Ultralong Hydroxyapatite Nanowires-Based Paper Co-Loaded with

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Ultralong Hydroxyapatite Nanowires-Based Paper Co-Loaded with Silver Nanoparticles and Antibiotic for Long-Term Antibacterial Benefit Zhi-Chao Xiong,† Zi-Yue Yang,‡ Ying-Jie Zhu,*,† Fei-Fei Chen,† Yong-Gang Zhang,† and Ri-Long Yang† †

State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, PR China ‡ Sino-German College of Technology, East China University of Science and Technology, Shanghai 200237, PR China S Supporting Information *

ABSTRACT: Hydroxyapatite is a kind of biocompatible, environmentally friendly, and versatile inorganic biomaterial. Herein, the preparation of ultralong hydroxyapatite nanowires (HAPNWs)-based antibacterial paper co-loaded with silver nanoparticles (AgNPs) and antibiotic is reported. HAPNWs are used to prepare AgNPs in situ using an aqueous solution containing AgNO3 under the sunlight without added reducing agent at room temperature. Subsequently, ciprofloxacin (CIP) as an antibiotic is loaded on the HAPNWs@AgNPs. The resultant HAPNWs@AgNPs-CIP paper possesses several unique properties, including high flexibility, high Brunauer− Emmett−Teller (BET) specific surface area (47.9 m2 g−1), high drug loading capacity (447.4 mg g−1), good biocompatibility, sustained and pH-responsive drug release behavior (5.40−6.75% of Ag+ ions and 37.7−76.4% of CIP molecules at pH values of 7.4−4.5 at day 8, respectively), and reusable recycling. In the antibacterial tests against Escherichia coli and Staphylococcus aureus, the HAPNWs@AgNPs-CIP paper exhibits large diameters of inhibition zones and low minimum inhibitory concentrations (30 and 40 μg mL−1), revealing the high antibacterial activity. Besides, the consecutive agar diffusion tests (8 cycles), long-term stability tests (over 56 days), and continuous contamination tests (5 cycles) demonstrate the excellent recycling performance and long-term antibacterial activity of the HAPNWs@AgNPs-CIP paper. These results indicate a promising potential of the HAPNWs@AgNPs-CIP bactericidal paper for tackling public health issues related to bacterial infections. KEYWORDS: hydroxyapatite, nanowires, paper, silver nanoparticles, drug delivery, antibacterial, ciprofloxacin

1. INTRODUCTION Over recent decades, bacterial infections have seriously threatened human health and become global public health issues.1,2 It is highly desirable for developing the new antibacterial agent with improved bactericidal efficiency. A number of metallic particles and the related compounds have been developed and demonstrated for effective treatment of bacterial infections.3−6 In some cases, the low stability and direct uptake characters of bactericides resulted in high drug dosage and serious cellular toxicity. A recent advance in nanotechnology provides an alternative approach to resolve the challenges in developing nanoscale antibacterial materials with higher treatment efficiencies and lower side effects. Among the metallic bactericides, silver nanoparticles (AgNPs) were recognized as a broad-spectrum antibacterial agent7,8 and have been receiving much attention in medical fields (e.g., wound dressing9 and surgical device)10 and daily consumer products (e.g., water disinfection,11 air filter,12 food preservation,13 and cosmetics).14 Generally, AgNPs need a supporting substance to keep the physicochemical characteristics and © XXXX American Chemical Society

antimicrobial efficacy. Consequently, AgNPs were frequently integrated, anchored, or incorporated into polymer fibers,15 cellulose paper,16 ceramics,17,18 and other inorganic materials.19 It is noteworthy that the immobilization of AgNPs in the supporting substance is very important from the viewpoints of antimicrobial efficacy and biological safety. Therefore, the development of the novel method for the preparation of AgNPs-based antibacterial nanocomposites has been a hot topic in this field. In addition, antibiotics have widely been used as efficient bactericidal agents to protect public health.20,21 Unfortunately, abuse or overuse of them resulted in ineffective infection treatment due to the drug-resistant bacteria.22 Currently, the combination of the traditional antibiotics and metallic bactericides to develop the new antimicrobial agent is a promising strategy for fighting against the drug-resistant Received: April 13, 2017 Accepted: June 15, 2017

A

DOI: 10.1021/acsami.7b05208 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces

paper is promising for the design and preparation of new kind of multicomponent and multifunctional ultralong HAP nanowires-based paper for various biomedical applications.

