Shell Hybrids as Drug Nanocarriers for

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GNRs/PPy/m-SiO2 Core/Shell Hybrids as Drug Nanocarriers for Efficient Chemo-Photothermal Therapy Juan Wang, Jie Han, Chunhua Zhu, Na Han, Juqun Xi, Lei Fan, and Rong Guo Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b02667 • Publication Date (Web): 06 Nov 2018 Downloaded from http://pubs.acs.org on November 8, 2018

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GNRs/PPy/m-SiO2 Core/Shell Hybrids as Drug Nanocarriers for Efficient Chemo-Photothermal Therapy Juan Wang,† Jie Han,*,† Chunhua Zhu,‡ Na Han,† Juqun Xi,‡ Lei Fan,† Rong Guo*,†

†School

of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu,

225002, P. R. China E-mail: [email protected]; [email protected] ‡School

of Medicine, Yangzhou University, Yangzhou, Jiangsu, 225002, P. R. China

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ABSTRACT: Combination therapy as a novel strategy with the combination of photothermal therapy and chemotherapy (photothermal-chemotherapy) has aroused the tremendously increasing interest owing to the synergistic therapeutic effect on destroying cancer cells since that the hyperthermia generated from photothermal therapy can promote drug delivery into tumors, which would highly increase therapeutic efficacy as compared to those sole treatments. Herein, we fabricated a novel nanomaterial-based carrier composed of GNRs, polypyrrole (PPy) and mesoporous silica to form GNRs/PPy/m-SiO2 core/shell hybrids. After loading the anticancer drug of doxorubicin (DOX), the photothermal effect and the drug-release behavior of GNRs/PPy@mSiO2-DOX hybrids were investigated. The in vitro and in vivo near-infrared (NIR) photothermalchemotherapy were also revealed. The results indicated the NIR-induced photothermal effect was beneficial to promote the release of the drug. In addition, combination therapy demonstrated the enhanced synergistic efficacy and excellent treatment efficacy for cancer therapy.

KEYWORDS: gold nanorod; conducting polymer; mesoporous silica; photothermal; drugcontrolled release; combination therapy


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INTRODUCTION Functional photothermal nanomaterials-based photothermal therapy, which can absorb nearinfrared (NIR) light and can effectively convert it into physical heat to ablate cancer cells, has aroused a tremendously increasing interest owing to its specific selectivity, minimal invasiveness and low systemic toxicity, which is recognized as a promising supplement to traditional cancer therapies.1-6 More interesting, because of the further development of nanotechnology in the forefront of medical and material science, researchers have exploited a novel strategy called “combination therapy” with the combination of photothermal therapy and chemotherapy (photothermal-chemotherapy).7-13 In recent decades, numerous results show that the combination therapy can exert a synergistic therapeutic effect on destroying cancer cells since that the hyperthermia generated from photothermal therapy can promote drug delivery into tumors, which would highly increase therapeutic efficacy.14-18 Therefore, it is vital to design efficient nanomaterial-based carriers on photothermal and drug delivery. Until now, a large variety of nanocomposites as photothermal agents and drug-carriers simultaneously have been developed for the effective combination therapy, which include metal nanoparticles,19-24 carbon-based materials,8, 25-26 and polymeric nanoparticles.27-31 Meanwhile, various photothermal agents can also be applied for drug delivery systems. Gold nanorods (GNRs) are the most frequently investigated photothermal nanomaterials among the explored class of photothermal agents because of their tunable absorption bands and high conversion efficiency especially in the range of NIR wavelength.32-35 In most of the cases, GNRs were hybridized to prevent their clustering and therefore to improve their stability. As polymeric photothermal agents, conducting polymers of typical polypyrrole (PPy) and polyaniline (PANI) have been recently established to be potential photothermal nanomaterials with outstanding


