Fluorescent Silicon Nanorods-Based Nanotheranostic Agents for Multimodal Imaging-Guided Photothermal Therapy
A kind of multifunctional silicon-based theranostic agent is fabricated and exploited for imaging-guided tumor-targeted photothermal therapy.
The obtained gold nanoparticles-decorated fluorescent silicon nanorods featuring high photothermal conversion performance and good photothermal stability enable a total ablation of tumors and prolong the survival time of mice.
KeywordsGold nanoparticle Fluorescent silicon nanorods Nanotheranostic Multimodal imaging Photothermal therapy Tumor target
Along with tremendous advances in cancer nanomedicine, more challenges such as the complexity and heterogeneity of tumors are gradually realized [1, 2]. Using diagnosis to guide/aid therapy procedures would show great prospects in the era of personalized medicine [3, 4]. To enhance the diagnosis accuracy, different imaging modalities are expected to be integrated together [5, 6, 7, 8, 9]. However, besides tedious manipulations, the rational integration of two or more imaging modalities into one therapy platform normally suffers from low yield and instability of products. As a consequence, great efforts are currently needed for the development of novel all-in-one multimodal imaging-based nanoplatform.
On the other hand, it is of particular interest to develop functional silicon nanostructures for biological and biomedical applications over the years, since silicon nanostructures possess several intrinsic advantages like excellent optical/electronic properties, favorable biocompatibility, and good biodegradability [10, 11, 12, 13, 14, 15, 16, 17]. Typically, zero-dimensional fluorescent silicon nanoparticles with robust photostability and negligible toxicity have been extensively explored for real-time and long-term bioimaging [18, 19, 20, 21, 22, 23]. One-dimensional silicon nanowires (SiNWs) have been developed as electrochemical and optical biosensors for detecting various biological targets in highly sensitive and specific manner [24, 25, 26, 27]. Of note, great efforts have recently been devoted for the exploitation of new-type one-dimensional fluorescent silicon nanostructures, i.e., silicon nanorods (SiNRs), which have drawn intensive attentions in optoelectronics and photovoltaics because of their unique optical properties (e.g., longer Auger lifetimes and higher carrier multiplication quantum yield than zero-dimensional silicon nanoparticles) [28, 29, 30, 31]. Lately, a kind of SiNRs-based ratiometric biosensor, featuring strong photostability, good biocompatibility, and broad detection range, was developed for investigating the intracellular pH fluctuation in a long-term and real-time manner . It is worthwhile to point out that recent studies have revealed that the elongated nanostructures like nanorods could exhibit special bio-behaviors such as rapid tumor penetration and enhanced tumor accumulation [33, 34, 35, 36, 37, 38, 39, 40]. Therefore, unique optical and special bio-behavioral properties make fluorescent SiNRs promising nanotheranostic agent for cancer diagnosis and therapy, which nevertheless remains vacant up to present.
We herein present the first example of silicon-based theranostic agent for multimodal imaging-guided tumor-targeted photothermal therapy (PTT). The agent is made of gold nanoparticles-decorated fluorescent silicon nanorods (Au@SiNRs), which are prepared via in situ growth AuNPs on microwave-synthesized SiNRs. Remarkably, the obtained Au@SiNRs feature high photothermal conversion performance (photothermal conversion efficiency: ~ 43.9%) and robust photothermal stability (preserving the same temperature elevation curve and morphology after five cycles of NIR laser irradiation), thus suitable for photoacoustic (PA) and infrared thermal imaging. After the surface modification with poly(ethylene glycol) (PEG) and targeting peptide ligands [one cyclic peptide containing the specific sequence of arginine-glycine-aspartic acid (named as c(RGDyC))], the as-fabricated active targeting RGD-PEG-Au@SiNRs have a significantly enhanced tumor accumulation (~ 8.74% ID g−1). Moreover, one-time irradiation with an 808-nm NIR laser at a low power density (0.8 W cm−2) induces the total ablation of tumors and drastically prolonged survival time of mice.
