenon lamp (12 mW/cm2).
Evaluation of cytotoxicity and cell viability
The cytotoxicity of the injected nanoparticles was evaluated using the EZ-Cytox reagent (Daeil Lab Service, Seoul, South Korea) based on the water-soluble tetrazolium (WST) method. HeLa cells were seeded at a density of 1 × 104 cells per well in a 96-well microassay plate and incubated for 24 h at 37 °C under a 5% CO2 atmosphere. The APTES–TiO2 NPs, PEG–Au NRs or Au NR–TiO2NCs were added to the incubated cells at various concentrations, followed by further incubation for an additional 24 h at 37 °C. Next, 10 μL of the EZ-Cytox reagent was added and the plates were incubated for 2 h at 37 °C. The absorbance of the EZ-Cytox reagent was measured at 450 nm using a microplate reader (VersaMax, Molecular Devices, USA). The cell viability (%) was calculated using the following equation: cell viability (%) = (OD450(sample)/OD450(control)) × 100. The control condition was maintained with cells not treated with anything, neither nanoparticles nor visible/NIR light.
The HeLa cells incubated with APTES–TiO2 NPs, PEG–Au NRs or Au NR–TiO2 NCs were irradiated for 30 min with the visible light (12 mW/cm2) emitted from a xenon lamp (Asahi Spectra, MAX-302, Japan) or/and 5 min with an 808 nm NIR laser (1 W/cm2) (see Additional file 1: Figure S5).
KSC led the project at KBSI, reviewed literature with JL and MY, designed the experimental processes. JL, YHL, and CBJ performed the experiments, collecting the data which were analyzed by JL, JSC, KSC and MY. JL, KSC and MY prepared the manuscript and all the authors contributed to the critical reading of the manuscript. All authors read and approved the final manuscript.
The authors thank Dr. Dong Uk Kim at the Korea Basic Science Institute for technical assistance to set up the optical system, and also thank Prof. Ill-Sun Yoon at Chungnam National University his allowance to lend the Xenon lamp in his lab.
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its Additional files.
Consent for publication
Ethics approval and consent to participate
No animal experiment, and not applicable.
This work was financially supported by the Korea Basic Science Institute grant (D38615) and R&D Program fund of TCS Inc (S. Korea) (to MY).
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