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stability.36-37 Therefore, the combination of GNRs and conducting polymers are believed to maintain both high photothermal conversion efficiency and stability, which have showed improved photothermal performance.5 However, most of the reported GNRs/conducting polymer hybrids were utilized as photothermal agents for photothermal therapy, the photothermal-chemotherapy of based on GNRs/conducting polymer hybrids has been rarely reported, possible due to the limited capacity of drug encapsulation. For the drug delivery system, mesoporous silica (m-SiO2) with high surface areas and tunable mesopores has been widespread adopted as delivery carriers for drugs.38-43 Therefore, designed-synthesis of hybrids containing GNRs, conducting polymer and mSiO2 for advanced photothermal-chemotherapy is highly desirable. Herein, we demonstrated a novel nanomaterial-based drug carrier composed of GNRs, PPy and m-SiO2 to form GNRs/PPy/m-SiO2 core/shell hybrids. GNRs/PPy core/shell hybrids were firstly synthesized according to our previous reports, followed by the silica-coating process. Finally, the anticancer drug of doxorubicin (DOX) was employed and encapsulated in GNRs/PPy/m-SiO2 hybrids. As a result, DOX loaded GNRs/PPy/m-SiO2 (GNRs/PPy/m-SiO2-DOX) nanoplatforms as drug-controlled release system were constructed. The photothermal effect and the drug-release behavior of GNRs/PPy/m-SiO2-DOX were investigated. The in vitro and in vivo NIR photothermal-chemotherapy were also revealed. The results indicated the NIR-induced photothermal effect was beneficial to promote the release of the drug, which featured an excellent NIR-triggered drug release property of GNRs/PPy/m-SiO2-DOX, as compared to GNRs/m-SiO2DOX that with poor photothermal effect upon an 808 nm NIR laser exposure. In addition, the successful in vitro and in vivo NIR combination therapy demonstrated the enhanced synergistic efficacy and excellent treatment efficacy for cancer therapy. Results confirmed that GNRs/PPy/m-


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SiO2-DOX showed potential as bifunctional nanoplatforms for effective photothermal and chemotherapy.

EXPERIMENTAL METHODS Materials: DOX was bought from Shanghai Damas-Beta Reagent Co. Ltd. Cell Counting Kit-8 (CCK-8) was obtained from Beyotime Biotechnology Co. Ltd. Dulbecco’s Modified Eagle Medium (DMEM) and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay were purchased from Thermo Fisher Scientific (USA). Other reagents were obtained from Sinopharm Chemical Reagent Co. Ltd. Synthesis of GNRs/PPy Core/Shell Hybrids GNRs were synthesized by using a method as reported.5, 44 GNRs/PPy core/shell hybrids was synthesized as follows: First, 2.0 mL of 1.0 mg/mL GNRs colloidal solution was mixed with 8 ml of transparent solution that contains 0.03 g F127 and pyrrole monomer (1, 3, 5, or 7 μL). After stirring for 1 h, 1.0 mL of ammonium persulfate (APS, the molar ratio of monomer to APS was set at 1:1) aqueous solution was added and the polymerization reaction was continued for 2 h. At last, the products were centrifuged with water three times and then dispersed in 2.0 mL water for further use. The obtained GNRs/PPy core/shell hybrids were denoted as GNRs/PPy(1), GNRs/PPy(3), GNRs/PPy(5), and GNRs/PPy(7) at the pyrrole monomer dosage of 1, 3, 5, and 7 μL, respectively. Synthesis of GNRs/m-SiO2 and GNRs/PPy/m-SiO2 Core/Shell Hybrids The m-SiO2 was coated on GNRs or GNRs/PPy via a hexadecyltrimethylammonium bromide (CTAB)-directed sol−gel process as follows: The above GNRs and GNRs/PPy were separately


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dispersed in 20 mL of water, after which 0.1458 g and 0.3645 g of CTAB were added into them and stirred until complete dissolution, and then a certain amount of 0.5 mol/L of NaOH was employed to adjust the pH between 10 and 11. Subsequently, 50 μL of TEOS in ethanol (25%) was dropped into the mixture under gentle stirring within 0.5 h. After stirring at 35 °C for 24 h, the products were centrifuged and washed with water three times. Then the collected nanoparticles were dispersed in 9.0 mL of methanol containing 0.5 mL of concentrated HCl solution and refluxed overnight to remove the CTAB templates. Finally, the as-prepared GNRs/m-SiO2 and GNRs/PPy/m-SiO2 were purified with water and ethanol several times and dried under vacuum. In Vitro Photothermal Performance The GNRs, GNRs/PPy, GNRs/m-SiO2 and GNRs/PPy/m-SiO2 (40 μg/mL) colloidal solutions were irradiated by the 808 nm-laser (3.0 W/cm2, MW-GX-808, Changchun Laser Technology Co., Ltd.). The temperature of the colloidal solution was recorded by a thermocouple thermometer. To investigate the photostability, the colloidal solution of GNRs/PPy/m-SiO2 core/shell hybrids was exposed to the laser for 10 min irradiation (laser on), then turned off the laser till the solution was cooled to room temperature (laser off). Six cycles of irradiation on/off with the laser were performed. Drug Loading and Releasing 2.0 mg of GNRs/m-SiO2 or GNRs/PPy/m-SiO2 core/shell hybrids were dispersed in 10 mL of PBS solution (pH = 8.0) containing different amounts (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg) of DOX, after which the mixture was stirred for 24 h. Then, the obtained GNRs/m-SiO2-DOX or GNRs/PPy/m-SiO2-DOX were collected via centrifugation and washed with PBS solution three times at 11000 rpm for 5 min. To evaluate the mass of DOX loaded into the nanomaterials, we collected all the supernatant solution and measured it by using a UV-vis spectrophotometer at the