2.1 Preparation of SiNRs and Au@SiNRs
The microwave system NOVA 2S used to synthesize nanostructures was purchased from Preekem of Shanghai, China. SiNRs were readily achieved through microwave synthesis according to our previous protocol . In detail, precursor solution was prepared through adding 1 mL (3-Aminopropyl)trimethoxysilane (APTES, 97%, bought from Sigma-Aldrich) to 8 mL N2-saturated trisodium citrate (99.0%, bought from Sinopharm Chemical Reagent Co., Ltd, China) aqueous solution (0.075 g). After that, 30 mg of milk was introduced into the aqueous solution, followed by 15-min stirring. After transferring to the exclusive vitreous vessel, the mixture was irradiated in the microwave system for 2 h at 150 °C. The impurities of free reagents were excluded from the as-prepared SiNRs by dialysis (1 kDa) and centrifugation (8000 rpm, 5 min/time, 3 times). Gold nanoparticles (AuNPs) were grown on the surface of SiNRs in situ by reducing chloroauric acid (HAuCl4, bought from Nanjing Chemical Reagent Co., Ltd, China) with –NH2 groups on SiNRs . Briefly, 100 μL of HAuCl4 aqueous solutions with different concentrations (5, 10, 15, or 20 mM) was added into 10 mL SiNRs (5.5 mg mL−1) suspension. After 40-min stirring and transferring into exclusive vitreous vessel, the Au@SiNRs were prepared through microwave irradiation (MWI) (1.5 h, 120 °C), and then collected by centrifugation (14,800 rpm, 5 min) when the temperature naturally cooled to lower than 30 °C. Before the following process, the sample was washed with deionized water for three times at least. Afterward, the content of gold element in Au@SiNRs was measured by inductively coupled plasma optical emission spectroscopy (ICP-OES). The contention of gold was measured to be 0.56 μg mL−1 when the concentration of as-prepared Au@SiNR was 300 μg mL−1. Based on this result, the yield of Au@SiNPs was calculated to be ~ 51% on the amount of gold element.
2.2 PEGylation of Au@SiNRs
In order to enhance the biocompatibility and water dispersibility of Au@SiNRs, 20 mg of Au@SiNRs powders was dispersed in 20 mL of deionized water and ultrasonicated for 30 min. Then, 20 mL methoxy-poly (ethylene glycol)-thiol (PEG-SH, molecular weight = 5 KD, bought from Kaizheng Biotech., Beijing, China) (20 mg mL−1) aqueous solution was added into the Au@SiNRs suspension, and the mixture was stirred for 24 h under dark condition. The prepared PEGylated Au@SiNRs were washed three times with deionized water by centrifugation at 13,000 rpm for 5 min.
2.3 Preparation of RGD-PEG-Au@SiNRs
The peptide c(RGDyC) (bought from Apeptide (Shanghai) Co., Ltd), which was known as a tumor-specific targeting ligand for selectively binding α5β1 and αvβ3 integrins, was used to modified Au@SiNRs . The Au@SiNRs was conjugated with c(RGDyC) molecules containing the -SH groups via Au–S bond through the established protocols [43, 44]. Briefly, the mixture of 50 μL peptide c(RGDyC) (50 mM, pH = 6.8) and 100 μL PEGylated Au@SiNRs (~ 10 mg mL−1, pH = 7.2) was gently shook in dark at 25 °C for 12 h to produce the c(RGDyC)-modified Au@SiNRs (RGD-PEG-Au@SiNRs). To purify the as-prepared RGD-PEG-Au@SiNRs, 3 kDa Nanosep centrifugal devices were used via centrifugation for 15 min at the speed of 6000 rpm. The sample was stored at 4 °C in the dark after dispersion in phosphate buffer saline (PBS).
2.4 Physicochemical Characterization
Transmission electron microscopy (TEM) overview images were taken at 200 kV through Philips CM 200 electron microscope and analyzed through the software of ImageJ. The atomic and weight fraction of elements existing in the as-prepared materials was taken via energy-dispersive X-ray (EDX) spectroscopy. High-resolution X-ray photoelectron spectroscopy (XPS) spectra were obtained on a Kratos AXIS UltraDLD ultrahigh vacuum (UHV) surface analysis system. Powder UV–vis-NIR absorption spectra were collected with a PerkinElmer Lambda 750 UV–vis-NIR spectrophotometer. Photoluminescence (PL) measurements were performed with a Horiba Jobin–Yvon Fluoromax-4 spectrofluorometer. Fourier transform infrared spectrometer (FTIR) spectra were conducted with a Bruker Hyperion FTIR spectrometer and cumulated scans at a resolution of 4 cm−1. The dynamic light scattering (DLS) and zeta potential of materials were detected using Malvern ZEN3690.
2.5 Photoacoustic Signals Detection
To investigate the PA signal-generating ability of Au@SiNRs, gradient concentrations of Au@SiNRs (0, 75, 150, 300, and 400 μg mL−1) were added into Eppendorf tubes (200 μL). Then, tubes were embedded into ultrasound gel and subjected to laser illumination in a PA imaging system (Visualsonic Vevo 2100 LAZER system). The wavelength of laser was set at 710 nm.