bacteria. Previous studies have proved the synergistic effects when AgNPs and antibiotics were used simultaneously against Gram-negative and -positive bacterial infections.23−25 Recently, Zheng et al. reported that the simultaneous use of AgNPs and antibiotic could improve bacterial killing efficiency with a synergistic performance through damaging the bacterial membrane and breaking bacterial DNA effectively.26 Moreover, it seems that the integration of AgNPs and antibiotic into a delivery system would be a promising approach in the antibacterial field.27 Nevertheless, a single nanocomposite that can simultaneously immobilize AgNPs and antibiotic and exhibit controlled release property is highly desirable. Hydroxyapatite (HAP), the main inorganic component of natural bone and tooth of vertebrate, is a versatile inorganic biomaterial with good biocompatibility and widely used for biomedical applications.28−31 Previously, bactericidal functions were achieved for HAP nanostructured materials or coatings by doping with Ag+ ions or hybridizing with AgNPs, resulting in excellent antibacterial activities.32−35 In general, calcium phosphate based materials provide abundant binding sites on their surface for drug delivery and controlled release.29 Among them, HAP exhibits high affinity for the drug in physiological environment (pH ∼7.4), and the drug can be rapidly released at low pH values, such as in the environment caused by cancer cells or pathogenic bacteria.36−38 This feature reveals that HAP materials are the ideal carrier for the bactericidal drug loading and controlled release. The research on dual or multiple guest agents loaded HAP composites with multifunction or enhanced performance for biomedical applications has become a hot topic.39−41 Free-standing paper-like materials have attracted significant attention in industrial production, energy, and environment issues.42,43 It is of great interest to fabricate two-dimensional materials using one-dimensional nanowires as the building blocks owing to their unique characteristics including high specific surface area, large porosity, high permeability, and easy functionalization.44−47 As previously reported by this group, new kinds of highly flexible and fire-resistant paper were successfully prepared using ultralong HAP nanowires.48−52 The as-prepared fire-resistant paper exhibited advantageous properties in printing and writing as well as in adsorption and removal of organic pollutants. Moreover, a new kind of inorganic composite paper with high antibacterial activity was fabricated by incorporating AgNPs onto ultralong HAP nanowires through a one-pot solvothermal process.53 The new kinds of highly flexible and fire-resistant paper based on ultralong HAP nanowires provide new opportunities for various applications of the free-standing inorganic paper. Furthermore, it is of great interest to integrate several kinds of functional agents into a single paper to achieve multifunctional performance. In this work, we report a new kind of ultralong HAP nanowires-based paper co-loaded with AgNPs and an antibiotic. An environmentally friendly process under the sunlight without using any added reducing agent at room temperature is employed for the immobilization of AgNPs. In addition, a representative antibiotic drug, ciprofloxacin hydrochloride (CIP), is chosen for loading in the ultralong HAP nanowiresbased paper. The combination of HAP nanowires and dual bactericides endows the ultralong HAP nanowires-based paper with several unique characters: high flexibility, good biocompatibility, sustained and controlled release properties, enhanced bactericidal efficiency, reusable recycling, and longterm antibacterial activity. The simple method proposed in this