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wavelength of 480 nm. The drug loading capacity of the GNRs/m-SiO2 and GNRs/PPy/m-SiO2 hybrids = (weight of DOX in nanocarriers/weight of nanocarriers). The drug encapsulation efficiency of the GNRs/m-SiO2 and GNRs/PPy/m-SiO2 hybrids = (weight of DOX in nanocarriers/initial weight of DOX). To investigate the DOX release behavior, we re-dispersed 3 mL of GNRs/m-SiO2 -DOX and GNRs/PPy/m-SiO2-DOX with the concentration of 40 μg/mL into a dialysis bag (cutoff molecular weight = 3,500 Da, Shanghai Yuanye Biological Technology Co. Ltd), followed by immersing them into 30 mL of PBS buffer dialysis solution (pH 7.4 or pH 5.3) at 37 °C under vibration at 100 rpm. For the DOX release experiment under irradiation, the nanocarriers were dispersed in PBS (pH = 5.3) with exposure to 808 nm laser irradiation (3 W/cm2). At different time intervals, 3 mL of supernatant was taken out to determine the DOX concentration released from nanoparticles by using an UV−Vis spectrophotometer (480 nm). In vitro and In vivo Chemo-Photothermal Therapy For the in vitro chemo-photothermal therapy, GNRs/m-SiO2,

GNRs/m-SiO2-DOX,

GNRs/PPy/m-SiO2, or GNRs/PPy/m-SiO2-DOX core/shell hybrids were dispersed in DMEM medium before testing, and the following MTT assay and chemo-photothermal therapy were similar to our previous work.5 For the in vivo chemo-photothermal therapy, the tumor-bearing mice were randomly divided into four groups (n = 6 per group) for various treatments: 1) PBS, 2) GNRs/PPy/m-SiO2-DOX, 3) GNRs/PPy/m-SiO2 + laser, 4) GNRs/PPy/m-SiO2-DOX + laser. The procedures were similar to our previous work.5 Details can be found in the Supporting Information. Statistical Analysis Statistical analysis was performed by Student's t-test. Statistical significance was marked as *p < 0.05, **p < 0.01, ***p < 0.001 and N. S. (no significant difference) p > 0.05.


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RESULTS AND DISCUSSION Formation Mechanism and Characterization Scheme 1 shows the procedures for the synthesis of GNRs/PPy/m-SiO2 core/shell hybrids. At first, GNRs was coated by a layer of PPy polymer through chemical polymerization of pyrrole using APS as the oxidant, leading to the formation of GNRs/PPy core/shell hybrids. The m-SiO2 was coated on surfaces of GNRs/PPy core/shell hybrids via the CTAB-directed sol−gel method by a process of hydration and condensation of tetraethoxysilane (TEOS) in a water/ethanol mixture, followed by the CTAB template removal process. Direct visualization of various nanomaterials were realized by TEM observations. Figure 1a shows the TEM image of GNRs, where the diameter and the length of GNRs are about 25 and 75 nm, respectively. As shown in Figure 1b, the coating thickness of PPy polymer is about 20 nm. The polymer thickness can be altered by changing the amount of pyrrole monomer (Figure S1). PPy polymer was found to coat on side surfaces, rather than the tip surfaces of GNRs at the low amount of monomer (Figure S1a). As the amount of monomer increases, the morphology transforms from clutter (Figure S1a) to regular capsule shape (Figures S3b-d). Meanwhile, the PPy polymer thickness also increases with the amount of monomer. Figure 1c shows the TEM image of GNRs/PPy/SiO2 core/shell hybrids using GNRs/PPy(5) core/shell hybrids as the template. After CTAB removal, the mesoporous channels of silica shells can be clearly evidenced (Figure 1d), where the mesoporous silica shell is about 15 nm. The size distribution of GNRs, GNRs/PPy and GNRs/PPy/m-SiO2 in solution is revealed by DLS measurement (Figure S2), which is about 75, 100, and 600 nm, respectively. The DLS results of GNRs and GNRs/PPy nanomaterials are basically consistent with the TEM observation. However, as to the GNRs/PPy/m-SiO2 core/shell hybrids, the DLS result is obviously higher, which is due