2.6 Calculation of the Photothermal Conversion Efficiency (η)
2.7 Cytotoxicity Assessment
For evaluating the cytotoxicity of Au@SiNRs, CT-26 cells were plated in 96-well plates at a density of 104 cells per well and incubated for 12 h. Then, old medium was replaced with fresh medium with gradient concentrations of PEG-Au@SiNRs (100 μL per well, 0 ~ 320 μg mL−1). Cells were treated with the materials for 24 or 48 h at 37 °C, respectively, and the cytotoxicity was evaluated through MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The efficacy of in vitro photothermal therapy was also investigated in this way. CT-26 cells were plated in a 24-well plate with a density of 105 cells per well. After 12-h incubation, the old medium was replaced by medium containing PEG-Au@SiNRs or RGD-PEG-Au@SiNRs with different concentrations (1 mL per well, 0 ~ 320 μg mL−1). After 4-h treatment, the medium was removed, and cells were washed with PBS (PH 7.4) for 2 times. Then, 200 μL PBS was added in each well. Cells were irradiated by an 808 nm laser (0.8 W cm−2) for 5 min. Finally, the cell viability was accessed by MTT assay.
2.8 Live/Dead Cell Staining
CT-26 cells were placed in the 24-well plate at a density of 105 cells/well and incubated for another 12 h. Then, 1 mL of fresh medium (blank control group) and medium containing 200 μg mL−1 PEG-Au@SiNRs or RGD-PEG-Au@SiNRs (experiment groups) was added. The treated cells were divided into two groups: W group (with NIR) and W/O (without NIR) group. For the W group, after the incubation for 4 h, cells were washed with PBS three times and treated with NIR (808 nm, 0.8 W cm−2, 5 min). For the W/O group, cells were washed with PBS for three times without NIR treatment. Finally, cells were stained by live/dead dyes (calcein-AM and propidium iodide dyes) according to the product protocol. The stained cells were recorded with the laser-scanning confocal microscope (LSCM, Leica, TCS-SP5) at 20 × objective.
2.9 Fluorescent Cell Labeling
CT-26 (integrin α5β 1 + positive) and 4T1 (integrin α5β 1 − negative) cells were plated onto 24-well plate with a density of 105 cells per well, and then incubated for 24 h (37 °C, 5% CO2). To label integrin α5β1, the cells were cultured with 100 μg mL−1 PEG-Au@SiNRs, RGD-PEG-Au@SiNRs, or RGD-PEG-Au@SiNRs in the presence of 1 μM of c(RGDyC) (blocking) in a binding buffer (pH 7.4) (37 °C, 5% CO2) for 1 h. (For the blocking group, cells were pre-treated with 1 μM of c(RGDyC) for 30 min.) After incubation, cells were washed by PBS (pH 7.4) three times. The labeled cells were mounted on slides in fluoromount (Sigma, F4680) with coverslips. Cell images were captured through LSCM. Imaging was carried out under 40% power of argon laser (λex = 405 nm), and the emissions ranging from 425 to 550 nm were recorded.
2.10 Tumor Xenograft
BALB/c nude mice (female, 6–7-week old) were selected to establish the xenograft mice models. 1.5 × 106 CT-26 cells in 125 μL of PBS were subcutaneously inoculated in each mouse at the back. The BALB/c nude mice and BALB/c mice were cared and used under protocols approved by Soochow University Laboratory Animal Center.
2.11 ICP-OES Analysis for Au Element Quantification
For bio-distribution analysis, the absolute Au contents were measured by ICP-OES (Thermo Scientific iCAP6300). When the tumors reached a uniform size of around 80 mm3, two groups (n = 3 in each group) of the mice were intravenously (i.v.) injected with 200 µL of PEG-Au@SiNRs and RGD-PEG-Au@SiNRs (20 mg kg−1) suspensions, respectively. Major organs (heart, liver, spleen, lung, kidney, and tumor) from mice were collected 24 h after i.v. injection. All those organs were weighed and solubilized by aqua regia for ICP-OES measurement.
2.12 In Vivo Photoacoustic Imaging
The PA signal generated by Au@SiNRs was applied in the first imaging strategy. Before PA imaging, the CT-26 tumor-bearing nude BALB/c nude mice were i.v. injected with PEG-Au@SiNRs or RGD-PEG-Au@SiNRs at a dose of 10 mg kg−1. The PA signal of the tumor region was detected at different time points (0, 12, and 24 h) through a PA imaging system (Visualsonic Vevo 2100 LAZER system) with an excitation wavelength at 710 nm.