2. EXPERIMENTAL SECTION 2.1. Reagents and Chemicals. Calcium chloride (CaCl2), sodium dihydrogen phosphate dihydrate (NaH2PO4·2H2O), sodium hydroxide (NaOH), and silver nitrate (AgNO3) were purchased from Sinopharm Chemical Reagent Co., Ltd. Oleic acid (OA), ciprofloxacin hydrochloride (CIP), commercial hydroxyapatite, and β-tricalcium phosphate (Ca3(PO4)2) were obtained from Aladdin Industrial Corporation. All chemicals used in the experiments were of analytical grade and used as received without further purification. 2.2. Synthesis of Ultralong HAP Nanowires (HAPNWs). HAPNWs were prepared according to the calcium oleate precursor solvothermal method which was reported previously by this research group.48−56 Briefly, 135.0 g of deionized water, 47.5 g of methanol, and 93.6 g of OA were mixed together under mechanical stirring. Then, 10.5 g of NaOH dissolved in 150.0 g of deionized water was poured into the above mixture and stirred for 30 min. Subsequently, 3.33 g of CaCl2 dissolved in 120.0 g of deionized water and 9.36 g of NaH2PO4· 2H2O dissolved in 180.0 g of deionized water were separately poured into the above suspension. The reaction system was poured into a 1 L Teflon-lined stainless-steel autoclave, sealed, and solvothermally treated for 24 h at 180 °C. After the solvothermal treatment and cooling, the product was collected by centrifugation, washed with ethanol and deionized water twice, respectively, and dispersed in deionized water for further use. 2.3. Immobilization of AgNPs and Loading with CIP on HAPNWs. For the immobilization of AgNPs and loading with CIP, 200 mg of HAPNWs and 60 mg of AgNO3 were dispersed in 100 mL of deionized water, and the resulting suspension was stirred for 3 h in the sunlight at room temperature. After filtration and washing with deionized water twice, the obtained HAPNWs@AgNPs nanowires (100 mg) were redispersed in 60 mL of deionized water, and CIP (100 mg) was added into the above suspension and stirred for 2 h. After filtration and washing with deionized water twice, the product (HAPNWs@AgNPs-CIP nanowires) was obtained. The structural formula of ciprofloxacin molecule is shown in Figure S1. In addition, the control experiment was conducted following the same procedure except in the dark environment. HAPNWs@AgNPs and HAPNWs@ AgNPs-CIP were prepared in sunlight except as otherwise described. 2.4. Preparation of HAPNWs@AgNPs-CIP Paper. The HAPNWs@AgNPs-CIP paper was prepared through a vacuumassisted filtration method.51−54 HAPNWs@AgNPs-CIP nanowires (50 mg) were dispersed in deionized water (30 mL) and poured onto the filter paper in a funnel with a diameter of 4.0 cm, and the freestanding HAPNWs@AgNPs-CIP paper with a thickness of 110 μm was obtained after drying at 95 °C for 3 min. 2.5. Determination of Silver Content, in Vitro Ag+ Ions, and CIP Release Tests. For determining the silver content, the sample was dissolved in 10 wt % nitric acid with a concentration of 1 mg mL−1 overnight and further diluted 20-fold. The Ag+ ion concentrations were measured by inductively coupled plasma (ICP) analysis. To obtain the in vitro release profiles of Ag+ ions and CIP, the sample (10 mg) was dispersed in 10 mL of phosphate-buffered saline (PBS) with different pH values of 4.5, 6.0, and 7.4, respectively. The suspension was shaken at 37 °C with a shaking rate of 150 rpm. At 6 and 12 h and 1, 2, 3, 4, 5, 6, 7, and 8 days, 1 mL of the supernatant was taken out after centrifugation, and fresh PBS with the same volume was added to maintain a constant volume. The cumulative released amount of Ag+ ions and CIP were measured by ICP and UV−vis absorption analyses, respectively. Three parallel samples were measured for each time point. 2.6. In Vitro Biocompatibility Tests. To determine the cell viability, human lung adenocarcinoma epithelial (A549) cells (Cell Resource Center, Shanghai Institutes for Biological Sciences, Shanghai, China) were seeded in 96-well plates at a concentration of 1 × 104 cells per well and cultured under a 5% CO2 humidified atmosphere at B


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Figure 1. (a) Schematic illustration of the fabrication process of hydroxyapatite nanowires co-loaded with both silver nanoparticles and ciprofloxacin, and the free-standing nanowire paper; (b) digital images of the corresponding HAPNWs, HAPNWs@AgNPs, and HAPNWs@AgNPs-CIP paper sheets with diameters of 4.0 cm (from left to right). (c, d) HAPNWs@AgNPs-CIP paper shows high flexibility.

Figure 2. SEM and TEM images of the as-prepared nanowires and the cross-section of paper sheets: (a−c) HAPNWs; (d−f) HAPNWs@AgNPs; (g − (i) HAPNWs@AgNPs-CIP. The SEM images are shown in (a, c, d, f, g, and i), and TEM images are shown in (b, e, and h). 37 °C for 24 h. Subsequently, a series of sterilized samples at different concentrations were separately added into the wells, and cocultured for 48 h. The cell viability was determined by the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay at a wavelength of 490 nm. The culture plate without any sample was used as a control group. Each experiment was performed in triplicate. 2.7. Antibacterial Test. Escherichia coli and Staphylococcus aureus were used as the model bacteria for antibacterial experiments. Each antibacterial test was carried out in triplicate. For the inhibition zone tests, the circular paper sample with a diameter of 7 mm and a thickness of 110 μm was adopted. A 100 μL aliquot of bacterial suspension at a concentration of 5 × 106 colony forming units mL−1 (CFU mL−1) was spread uniformly on a solid nutrient agar plate. After drying in air, each testing sample was placed on the center of an agar plate and incubated overnight at 37 °C. The presence of inhibition zone was visualized and recorded using a digital camera.