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to the aggregation of nanoparticles. For comparison, GNRs/m-SiO2 core/shell hybrids with similar silica shell thickness were also synthesized (Figure S3). The high angle annular dark field scanning transmission electron microscope (HAADF-STEM) image (Figure 1e) and the energy-dispersive X-ray spectroscopic (EDS) elemental maps (Figure 1f−h) further confirm the expected GNRs/PPy/m-SiO2 core/shell structure. XRD patterns of GNRs, SiO2, GNRs/m-SiO2 and GNRs/PPy/m-SiO2 core/shell hybrids were shown in Figure 2a. The weak broad peak at about 23° of SiO2 and of GNRs/m-SiO2 core/shell hybrids can be assigned to the amorphous m-SiO2, and the wide and relative intensive peak at about 23° of GNRs/PPy/m-SiO2 core/shell hybrids is attributed to both amorphous m-SiO2 and amorphous PPy polymer. Moreover, other well-defined characteristic peaks, such as (111), (200), (311) and (220), agree well with the cubic phase of Au (JCPDS 04-0784). Results above indicate the successful coating of SiO2 and the well-retained phase structure of GNRs after silica and PPy coating. Figure 2b and shows the N2 adsorption-desorption curves of GNRs/PPy/m-SiO2 core/shell hybrids. The BET surface area of GNRs/PPy/m-SiO2 core/shell hybrids as measured from the desorption curve using the BET method is up to 256 m2/g. The pore size distribution of the sample as determined using the BJH method from the desorption curve of the isotherm is shown in the inset in Figure 2b. The pore size of GNRs/PPy/m-SiO2 core/shell hybrids is 3.0 nm, which is suitable for the drug loading. Moreover, the pore volume of GNRs/PPy/mSiO2 core/shell hybrids is about 0.68 cm3/g. Photothermal and Photostability Performance Figure 3a shows the UV-vis absorption spectra of the GNRs and GNRs/PPy core/shell hybrids.


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The PPy synthesized without GNRs shows a weak absorption peak at about 350 nm (Figure S4). The longitudinal plasmon resonance of GNRs at 710 nm shows a clear red shift after the PPy coating. The longitudinal plasmon resonance of GNRs at 710 nm shows a clear red shift after the PPy coating. It is reasonable as both the shortened extent of electronic vibration in GNRs and extra electronic oscillation of PPy originated from its conductive nature contribute to the red shift of absorption bands for GNRs/PPy core/shell hybrids.45 GNRs, PPy and GNRs/PPy core/shell hybrids were then exposed to the 808 nm-laser to assess their photothermal performance due to its weak autofluorescence and strong penetration in live tissues.46-48 It was observed that the extent of temperature increment was consistent with the absorbance at the wavelength of 808 nm (Figure 3b). As GNRs/PPy(5) core/shell hybrids exhibited the best photothermal performance, then it was selected as the candidate for the follow-up synthesis of GNRs/PPy/m-SiO2 core/shell hybrids. Figure 3c shows UV-vis spectra of GNRs, GNRs/m-SiO2, GNRs/PPy and GNRs/PPy/m-SiO2. It can be seen that there is no significant shift in absorption peaks when the silica layer is coated on surfaces of GNRs or GNRs/PPy core/shell hybrids. Though the coated silica shell could weaken the capability of absorbing light of the composites, the value of absorbance of GNRs/PPy/m-SiO2 at 808 nm is much higher than that of GNRs/m-SiO2.48 As shown in Figure 3d, the temperature of the colloidal aqueous solution containing GNRs, GNRs/m-SiO2, GNRs/PPy, and GNRs/PPy/mSiO2 nanoparticles were increased by 10.8, 3.1, 21.6 and 17.7 C with the 808 nm laser irradiation (3 W/cm2) for 10 min, respectively. Apparently, the silica shell weakens the photothermal performance of the nanomaterials, but the temperature increment of GNRs/PPy/m-SiO2 (17.7 C) is also much larger than that of GNRs/m-SiO2 (3.1 C). The temperature increase observed for GNRs/m-SiO2 can be ignored like the water. Results shows that GNRs/PPy/m-SiO2 core/shell