2.13 In Vivo PTT Treatment
The body weight was recorded using laboratory balance every 2 days.
2.14 Histology Analysis
The mice were sacrificed after PTT treatments, and tumors as well as other major organs were collected. Briefly, the organs were first fixed overnight in 4% formalin, and then embedded in paraffin. After deparaffinization in xylene twice, the tissue sections were sequent dehydrated by 100% alcohol twice (5 min once), 95% alcohol (2 min), 70% alcohol (2 min), and distilled water. For hematoxylin and eosin (H&E) staining, the sliced tumor sections were counterstained in hematoxylin solution (2%) and in eosin solution (0.5%), respectively.
2.15 Hematology Analysis
Twenty healthy BALB/c mice were i.v. injected with RGD-PEG-Au@SiNRs (10 mg kg−1). Five mice at each time point (1, 7, 14, and 30 days) were sacrificed to collect blood for blood biochemistry and complete blood panel analysis. Healthy mice untreated were chosen as the control.
2.16 Cytokines Detection
Serum samples were collected from treated mice at different time points and diluted for analysis. Interferon gamma (IFN-γ), interleukin-6 (IL-6), interleukin-2 (IL-2), and interleukin-1 (IL-1) were analyzed with ELISA kits according to vendors’ instructions (Biocentury).
3 Results and Discussion
3.1 Preparation and Characterization of Au@SiNRs
3.2 Photophysical Properties of Au@SiNRs
Notably, the calculated photothermal conversion efficiency (η) of Au@SiNRs was as high as 43.9% in comparison with that of ~ 21% for gold nanorods (Figs. 2e and S7a) . According to previous studies on metal-decorated SiNWs nanohybrids (AuNPs@SiNWs, PtNPs@SiNWs, and AgNPs@SiNWs) [48, 50, 51], it can be speculated that AuNPs on SiNRs would substantially enhance light conversion to heat, resulting in more pronounced photothermal performance of Au@SiNRs than free SiNRs or AuNPs. Moreover, Au@SiNRs also demonstrate a great photothermal stability, which is proved by the negligible change in their temperature elevation curve, absorption spectra, and morphology after five-cycle NIR laser irradiation (Figs. 2f and S8).
PA imaging has emerged as a novel and promising biomedical imaging modality, due to its significant improvement in imaging depth and spatial resolution in vivo [52, 53]. In PA imaging, ultrasound signals will be generated when tissues or contrast probes absorb and convert the delivered energy into heat. As described above, as-prepared Au@SiNRs have an extremely high photothermal conversion efficiency, providing possibilities to be used as contrast agents for PA imaging. As shown in Fig. 2g, Au@SiNRs solutions show a concentration-dependent PA signal intensity. The quantitative analysis further demonstrates there is a positive linear relationship between signal intensities and concentrations (Fig. S9). In contrast, no PA signal was detected for SiNRs or AuNPs under identical conditions (Fig. S10). These findings demonstrate the potential of Au@SiNRs as a multimodal contrast agent with tunable fluorescence signal, high photothermal conversion efficiency and good photostability.
3.3 In vitro Assessment of Biocompatibility, Targeted imaging, and Photothermal Effect
The biological activity of the prepared RGD-Au@SiNRs was verified in vitro. As shown in Fig. 3b, the RGD-Au@SiNRs-treated CT-26 cells (integrin α5β1 positive) exhibit strong fluorescence, while only feeble fluorescence could be observed from those treated with Au@SiNRs. Additionally, the fluorescence intensity of CT-26 cells treated with RGD-Au@SiNRs was significantly reduced when the integrin receptors were blocked with free RGD peptides. In contrast, integrin α5β1 negative cells (4T1 cells, the murine breast carcinoma cancer cell line) express weak fluorescence signal no matter how they were treated with Au@SiNRs, RGD-Au@SiNRs or blocked with RGD peptides before the treatment of RGD-Au@SiNRs. The results were supported by the different average fluorescent intensities quantified by the LSCM software (Fig. S14). Furthermore, the time-dependent cellular uptake of RGD-Au@SiNRs by CT-26 cells was investigated by flow cytometry, which showed that after incubation for only 0.5 h, more than 80% cells have uptaken the nanoagents (Fig. S15). These data confirm the targeting ability of RGD-Au@SiNRs to some integrin (αvβ3 and α5β1), which is in accordance with the previous studies [55, 56].
