Letter www.acsami.org
Janus Silver-Mesoporous Silica Nanocarriers for SERS Traceable and pH-Sensitive Drug Delivery in Cancer Therapy Dan Shao,†,‡ Xin Zhang,†,‡ Wenliang Liu,‡ Fan Zhang,‡ Xiao Zheng,‡ Ping Qiao,‡ Jing Li,*,‡ Wen-fei Dong,§ and Li Chen‡,⊥ ‡
Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, and School of Nursing, Jilin University, Changchun 130021, China § CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China ⊥
S Supporting Information *
ABSTRACT: A facile and cheap strategy was used to fabricate the novel Janus silver-mesoporous silica nanoparticles with excellent SPR and mesoporous properties for simultaneous SERS imaging and pHresponsive drug release, leading to the efficient cancer theranostic with less toxic effects.
KEYWORDS: silver mesoporous silica, Janus, SERS, selective, cancer therapy
W
anticancer drugs, resulting in limitation of therapeutic effects. Therefore, developing sophisticated multifunctional nanoplatform with a better use of the intrinsic properties of the nanomaterials for cancer theranostics is critically desired. The Janus nanoparticles which possess dual surface structures, is anisotropic in composition, shape, and surface chemistry, which have attracted great interest in cell targeting, noninvasive imaging, and/or therapeutic intervention.12,13 Although Janus nanoparticles combine individual components together, their fingerprint optical, magnetic, and electronic properties are not often altered, interfered or completely lost, in contrast with other isotropic nanoparticles.14,15 We have previously constructed magnetic and gold-mesoporous silica Janus nanoparticles via a simple sol−gel method, which had been used as good candidates for cancer theranostics.16−18 However, to the best of our knowledge, synthesis of silver-based Janus mesoporous silica nanocomposites, especially with multifunctionality, has never been reported yet. Herein, we report a simple and cheap method to synthesize novel Janus nanoparticles (Ag-MSNs) with a silver nanosphere as a head and a mesoporous silica ordered mesostructure as a body. As Ag-MSNs show excellent SPR and mesoporous properties for the enhancement of the drug-loading capacity,
ith the rapid advances of nanobiotechnology, the development of inorganic biomaterials with unique physicochemical properties has offered the opportunity to design multifunctional nanoplatforms that integrate different theranostic modalities for multimodal imaging and simultaneous cancer diagnosis and therapy.1,2 Of all kinds of noble metal materials, silver nanoparticles with well-defined sizes and controllable shapes are extensively studied as the most promising plasmonic nanomaterials because of their remarkable surface plasmon resonance (SPR) properties and superior surface-enhanced Raman scattering (SERS) activity.3−5 More recently, to endow plasmonic nanostructures with multifunctional and synergistic properties, many attempts have been made to rationally design the nanocomposites which contain additional desirable functionalized components and sophisticated structures.6 Mesoporous silica has been employed to protect silver cores because of its unique properties such as mesoporous structure, high surface area, easy surface modification, and fine biocompatibility, which render mesoporous silica-coated silver nanostructures the potential using as an ideal carrier for loading molecules in cancer theranostics.7−9 Until now, a lot of work has been carried out on uniform Ag@ SiO2 core−shell nanospheres for simultaneous SERS imaging, anticancer drug delivery and photothermal therapy.10,11 Despite the above-mentioned NPs owned superior applications in cancer diagnosis and therapy, the lower specific surface area of thin mesoporous silica shell reduced loading amount of © XXXX American Chemical Society
Received: November 23, 2015 Accepted: February 4, 2016
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DOI: 10.1021/acsami.5b11310 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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ACS Applied Materials & Interfaces
Figure 1. Synthesis of Janus Ag-MSN composites. (a) Schematic diagram of the fabrication procedure for the DOX-loaded Ag-MSNs and application for SERS imaging and pH-sensitive drug delivery in cancer therapy, (b) TEM images of Ag nanospheres, (c) SEM, (d) TEM images of Ag-MSNs, (e) corresponding energy-dispersive X-ray spectroscopy (EDS) element mapping of Ag, Si, and O, respectively. The morphological evolution vs reaction time of the as-obtained Janus nanoparticles: (f) 1, (g) 2, (h) 5, and (i) 10 min.