For the measurement of minimum inhibitory concentration (MIC) value, the bacteria were cultured in liquid broth and diluted to a concentration of 1 × 107 CFU mL−1. A 300 μL aliquot of bacterial suspension was separately added into 2.7 mL of liquid broth containing the testing sample at different concentrations, and the mixture was incubated for 24 h at 37 °C. The MIC value was obtained according to the lowest concentration of testing sample that completely inhibited the bacteria by the spread plate count method. For the bacterial growth kinetic tests, the bacteria were cultured in liquid broth and diluted to a concentration of 1 × 107 CFU mL−1. A 1 mL aliquot of bacterial suspension was added to 9 mL of liquid broth containing the testing sample at a concentration of 50 μg mL−1; then, the mixture was incubated on a 37 °C shaker at 160 rpm for 24 h. At fixed time points, 100 μL of the bacterial suspension was extracted, diluted, and spread on an agar plate. After incubation at 37 °C for 24 h, the visible bacterial colonies were counted carefully. In cyclic tests, the same paper was consecutively placed on different agar plate 8 cycles with 24 h for each cycle. The diameters of inhibition C


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Figure 3. (a) Nitrogen adsorption−desorption isotherms and BJH desorption pore size distribution curves (inset) of (i) HAPNWs and (ii) HAPNWs@AgNPs; (b) X-ray powder diffraction (XRD) patterns of (i) HAPNWs, (ii) HAPNWs@AgNPs prepared in the dark, (iii) HAPNWs@ AgNPs prepared in the sunlight, and (iv) HAPNWs@AgNPs-CIP prepared in the sunlight; (c) X-ray photoelectron spectra (XPS) patterns of (i) HAPNWs@AgNPs prepared in the dark, (ii) HAPNWs@AgNPs prepared in the sunlight, and (iii) HAPNWs@AgNPs-CIP prepared in the sunlight; (d) XRD patterns of HAPNWs@AgNPs prepared in the sunlight using different amounts of AgNO3: (i) 10 mg, (ii) 30 mg, (iii) 60 mg, and (iv) 100 mg. zones were recorded to investigate the cyclic antibacterial performance. Besides, in long-term stability tests, the paper sheets were stored at room temperature for different times. At 1, 7, 14, 21, 28, 35, 42, 49, and 56 days, paper sheets were adopted for the antibacterial experiments, and the diameters of inhibition zones were determined.

Figure 2 shows scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of HAPNWs paper, HAPNWs@AgNPs paper, and HAPNWs@AgNPs-CIP paper. The sample of HAPNWs consists of ultralong nanowires with diameters of approximately 20 nm and lengths of several hundred micrometers. The HAPNWs can be obtained in a scaled up production using the autoclave with 1 L or even larger volume. In addition, the ultralong HAP nanowires selfassemble into nanowire bundles and interwine with each other to form a three-dimensional porous network with a Brunauer− Emmett−Teller (BET) specific surface area of 52.8 m2 g−1 and a Barrett−Joyner−Halenda (BJH) average pore size of about 17.0 nm (Figure 3a), which is beneficial to the immobilization of nanoparticles and bactericidal drug. In the as-prepared HAPNWs@AgNPs nanocomposite (Figure 2d, e), AgNPs are well-dispersed and decorated on the surface of nanowires. The BET surface area of the HAPNWs@AgNPs nanocomposite decreases to 47.9 m2 g−1, and the BJH average pore size is about 17.3 nm (Figure 3a). In addition, AgNPs have an average size of about 50 nm. Besides, after loading with CIP, the morphologies of both HAPNWs and AgNPs have no obvious change.