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hybrids show better photothermal performance compared with that of GNRs/m-SiO2 core/shell hybrids, which demonstrates that the temperature elevation is in consistent with the absorbance at 808 nm. The photostability of GNRs, GNRs/PPy, and GNRs/PPy/m-SiO2 was studied. After being exposed to the 808 nm-laser for 10 min, the solution was cooled to room temperature without the NIR irradiation. As shown in Figure 4, the temperature elevation of GNRs changes from 10.1 to 7.1 oC (down to 70%), whereas there is no significant decrease in temperature for GNRs/PPy and GNRs/PPy/m-SiO2 core/shell hybrids after six cycles. Results indicated that the GNRs/PPy/mSiO2 core/shell hybrids not only exhibit excellent NIR photothermal effect, but also show outstanding photostability. Drug Loading and Releasing GNRs/PPy/m-SiO2 and GNRs/m-SiO2 core/shell hybrids are suitable for drug delivery due to the mesoporous silica shell can provide voids for the drug encapsulation. The anticancer drug DOX was firstly loaded into GNRs/PPy/m-SiO2 and GNRs/m-SiO2 core/shell hybrids. By increasing the concentration of DOX, the drug loading capacity would increase, whereas the drug encapsulation efficiency firstly increased and then decreased (Table 1). It was also noted that both the drug loading capacity and drug encapsulation efficiency of GNRs/PPy/m-SiO2 core/shell hybrids were higher than those of GNRs/m-SiO2 core/shell hybrids. The zeta potential of GNRs, GNRs/PPy, GNRs/m-SiO2, GNRs/PPy/m-SiO2, were measured to be 42.3 mV, 18.5 mV, -20.2 mV, -18.2 mV. The negative charges of GNRs/m-SiO2 and GNRs/PPy/m-SiO2 core/shell hybrids were due to the successful coating of the silica. The zeta potential of GNRs/m-SiO2-DOX and


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GNRs/PPy/m-SiO2-DOX were measured to be 20.5 mV and 21.4 mV, respectively, which confirmed the successful drug loading for GNRs/m-SiO2 and GNRs/PPy/m-SiO2 core/shell hybrids. To investigate the effect of DOX drugs on the photothermal effect of GNRs/PPy/m-SiO2 and GNRs/m-SiO2 core/shell hybrids, the nanocarriers and drug-loaded nanocarriers were exposed to the NIR laser (808 nm, 3 W/cm2) for 10 min. It can be seen that the photothermal performances of both GNRs/PPy/m-SiO2 and GNRs/m-SiO2 are decreased after drug loading. The results are reasonable as the DOX drugs loaded in the mesoporous pores will hamper the penetration of the light to the absorbing cores and the heat transfer outwards. Both the pH and NIR light are effective tools to control the release of GNRs/PPy/mSiO2-DOX and GNRs/m-SiO2-DOX nanocarriers. First, we detected the DOX release behavior in pH 7.4 and pH 5.3, which were designed to simulate a normal physiological environment and a cellular lysosome environment. Figure 6a shows that the release rate of DOX from GNRs/PPy/m-SiO2-DOX and GNRs/m-SiO2-DOX nanocarriers was largely improved when the pH changed from 7.4 to 5.3, which may be caused by the increased solubility of the protonated DOX at an acidic environment. This pH-dependent release behavior with more DOX release for the nanocarriers at pH 5.3 (like acidic extracellular microenvironment around tumor) is beneficial for increasing the cancer therapy efficacy and reducing the side effects. Next, the effect of NIR irradiation on DOX release was investigated. As for GNRs/PPy/m-SiO2-DOX nanocarriers, ~ 65% DOX drugs were released


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with NIR irradiation whereas only ~25% DOX drugs were released without NIR irradiation. However, as for GNRs/m-SiO2-DOX nanocarriers, the NIR irradiation has little effect on the release of DOX drugs (Figure 6b). The results are reliable as the photothermal performance of GNRs/PPy/m-SiO2-DOX is better than that of GNRs/m-SiO2-DOX nanocarriers (Figure 5). The NIR-triggered DOX release may be attributed to the photothermal effect of GNRs/PPy/m-SiO2-DOX, for which the heat generated by the photothermal effect of the GNRs/PPy/m-SiO2 weakens the interactions between DOX and the silica. Results demonstrated that GNRs/PPy/m-SiO2 core/shell hybrids could be a better drug carrier candidate for pH and NIR-stimulus synergistic photothermochemotherapy therapy. Cytotoxicity Assay and In vitro Chemo-Photothermal Therapy The cytotoxicity of the nanocarriers were then investigated before their use in biological applications. CCK-8 cell viability assay was carried out to justify the relative viability of CT26 cells after they were pre-incubated with GNRs/PPy/m-SiO2 and GNRs/m-SiO2 core/shell hybrids for 24 h. The results showed a negligible negative effect on cell viability when the concentration of the nanomaterials was below 25 μg/mL (Figure 7a), indicating the good biocompatibility of GNRs/PPy/m-SiO2 and GNRs/m-SiO2 core/shell hybrids within a certain concentration. We then conducted in vitro chemo-photothermal therapy of GNRs/PPy/m-SiO2-DOX and GNRs/m-SiO2-DOX and compared their therapeutic effects. As shown in Figure 7b and 7c, GNRs/PPy/m-SiO2-DOX and GNRs/m-SiO2-DOX