Figure 2. Characterization of Janus Ag-MSN composites. (a) Wide-angle XRD patterns of Ag and Ag-MSNs, (b) N2 sorption isotherms of AgMSNs, (c) normalized UV−vis−NIR extinction spectra of Ag and Ag-MSNs, (d) SERS spectra of Ag-MSNs, free DOX, and Ag-MSNs-DOX.
which can be achieved simultaneous SERS imaging and pHresponsive drug delivery in cancer cells, leading to the efficient cancer therapy with less toxic effects. The preparation and application procedure for the Ag-MSN nanocarriers is
described in Figure 1a, the starting materials of water-soluble silver nanospheres with 80 nm were prepared by reducing an aqueous solution of AgNO3 with glucose in the presence of polyvinylpyrrolidone (PVP) (Figure 1b). Then, the Janus AgB
DOI: 10.1021/acsami.5b11310 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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ACS Applied Materials & Interfaces
Figure 3. DOX-loaded Ag-MSNs exhibited selective drug release behavior and SERS imaging in liver cancer cells. (a) pH-dependent drug release profiles of Ag-MSNs-DOX. (b) Quantitative analysis of fluoresence intensity of DOX in free DOX or DOX-loaded Ag-MSNs treated HepG2 and HL-7702 cells for 3 h. These data represent three separate experiments and are presented as mean values ± SD *P < 0.05 versus control group, #P < 0.05 versus DOX group. (c )CLSM images of HepG2 and HL-7702 cells incubated with DOX-loaded Ag-MSNs for 3 h, scale bars are 10 μm. (d) Microscopy image of the HepG2 cells incubated with DOX-loaded Ag-MSNs and (e) corresponding Raman spectra at three different spots. The numbers indicate the 633 nm laser spots across the HepG2 cell.
MSNs were synthesized by a modified sol−gel process using asprepared silver nanospheres as a substrate, tetraethyl orthosilicate (TEOS) as a silica source, hexadecyltrimethylammonium bromide (CTAB) as a template. The scanning electron microscopy (SEM) image (Figure 1c) showed that the Ag-MSN composites obtained after the removal of CTAB templates have uniform bullet-like morphology. The transmission electron microscopy (TEM) images (Figure 1d) further confirmed the bullet-based Janus structure with an average length of approximately 300 nm. Moreover, the TEM image of a single Ag-MSN nanocarrier, together with EDX elemental mapping and the scanning TEM (STEM) of Ag, Si, and O, clearly showed one silver ball was embedded on a single SiO2 stick (Figure 1e andFigure S1). To understand the growth mechanism of Janus nanoparticles, time-resolved transmission electron microscopy were
used to monitor the growth process. Figure 1f−i displays the morphological evolution of the Janus nanoparticles as a function of reaction time. After the Ag NPs were mixed with TEOS for only 1 min, some organosilica floccules that derived from the hydrolysis and condensation of the TEOS started to anchor to the Ag NPs (Figure 1f). These soft floccules then grew into small organosilica blocks on the one surface of the Ag NPs (Figure 1g), while continuous growth of silica structure took place when the reaction time increased from 5 to 10 min, finally producing ball−stick-like Janus nanoparticles (Figure 1h, i. According to the results above, we have proposed a possible mechanism for the formation of the Janus Ag-MSNs through changing in the total surface energy (Δσ), which was accompanied by an overall deposition process could be represented as Δσ = σmSiO2‑water − σAg‑water + σAg‑mSiO2. Compared with water−alcohol reaction system, the surface C
DOI: 10.1021/acsami.5b11310 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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nanoparticles between the cancer cells and the normal cells. Collectively, these results envisioned that Ag-MSN composites might be a possible tool for the targeted delivery of chemotherapeutic and diagnostic agents to tumor sites. We further introduced the carboxylate functional group on the pore surface of Ag-MSNs to achieve responsive releasing in low pH environment of cancer cells, and selected hydrophobic doxorubicin (DOX) as model drugs, which are commonly used in treatments of human liver and breast cancers (Figure S5). As determined by UV−vis characterization, the loading efficiency and drug-loading content of DOX in the Ag-MSNs was 63.9 and 10.6%, respectively. Then drug release behavior in vitro was studied in pH 7.4 and 5.5 phosphate buffer solution (PBS) to simulate a neutral environment of normal cells and acidic conditions in cancer cells. As shown in Figure 3a. there is more than 40% release within 24 h in pH 5.5. In sharp contrast, about less 5% DOX was released at pH 7.4 in 24 h, due to protonation and solubility of DOX in acidic environments. To further determine pH-dependent