Encouraged by the good photothermal efficacy and biocompatibility of Au@SiNRs, the PTT effect was first evaluated in vitro. After incubation with different agents (PBS, AuNPs, SiNRs, Au@SiNRs, and RGD-Au@SiNRs) for 4 h, the CT-26 cells were washed and non- or irradiated with a NIR laser (808 nm, 0.8 W cm−2) for 5 min. The efficacy of photothermal therapy of Au@SiNRs and RGD-Au@SiNRs was quantitatively assessed by measuring the cell viability via MTT method. Both Au@SiNRs and RGD-Au@SiNRs show a dose-dependent PTT efficacy, while RGD-Au@SiNRs had a better ablation effect than that of Au@SiNRs (Fig. 3c). The live/dead [calcein-AM/propidium iodide (PI)] staining was also applied to visually evaluate the cell viability, where the green and red fluorescence indicates the live and dead cells, respectively. The results clearly demonstrate the treatment of Au@SiNRs or RGD-Au@SiNRs would induce cells death when the cells were irradiated with a laser, while AuNPs and SiNRs have no affect on the viability of CT-26 cells at the tested concentrations (Fig. S16). In addition, the efficacy of RGD-Au@SiNRs is better due to the targeting ability of c(RGDyC) peptides. In contrast, without NIR laser irradiation, AuNPs, SiNRs, Au@SiNRs, and RGD-Au@SiNRs have negligible effect on the viability of CT-26 cells at the tested concentrations.
3.4 In Vivo Tumor-targeted Multimodal Imaging
Through PA imaging of the bladders of mice i.v. injected with RGD-Au@SiNRs, it was found that the signal of bladders reached to the highest level at 8-h post-injection, and then gradually decreases (Fig. S17a, b), while the blood circulation half-life of i.v. injected RGD-Au@SiRNs was measured to be ~ 4.0 h (Fig. S17c). In order to quantify the bio-distribution of our nanostructures in vivo, the gold element-based ICP-OES analysis was employed at 24-h post-injection. Significantly, the tumor uptake of RGD-Au@SiNRs was measured to be 8.74% ID g−1, which was obviously higher than that of Au@SiNRs (5.32% ID g−1) (p < 0.01) (Fig. 4h). Meanwhile, high levels of Au content were observed in the liver and spleen, which were reticuloendothelial systems (RES) responsible for the metabolism and clearance of nanorods [60, 61]. Thus, RGD-Au@SiNRs have a remarkable PA/PL/PTT triple-modal imaging capability and an obvious tumor-homing effect.
3.5 Antitumor Effect and Biosafety Assessment
This novel SiNRs-based imaging-guided NIR hyperthermia agent shows non-/low toxic effects on mice. During the therapeutic period, the mouse body weight of all groups showed negligible drop with or without irradiation (Fig. S20). Moreover, as shown in Fig. 5e, f, several classes of dominant serum biochemical markers, and blood count parameters were all normal at different time points (1, 7, 14, and 30 days) at post-intravenous injection of RGD-Au@SiNRs. Histology analysis of dominant organs also showed no obvious pathological abnormalities or lesions (Figs. 5g and S21). Noteworthy, there were temporary rises in IL-6 and IFN-γ after 4- or 24-h treatment with RGD-Au@SiNRs, while the levels of both of them decrease to normal within 48 h (Fig. S22).
In summary, we present a kind of silicon-based multifunctional nanostructures, i.e., the Au@SiNRs, which are exploited as high-quality theranostic agent for multimodal imaging-guided cancer therapy. The as-prepared Au@SiNRs featuring high photothermal conversion efficacy and good photothermal stability could serve as multifunctional agents, enabling PA- and infrared thermal imaging-guided PTT. A facile surface modification makes the fabricated RGD-PEG-Au@SiNRs having an obvious tumor-homing effect, resulting in an efficient therapeutic effect on tumors after a systemic administration. Moreover, no appreciable toxicity was observed after intravenous injection of Au@SiNRs into mice. Given that silicon nanostructures have several intrinsic advantages like abundant source and biodegradability, the developed Au@SiNRs may act as practical nanotheranostic agents for imaging-guided cancer treatment, holding high prospects in the era of personalized medicine.
We appreciate financial support from the National Basic Research Program of China (973 Program, 2013CB934400), the National Natural Science Foundation of China (21825402, 31400860, 21575096, and 21605109), the Natural Science Foundation of Jiangsu Province of China (BK20170061), Collaborative Innovation Center of Suzhou Nano Science and Technology, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the 111 Project as well as Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.
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