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without NIR irradiation both have a certain cytotoxicity to cells, which results from the DOX that incorporated into the therapeutic agents. Furthermore, when NIR irradiation was introduced, the GNRs/PPy/m-SiO2-DOX nanocarriers induced much higher cytotoxicity than that of GNRs/m-SiO2-DOX nanocarriers, since the GNRs/PPy/m-SiO2DOX nanocarriers exhibited a better NIR photothermal effect (Figure 5). For the combined therapy, cells that incubated with GNRs/PPy/m-SiO2-DOX nanocarriers under the NIR irradiation were almost destroyed at the concentration of 12.5 μg/mL. The above results demonstrated that the combination therapy of the GNRs/PPy/m-SiO2-DOX nanocarriers showed the most outstanding therapeutic effect for cancer cells. In vivo Chemo-Photothermal Therapy Based on the results of the in vitro chemo-photothermal therapy, we conducted in vivo experiments by assessing the tumor growth inhibition. For the NIR laser treatment groups, each mouse was intravenously injected via tail vein using GNRs/PPy/m-SiO2 and GNRs/PPy/m-SiO2-DOX core/shell hybrids followed by irradiation for 10 min. The other two groups included the injection with PBS and GNRs/PPy/m-SiO2-DOX core/shell hybrids without NIR irradiation. The temperature increment of the tumor site was recorded by an IR thermal camera every two minutes. As shown in Figure 8, there is a sharp increment for the tumor temperature of GNRs/PPy/m-SiO2 under laser irradiation. In contrast, the tumor temperature in the group of the mice injected with PBS is almost unchanged with irradiation. The tumor volumes were monitored and recorded every three days during the


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subsequent 15 days. Figure 9a shows that the tumors in the NIR laser treatment groups were effectively decreased, especially the volume of the group injected GNRs/PPy/mSiO2-DOX under irradiation is “zero” after 15 days. Compared with the PBS group, the group of GNRs/PPy/m-SiO2-DOX for single chemo-therapy without laser irradiation has a relatively better effect of inhibiting the enlargement of the tumor, but neither of them shows tumor regression. As shown in Figure 9b, there is no significant change in the body weight of the mice, which demonstrates unnoticeable toxic side effects caused by GNRs/PPy/m-SiO2

and

GNRs/PPy/m-SiO2-DOX

nanocarriers.

These

preliminary

investigations revealed that GNRs/PPy/m-SiO2 and GNRs/PPy/m-SiO2-DOX can possibly be a safe therapeutic agent. In addition, Figure 10 shows that the mice treated with GNRs/PPy/m-SiO2 and GNRs/PPy/m-SiO2-DOX nanocarriers under NIR irradiation were cured and survived for more than 30 days, while the mice treated with GNRs/PPy/m-SiO2DOX died in less than 24 days and the mice treated with PBS died in less than 12 days. Taken all the results together, GNRs/PPy/m-SiO2-DOX used for combination therapy demonstrated an enhanced synergistic efficacy and excellent treatment efficacy for cancer therapy.


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CONCLUSION In summary, GNRs/PPy/m-SiO2 core/shell hybrids have been successfully fabricated, which have shown excellent photothermal performance and drug loading capacity. In comparison with GNRs/m-SiO2-DOX core/shell hybrids, GNRs/PPy/m-SiO2-DOX core/shell hybrids exhibited a better therapeutic effect for chemo-photothermal therapy. Therefore, the as-prepared GNRs/PPy/m-SiO2 core/shell hybrids show high potential as drug nanocarriers for effective chemo-photothermal therapy.

ASSOCIATED CONTENT Supporting Information. Additional TEM images of GNRs/PPy, GNRs/SiO2, and GNRs/m-SiO2 core/shell hybrids. This information is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected]

ACKNOWLEDGMENTS The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (21673202 and 21703198), Qing Lan Project and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We would also like to acknowledge the technical support received at the Testing Center of Yangzhou University.