3. RESULTS AND DISCUSSION 3.1. Preparation and Characterization of the HAPNWs@AgNPs-CIP Paper. The fabrication procedure of the HAPNWs@AgNPs-CIP paper is shown in Figure 1a. First, HAPNWs were synthesized through a solvothermal process. Then, AgNPs were formed on the surface of HAPNWs under the sunlight in the absence of any reducing agent at room temperature. Subsequently, CIP was further immobilized on the surface of the HAPNWs@AgNPs through the interactions between CIP molecules and HAPNWs. Finally, the composite nanowires were filtered to obtain HAPNWs@AgNPs-CIP paper. In comparison to the white HAPNWs paper, the HAPNWs@AgNPs and HAPNWs@AgNPs-CIP paper sheets display light yellow and brown color, respectively (Figure 1b). Besides, similar to the HAPNWs paper,48 the HAPNWs@ AgNPs-CIP paper is highly flexible and maintains its shape without visible damage after repeated bending to nearly 180° or rolling around a glass rod (Figure 1c,d). D


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Figure 4. (a) Energy-dispersive spectrum (EDS) of HAPNWs@AgNPs-CIP; (b) TG curves of (i) HAPNWs, (ii) HAPNWs@AgNPs, (iii) HAPNWs@AgNPs-CIP, (iv) HAPNWs@CIP, and (v) ciprofloxacin; (c) UV−vis absorption spectra of (i) HAPNWs, (ii) HAPNWs@AgNPs, and (iii) HAPNWs@AgNPs-CIP; (d) FTIR spectra of (i) HAPNWs, (ii) HAPNWs@AgNPs, (iii) HAPNWs@AgNPs-CIP, and (iv) ciprofloxacin.

in the product.58 Second, the commercial β-calcium phosphate (Ca3(PO4)2) powder without hydroxyl groups was adopted as the starting material following the same procedure in the sunlight as a control experiment, and only Ag3PO4 is found in the product (Figures S3 and S4). Furthermore, AgNPs are formed in the cases of using higher amounts of AgNO3 (Figure 3d). These results demonstrate that the sunlight, the hydroxyl group, and the starting amount of AgNO3 have strong effects on the formation of AgNPs. This prerequisite for the formation of AgNPs is correct in both cases of HAPNWs and commercial HAP powder (Figure S5). In previous reports, AgNPs were usually synthesized by the chemical reduction using reducing agents.11−16,23−27 Chen et al.18 elucidated that Ag+ ions were complexed with hydroxide (OH−) on the surface of layered double hydroxide and formed the unstable intermediate (AgOH), resulting in the formation of Ag2O, and subsequently, AgNPs were produced by the photochemical decomposition of Ag2O without a chemical reduction. Therefore, we propose that some Ca2+ ions on HAPNWs surface are substituted with Ag+ ions, and the doped Ag+ ions are complexed with hydroxyl groups, subsequently followed by the nucleation, growth, and formation of the intermediate Ag2O. Furthermore, AgNPs are formed from Ag2O through a similar mechanism in the absence of any reducing agent. At the same time, some Ag+ ions react with PO43− ions to form Ag3PO4. The simultaneous formation of AgNPs and Ag3PO4 in the HAPNWs@AgNPs sample prepared in the sunlight can also be validated by XPS spectra in Figure 3c. Moreover, the silver contents of HAPNWs@AgNPs

SEM characterization was also carried out to investigate the morphology of the cross section of the paper. As shown in Figure 2c,f, both the HAPNWs paper and HAPNWs@AgNPs paper exhibit the well-defined layered structure (SEM images with higher magnification are shown in Figure S2a,b). The layered structure is beneficial to the storage of CIP with a high capacity. After loading with CIP, the HAPNWs@AgNPs-CIP paper still retains a layered structure but with a reduced interlayer spacing (Figures 2i and S2). This phenomenon may be explained by the interactions between CIP molecules and HAPNWs in two ways: chelating carboxyl groups in CIP molecules with Ca2+ ions in HAPNWs; hydrogen bonding between the carboxyl groups/imino groups in CIP molecules and the hydroxylated surface of HAPNWs. Therefore, these interactions reduce the spacing between layers of the nanowire paper. Additionally, the dense and layered structure is propitious to the reduction of the drug release rate. In the present work, AgNPs are formed on the surface of HAPNWs under the sunlight without any reducing agent at room temperature. In the further experiments, we have found that the sunlight, hydroxyl groups and the starting amount of AgNO3 play important roles in the formation of AgNPs. First, HAPNWs@AgNPs were synthesized following the same preparation procedure except in the dark environment. As a result, the diffraction peaks at 2θ = 33.3 and 36.6° in the X-ray powder diffraction (XRD) pattern in Figure 3b(ii) correspond to the (210) and (211) crystal planes of Ag3PO4.57 Besides, the binding energies at 374.8 and 368.8 eV in the XPS spectrum in Figure 3c(i) show the formation of Ag3PO4 instead of AgNPs E