drug-releasing properties of DOX-loaded Ag-MSNs in vitro, we investigated their intracellular drug release behaviors in HepG2 and HL-7702 cells. Quantitative analysis showed that the release of DOX from DOX-loaded Ag-MSNs was remarkably higher than free DOX in HepG2 cells, as comparing to that in HL-7702 cells (Figure 3b and Figure S6). A consensus has been reached that DOX molecules distributed in nuclei can induce significant cell death. Thus, we further evaluated the internalization of the released DOX using CLSM (Figure 3c), the amount of red spots corresponding to DOX was colocalized in the nucleus (blue spots) of HepG2 cells, indicating that the majority of DOX was released and transported into the nucleus. Conversely, DOX red fluorescence was significantly weaker in the cytoplasm especially in the nucleus of HL-7702 cells, which was in line with the lower DOX release manner proved from FACS results. We attributed such selective DOX accumulation to pHsensitively cellular drug release behavior, as well as relative higher endocytosis capacity of DOX-loaded Ag-MSNs in tumor cells. To further gain insight into monitoring drug delivery, we investigated the intracellular SERS performance of the DOXloaded Ag-MSNs by a Raman microscope equipped with a 633 nm laser. We recorded the mean SERS spectra of three different locations within HepG2 cell after incubation for 3 h, the first site was from the cytoplasm (Figure 3e, curve 1), the second location was from nucleus (Figure 3e, curve 2), and the third spot was chosen from the substrate (Figure 3e, curve 3), which correspond to the white frames 1, 2, and 3 in Figure 3d, respectively. It could be seen that the strong signals of DOX that appeared at the cytoplasm while the signal at the nucleus was nearly undetected because of the cytosolic location of DOX-loaded Ag-MSNs. These results demonstrated that DOXloaded Ag-MSN nanocarriesr could preserve the SERS signal to realize the targeted detection and traceable drug delivery, which was based on the high SERS activity. Finally, we evaluated the toxicity of the prepared DOXloaded Ag-MSNs in various cancer cell lines including hepatocarcinoma HepG2, lung cancer A549 and breast cancer MCF-7 and normal cell lines including hepatic embryo cell line HL-7702, human umbilical vein endothelial cells (HUVEC) and bone marrow mesenchymal stem cells (BMSCs) through SRB assay. Indeed, the DOX-loaded Ag-MSNs resulted in significant time and concentration-dependent cell death, similar to that of free DOX in cancer cell lines (Figure 4 and Figure
energy of the mSiO2 (σmSiO2‑water) was significantly increased in alcohol-free reaction system. The Δσ > 0 caused by σmSiO2‑water was larger than σAg‑water indeed, which has blocked the CTAB/ silicate micelles to spread on the surface of Ag cores. As the energy barrier of the mSiO2 growth in the heterogeneous direction is much higher than that of homogeneous direction, an anisotropic growth of mSiO2 onto the Ag core was induced by it. Finally, the Ag-MSN Janus nanocomposites with an Ag core and an mSiO2 mesostructure were realized through this anisotropic growth. The wide-angle X-ray diffraction (XRD) pattern of the Ag NPs and obtained Ag-MSN powder after the removal of CTAB templates (Figure 2a) both showed the characteristic diffraction peaks of silver at 38, 44, 64, 78, and 82° corresponding respectively to (111), (200), (220), (311), and (222). As shown in Figure 2b and Figure S2, N2 adsorption/desorption isotherms of Ag-MSN composites revealed type IV isotherms, further confirming the mesoporous structure of the Janus nanoparticles. The average mesopore size, surface area and total pore volume were calculated to be as high as 2 nm, 828.7 m2 g−1 and 1.2 cm3 g−1, respectively. Compared to as-prepared and other groups reported Ag@SiO2 core−shell nanopartciles, Janus Ag-MSN composites were obviously higher in surface area and the total pore volume, indicating a stronger drugloading efficiency for the improvement of cancer therapy.8,19 We next carefully studied the SPR properties of Ag nanospheres and Janus Ag-MSNs by UV−vis spectrometer. As shown in Figure 2c, two types of Ag NPs all exhibited SPR absorption peak, the original Ag nanospheres showed a maximum absorption at 430 nm, a little red-shift of about 10 nm was observed in the VIS and NIR regions of Janus AgMSN. These results indicated that Janus structures model has less effects on the SPR of Ag nanospheres, which is an advantage to their applications for SERS detecting and photothermal therapy. Considering these, next we verified the whether Janus Ag-MSNs could be an ideal candidate for SERS application (Figure 2d). Compared with the neat doxorubicin (DOX) sample, three distinct enhancement peaks