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FIGURE CAPTIONS Scheme 1 Schematic illustration for the synthesis of GNRs/PPy/m-SiO2 core/shell hybrids. Figure 1 TEM images of (a) GNRs, (b) GNRs/PPy, (c) GNRs/PPy/SiO2, and (d) GNRs/PPy/mSiO2. (e) HAADF-STEM image of GNRs/PPy/m-SiO2 core/shell hybrids. (f−h) EDS maps of GNRs/PPy/m-SiO2 core/shell hybrids for (f) Au, (g) N, and (h) Si. Figure 2 (a) XRD patterns of GNRs, SiO2, GNRs/m-SiO2 and GNRs/PPy/m-SiO2 core/shell hybrids. (b) Nitrogen adsorption-desorption isotherms of GNRs/PPy/m-SiO2 core/shell hybrids. Inset shows the pore size distribution of GNRs/PPy/m-SiO2 core/shell hybrids. Figure 3 (a) UV−vis absorption spectra of GNRs and GNRs/PPy core/shell hybrids. (b) Temperature

change curves of GNRs and GNRs/PPy upon exposure to the NIR laser (808 nm, 3 W/cm2, 10 min). (c) UV−vis absorption spectra of GNRs, GNRs/PPy, GNRs/m-SiO2 and GNRs/PPy/m-SiO2


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core/shell hybrids. (d) Temperature change curves of GNRs, GNRs/PPy, GNRs/m-SiO2 and GNRs/PPy/m-SiO2 core/shell hybrids upon exposure to the NIR laser (808 nm, 3 W/cm2, 10 min). Figure 4 Temperature elevation of GNRs, GNRs/PPy, and GNRs/PPy/m-SiO2 over six laser on/off cycles of NIR irradiation. Figure 5 (a) Temperature change curves of GNRs/m-SiO2 and GNRs/PPy/m-SiO2 upon exposure to the NIR laser (808 nm, 3 W/cm2, 10 min) before and after DOX loading. Figure 6 (a) DOX release curves of GNRs/m-SiO2 and GNRs/PPy/m-SiO2 in PBS (pH = 7.4 and 5.3) at 37 oC. (b) DOX release curves of GNRs/m-SiO2 and GNRs/PPy/m-SiO2 in PBS (pH = 5.3) with NIR laser irradiation (808 nm, 3 W/cm2). Figure 7 In vitro experiments. (a) Relative viabilities of CT26 cells incubated with GNRs/m-SiO2 and GNRs/PPy/m-SiO2 at various concentrations for 24 h. (b, c) Relative viabilities of CT26 cells incubated with (b) GNRs/m-SiO2, GNRs/m-SiO2-DOX, and GNRs/m-SiO2-DOX+laser, and (c) GNRs/PPy/m-SiO2, GNRs/PPy/m-SiO2-DOX, and GNRs/PPy/m-SiO2-DOX+laser at various concentrations for 24 h. Figure 8 In vivo photothermal therapy of the CT26 tumor bearing mice after the injection of GNRs/PPy/m-SiO2 through the tail vein: IR thermal images of the tumors with NIR laser irradiation (808 nm, 3 W/cm2). Figure 9 In vivo photothermal therapy of the CT26 tumor bearing mice after the injection of GNRs/PPy/m-SiO2 and GNRs/PPy/m-SiO2-DOX through the tail vein: (a) Relative tumor-growth curves after various treatments indicated in 15 days. (b) The body weight after various treatments indicated in 15 days. Figure 10 Survival curves of various groups of the CT26 tumor bearing mice after various treatments.


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Scheme 1


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Figure 1


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Au (111)

(a)

Au(200) GNRs

Intensity (a.u.)

Au (311)

Au (220)

GNRs/PPy/m-SiO2

GNRs/m-SiO2 SiO2

20

40

60

80

2-Theta (degree) 500

(b)

400

dV/dD (cm 3 /nm/g )

0.10 0.08 0.06

3

Volume (cm /g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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300

0.04 0.02

200

0.00

0

5

10

15

Pore diameter (nm)

20

100 0

0.0

0.2

0.4

0.6

0.8

Relative pressure (P/P0)

1.0

Figure 2


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GNRs GNRs/PPy (1) GNRs/PPy (3) GNRs/PPy (5) GNRs/PPy (7)

25

(a)

1.5

1.0

0.5

0.0 400

15 10 5

500

600

700

800

0

900

0

2

25

(c)

GNRs GNRs/PPy (5) GNRs/m-SiO2

20

1.0

0.5

0.0 400

6

8

10

(d)

GNRs GNRs/PPy (5) GNRs/m-SiO2 GNRs/PPy/m-SiO2 water

GNRs/PPy/m-SiO2

 T ( oC )

1.5

4

Irradiation time (min)