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Figure 5. In vitro release profiles in PBS solutions with different pH values: (a) cumulative released percentage of ciprofloxacin from HAPNWs@ AgNPs-CIP; cumulative released concentrations of Ag+ ions from HAPNWs@AgNPs-CIP (b) and HAPNWs@AgNPs (c); (d) cumulative released percentage of Ag+ ions from HAPNWs@AgNPs-CIP and HAPNWs@AgNPs.

assigned to the bending mode of the O−P−O bond of the PO43− group. Additionally, the broad absorption peak at around 3571 cm−1 is attributed to the stretching mode of the hydroxyl group of HAP. The typical absorption peaks at 3411 and 1637 cm−1 are ascribed to the adsorbed water. Compared with the FTIR spectrum of HAPNWs, there is no new absorption peak in the spectrum of HAPNWs@AgNPs. Furthermore, the FTIR spectrum of HAPNWs@AgNPs-CIP shows the characteristic peaks of HAP and CIP. The absorption peaks at 1620 and 1384 cm−1 are due to the symmetric stretching vibration of the carbonyl group. The characteristic peak at 1273 cm−1 is attributed to the C−F vibration of CIP. The absorption peaks between 900 and 660 cm−1 are assigned to the C−H bending vibration of the aromatic ring. It is noteworthy that a new peak at 1589 cm−1 belonging to the antisymmetric stretching vibration of the carboxylic group appears, resulting from the interaction between the carboxylic groups of CIP molecules and Ca2+ ions in HAPNWs@AgNPs. 3.2. In Vitro Ag+ Ions and CIP Release Behaviors. The Ag+ ions and CIP release behaviors in PBS with different pH values were studied. Figure 5a shows the release profiles of CIP from HAPNWs@AgNPs-CIP in PBS with different pH values. At physiological pH value (i.e., 7.4), CIP releases slowly, and sustained drug release performance is observed. However, at a lower pH value, CIP releases faster. For comparison, approximately 69.9, 49.4, and 23.0% of the loaded CIP is released for 24 h at pH values of 4.5, 6.0, and 7.4, respectively. Moreover, at day 8, about 76.4, 70.1, and 37.7% of CIP molecules are released at the three pH values, respectively. The

prepared in the sunlight and in the dark are 5.08 and 2.21 wt %, respectively. As previously demonstrated, the silver in HAPNWs@AgNPs prepared in the dark is in the form of Ag3PO4. After calculation, the silver content in the form of AgNPs is estimated to be about 2.87 wt %. After further loading with CIP, the diffraction peaks of Ag3PO4 disappear (Figure 3b(iv)), and the intensity of the diffraction peak of AgNPs has little change, the silver content is measured to be 2.11 wt %. In Figure 4a, the EDS analysis result shows the elements of Ca, P, O, C, F, and Ag in HAPNWs@AgNPs-CIP, revealing the successful immobilization of AgNPs and CIP on HAPNWs. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) results are shown in Figures 4b and S6. The weight losses belonging to CIP in HAPNWs@AgNPs-CIP and HAPNWs@CIP are 30.02 and 33.62 wt %, respectively. After calculation, the loading amounts of CIP in the two samples are 447.4 and 527.7 mg g−1, respectively. The AgNPs on HAPNWs have a strong influence on the loading amount of CIP, and the drug loading amount decreases by 15.2 wt %. The result shows that the HAPNWs paper is a promising nanoplatform for drug delivery with high loading capacity. Moreover, the formation of AgNPs can also be verified by the characteristic peak at around 385 nm in the UV−vis spectrum in Figure 4c. Fourier transform infrared (FTIR) spectrum was recorded to characterize the chemical composition of the sample (Figure 4d). In the FTIR spectrum of HAPNWs, the characteristic absorption bands at 1095, 1032, and 962 cm−1 correspond to the PO43− group with asymmetric and symmetric stretching modes. The absorption peaks at 630, 604, and 561 cm−1 are F


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Figure 6. Digital images of the inhibition zones of four paper samples against: (a) E. coli, and (b) S. aureus. (i) HAPNWs, (ii) HAPNWs@AgNPs, (iii) HAPNWs@CIP, and (iv) HAPNWs@AgNPs-CIP.