centered at 443, 1208, 1242, 1412, 1445, and 1576 cm−1 can be observed for DOX-labeled Ag-MSNs, where the Raman shift values (cm−1) were similar to those in previous studies.20,21 However, no SERS signal was present on Ag-MSNs only under irradiation of 633 nm laser, indicating Janus Ag-MSN composites would benefit for tracking the intracellular anticancer drug distribution. The permeability of the obtained Janus Ag-MSN composites into cells was investigated by using fluorescein isothiocyanate (FITC) as a tracer. The confocal laser scanning microscope (CLSM) images of HepG2 liver cancer cells displayed a remarkable intracellular fluorescence, while a weak fluorescence signal was observed in the HL-7702 normal liver cells (Figure S3). The overlay images show that the colocalization of FITClabeled Ag-MSNs with LysoTracker-Red in both cancer and normal cells, implying some Ag-MSNs have entered lysosomes while the rest are in the cytoplasm. It is worth noting that almost no particles were observed in the nucleus, because AgMSNs were not small enough to penetrate into the nucleus membranes. Furthermore, as assessed by fluorescence-activated cell sorting (FACS), the uptake of Ag-MSNs proved celldependent in both the cancer and normal cells, with the uptake in the HepG2 cells being routinely more than 2-fold higher than that in the HL-7702 cells (Figure S4), mainly due to the difference in the macropinocytosis uptake pathways of D
DOI: 10.1021/acsami.5b11310 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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Figure 4. Selective killing behavior of DOX-loaded Ag-MSNs in liver cancer cells. The cytotoxicity of Ag-MSNs, free DOX, and DOX-loaded AgMSN against (a) HepG2, (b) A549, (c) MCF-7, (d) HL-7702, (e) HUVEC, and (f) BMSC cells at different levels of concentration after 48 h, relatively. These data represent three separate experiments and are presented as mean values ± SD *P < 0.05 versus control group, #P < 0.05 versus DOX group.
S7). More importantly, DOX-loaded Ag-MSNs displayed significantly reduced damage to normal cells, indicating that DOX-loaded Ag-MSNs could minimize detrimental effect of molecular DOX to normal tissue cells. It is worth noting that, in comparison to severe cytotoxicity of the DOX-loaded AgMSNs, cells incubated with pure Ag-MSNs preserve high cell viability (>95%), indicating that the Ag-MSNs may serve as noncytotoxic drug nanocarriers because of the favorable biocompatibility of silicon.22 Apoptotic results further confirmed that DOX-loaded Ag-MSNs induced highest apoptosis rate in HepG2 cells, suggesting an intensified cytotoxicity compared with the free DOX group in cancer cells (Figure S8 in the Supporting Information). All these findings were correlated with pH-responsive drug release behavior of DOXloaded Ag-MSNs as we mentioned before, demonstrating the advantage for their selective cancer treatment.
In summary, we have reported a facile and mild route to prepare novel Janus silver-mesoporous silica nanoparticles (AgMSNs). The assembling mechanism is based on the anisotropic island nucleation and growth of mesosilica body in alcohol-free reaction system. Due to the unique Janus structure, the SPR and mesoporous properties of Ag-MSN nanocomposites combined with individual components together were not interfered or slacken down. Ag-MSN nanocariers were found to be an effective drug delivery system, which was favorable for easy endocytosis, pH-responsive drug release and simultaneous SERS imaging. More importantly, DOX-loaded Ag-MSNs selectively inhibited cancer cell growth, rather than human normal cells. This work highlighted the potential of Janus AgMSN nanocariers as a realizable tool for efficient cancer theranostics. E
DOI: 10.1021/acsami.5b11310 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.5b11310. Experimental procedures, characterization of Ag-MSN, CLSM images, FACS analysis, cytotoxicity, and supporting figures and text (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Author Contributions †
D S. and X Z. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (81371681 and 81201804), the Opening Project of State Key Laboratory of Supramolecular Structure and Materials of Jilin University under Grant No. SKLSSM 201504, and the Frontier Interdiscipline Program of Norman Bethune Health Science Center of Jilin University (2013101001). Prof. Guangfan Chi, Prof. Bing Zhao, Dr. Yingshuai Wang, Dr. Chao Yang, Dr. Yue Pan, Dr. Lu Zhang, Dr. Zheng Wang, Jinying Xu, and Weina Cheng are acknowledged for their help in preparing the paper. All experiments were carried out in Jilin Province Engineering Laboratory for Nanomedicine.
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