Wavelength (nm)

2.0

(b)

GNRs PPy GNRs/PPy (1) GNRs/PPy (3) GNRs/PPy (5) GNRs/PPy (7)

20

 T ( oC )

Absorbance

2.0

Absorbance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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15 10 5

500

600

700

800

0

900

0

2

Wavelength (nm)

4

6

8


10

Figure 3


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GNRs/PPy/m-SiO2 GNRs/PPy GNRs

21  T ( oC )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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100%

100%

14 7

70%

0 0

30

60

90

120

150

Time (min) Figure 4


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25 GNRs/m-SiO2 GNRs/m-SiO2-DOX

20

GNRs/PPy/m-SiO2 GNRs/PPy/m-SiO2-DOX

 T ( oC )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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15 10 5 0

0

2

4

6

8

10

Irradiation time (min) Figure 5


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(a)

GNRs/m-SiO2-DOX pH=7.4 GNRs/m-SiO2-DOX pH=5.3

80

GNRs/PPy/m-SiO2-DOX pH=7.4 GNRs/PPy/m-SiO2-DOX pH=5.3

60 40 20 0

0

5

10

15

20

25

30

Time (h)

DOX Release (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

DOX Release (%)

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80

GNRs/m-SiO2-DOX+ Laser

60

GNRs/PPy/m-SiO2-DOX

(b)

GNRs/PPy/m-SiO2-DOX+ Laser GNRs/m-SiO2-DOX

40

20

0

0

1

2

3

4

Time (h) Figure 6


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Cell Viability (%)

180

(a)

GNRs/m-SiO2 GNRs/PPy/m-SiO2

150

***

120

N.S.

90 60 30 0

0

180

Cell Viability (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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3.125

6.25

12.5 Concentration (g/mL)

GNRs/m-SiO2+ Laser

(b)

GNRs/m-SiO2-DOX

150

25

GNRs/m-SiO2-DOX+ Laser

120

*** **

90 60 30 0

0

3.125

6.25

12.5

25

Concentration (g/mL)


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180

Cell Viability (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 41

GNRs/PPy/m-SiO2+ Laser

(c)

GNRs/PPy/m-SiO2/DOX

150

GNRs/PPy/m-SiO2/DOX+ Laser

120

*** **

90 60 30 0

zero

0

3.125

6.25

12.5

25

Concentration (g/mL) Figure 7


36

Page 37 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Figure 8


37

Langmuir

Relative Tumor Volume (V/V0)

10 8

PBS GNRs/PPy/m-SiO2+ Laser GNRs/PPy/m-SiO2-DOX

All died

GNRs/PPy/m-SiO2-DOX+ Laser

***

(a)

6 ***

***

4 2 0 0

3

6

9

Time (day)

12

15

18

(b)

PBS GNRs/PPy/m-SiO2+ Laser

26

Body Weight (g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 41

GNRs/PPy/m-SiO2-DOX GNRs/PPy/m-SiO2-DOX+ Laser

24 22

N.S.

20 18 0

3

6

9

Time (day)

12

15

Figure 9


38

Page 39 of 41

150

Survival rate (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

PBS GNRs/PPy/m-SiO2+ Laser GNRs/PPy/m-SiO2-DOX GNRs/PPy/m-SiO2-DOX+ Laser

125 100 75 50 25 0 0

6

12

18

Time (day)

24

30

Figure 10


39

Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 40 of 41

Table 1 Summary of the loading capacity and encapsulation efficiency of GNRs/m-SiO2 and GNRs/PPy/m-SiO2 nanocarriers with DOX. GNRs/m-SiO2:DOX

GNRs/PPy/m-SiO2:DOX

Weight ratio of nanocarrier to drug 4:1

4:2

4:3

4:4

4:1

4:2

4:3

4:4

15.

36.

51.

57.

17.

38.

53.

68.

9

4

5

7

5

7

4

7

63.

72.

68.

57.

70.

77.

71.

68.

6

8

7

7

0

4

2

7

Loading capacity (%)

Encapsulation efficiency (%)


40

Page 41 of 41

TOC Graphical

20

GNRs GNRs/PPy (5) GNRs/m-SiO2

15

GNRs/PPy/m-SiO2 water

80

DOX Release (%)

T ( oC )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

10 5 0

0

2

4

6

8


10

GNRs/m-SiO2-DOX+ Laser GNRs/PPy/m-SiO2-DOX+ Laser GNRs/m-SiO2-DOX

60

GNRs/PPy/m-SiO2-DOX

40 20 0

0

1

2

Time (h)

3

4


41

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