As shown in Figure S7, the inhibition zone test results show that the silver content has a strong influence on the antibacterial activity of the as-prepared HAPNWs@AgNPs paper. As a reasonable choice, 60 mg of AgNO3 is adopted in further research. Furthermore, Figure 6 shows the inhibition zone test results of four paper samples toward E. coli and S. aureus. No inhibition zone is observed for the HAPNWs paper. Furthermore, the other paper samples create obviously circular inhibition zones, revealing that AgNPs and CIP possess high inhibition activities, which is attributed to the released Ag+ ions and CIP molecules. Besides, the HAPNWs@AgNPs-CIP paper presents the largest inhibition zones and thus the highest antibacterial activity. The diameters of inhibition zones against E. coli are measured to be 9.2, 9.7, and 16.8 mm for the paper sheets of HAPNWs@AgNPs, HAPNWs@CIP, and HAPNWs@AgNPs-CIP, respectively. As for S. aureus, the diameters of inhibition zones are about 6.1, 6.2, and 14.2 mm, respectively. The three paper samples display higher antibacterial activities against E. coli compared with S. aureus. It is possible that the thin outer membrane of E. coli results in higher permeability and better antibacterial effect. Therefore, these experimental results reveal the enhanced antibacterial activity of the HAPNWs@AgNPs-CIP paper. The minimum inhibitory concentration (MIC) tests were performed to quantitatively determine the antibacterial activities of the as-prepared samples, and AgNPs were used as a control sample (30−60 nm in diameter). The results are shown in Tables S1 and S2. The MIC values of HAPNWs@ AgNPs, HAPNWs@CIP, HAPNWs@AgNPs-CIP and AgNPs are 60, 75, 30, and 5.5 μg mL−1 against E. coli and 75, 100, 40, and 6.0 μg mL−1 against S. aureus, respectively. The normalized MIC values of HAPNWs@AgNPs against E. coli and S. aureus are 3.05 and 3.81 μg mL−1, respectively, which are lower than the MIC values of AgNPs, showing that the HAPNWs@AgNPs has higher antibacterial activity than AgNPs at the same silver concentration. However, the lower MIC values indicate the higher antibacterial activity of HAPNWs@AgNPs-CIP. AgNPs dissolve to generate Ag+ ions in aqueous solution and the free Ag+ ions bind to the proteins of bacteria, leading to the destruction of ATP production and DNA replication that directly cause bacterial death.59,60 At the same time, the released CIP molecules enter the bacterial membrane, causing the malfunction of DNA replication and cell growth.61,62 The simultaneous Ag+ ions and CIP molecules greatly inhibit the

CIP release profile exhibits a pH-responsive feature. The accelerated drug release under acidic conditions may be due to the weaker interactions between CIP molecules and HAPNWs and the dissolution effect of the drug carrier. These experimental results indicate that the as-prepared HAPNWs@ AgNPs-CIP can be applied as a controlled release platform for drug delivery. In the further study of the release profiles of Ag+ ions, an accelerated effect is observed. Figure 5b shows the release profiles of Ag+ ions from HAPNWs@AgNPs-CIP. It is clear that the sample exhibits a rapid release of Ag+ ions in the first 12 h and then a slower sustained release over the following 7 days. In addition, higher concentrations of Ag+ ions are observed under lower pH values. The Ag+ ions release profile exhibits a pH-responsive character. The cumulative released concentrations of Ag+ ions from HAPNWs@AgNPs-CIP over 8 days at three different pH values (4.5, 6.0, and 7.4) are approximately 14.37, 13.29, and 11.51 ppm, respectively. In order to confirm the accelerated effect of CIP on the Ag+ ions release, the release profiles of Ag+ ions from HAPNWs@AgNPs were studied. As shown in Figure 5c, the Ag+ ions release profile also presents a pH-responsive behavior. The cumulative released concentrations of Ag+ ions over 8 days at the three different pH values are around 12.79, 10.42, and 8.52 ppm, respectively. These values are lower than those of HAPNWs@ AgNPs-CIP. Furthermore, Figure 5d shows that the cumulative release percentage of Ag+ ions from HAPNWs@AgNPs-CIP is obviously higher than that from HAPNWs@AgNPs under the same conditions. At day 8, about 6.75, 6.24, and 5.40% of Ag+ ions are released at the pH values of 4.5, 6.0, and 7.4, respectively. This is because the released CIP molecules are complexed with Ag+ ions, promoting the dissolution of AgNPs to Ag+ ions. The HAPNWs@AgNPs-CIP paper loaded with dual bactericides exhibits an accelerated effect on the release behavior and a long-term sustained release feature. Therefore, the above experimental results reveal that the as-prepared HAPNWs@AgNPs-CIP paper is promising for high-performance antibacterial application. 3.3. Antibacterial Activity of the HAPNWs@AgNPs-CIP Paper. The antibacterial activity of the HAPNWs@AgNPs-CIP paper was examined using E. coli and S. aureus by the agar diffusion method and the colony-forming unit plate-counting method.53 The paper sheets of HAPNWs, HAPNWs@AgNPs, and HAPNWs@CIP were employed as control samples. G


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Figure 7. Bacterial growth curves of (a) E. coli and (b) S. aureus cultured with or without the samples; (c) Digital images of recultured E. coli and S. aureus colonies on solid nutrient agar plates after culture with the samples for 24 h: (i) HAPNWs, (ii) HAPNWs@AgNPs, (iii) HAPNWs@CIP, and (iv) HAPNWs@AgNPs-CIP.

Figure 8. (a) Consecutive cycling test results of the HAPNWs@AgNPs-CIP paper against E. coli and S. aureus for 8 cycles by the inhibition zone method; (b) long-term stability test results of the HAPNWs@AgNPs-CIP paper against E. coli and S. aureus for 2 months; 5 cycles of antibacterial tests of the HAPNWs@AgNPs-CIP paper against (c) E. coli and (d) S. aureus by the liquid broth culture method. At each initial point, fresh bacterial fluids were added to the liquid broth and each cycle time was 24 h.

H


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3.5. In Vitro Cytocompatibility Tests. The in vitro cytocompatibility of the samples is determined by cell viability evaluation using human lung adenocarcinoma epithelial cell line A549, and the results are shown in Figure 9. After incubation

bacteria growth. These factors make the HAPNWs@AgNPsCIP paper as a powerful material for killing both Gram-negative and -positive bacteria. Moreover, the bacterial growth curve was also recorded to investigate the antibacterial activity. For the bacterial broth without adding any material or only incubated with HAPNWs, the bacteria grow well within 24 h (Figure 7a,b). However, the HAPNWs@AgNPs-CIP inhibits bacterial growth effectively: The values of CFU mL−1 decrease greatly in the first 4 h and then decrease to 0, consistent with the MIC result. For the control samples of HAPNWs@AgNPs and HAPNWs@CIP, these samples exhibit ineffective bacterial inhibition when the concentrations are lower than these MIC values. The situation is also supported by the digital images of recultured bacterial colonies on solid nutrient agar plates after culture with the sample for 24 h (Figure 7c). These results further demonstrate the enhanced antibacterial activity of the HAPNWs@AgNPsCIP paper. 3.4. Consecutive Cycling and Long-Term Stability Tests. The consecutive cycling performance and long-term stability of the HAPNWs@AgNPs-CIP paper are tested. As shown in Figure 8a, after 8 cycles, the HAPNWs@AgNPs-CIP paper retains more than 95% of antibacterial activities against both E. coli and S. auerus. As discussed above, the HAPNWs@ AgNPs-CIP paper shows long-term and sustained release of Ag+ ions and CIP. In addition, the free-standing characteristic endows the paper with recyclable ability. These advantageous characteristics of the HAPNWs@AgNPs-CIP paper imply that it can be used as a reusable paper with high antibacterial activity. In addition, the long-term stability test results of the HAPNWs@AgNPs-CIP paper are displayed in Figure 8b, the paper retains more than 95% of antibacterial activities toward both E. coli and S. aureus, showing the high antibacterial stability. The stable antibacterial performance of the HAPNWs@AgNPs-CIP paper can be assigned to the high chemical stabilities of AgNPs and CIP molecules. Furthermore, the HAPNWs@AgNPs-CIP paper was incubated with liquid broth and continuously stained by bacteria every 24 h. As shown in Figure 8c,d, the HAPNWs@AgNPsCIP paper remains 100% of the antibacterial efficiencies after continuous five cycles toward both E. coli and S. aureus. The robust antibacterial ability is attributed to the long-term and sustained bactericide release properties of the HAPNWs@ AgNPs-CIP paper. In a recent report, a kind of antibiotic (levofloxacin) loaded and silver-core-embedded mesoporous silica (MSNs) was developed as a synergistic antibacterial material for against bacterial infections.27 The MIC values of antibiotic-loaded MSNs (∼230 μg mg−1), silver-core-embedded MSNs (silver content of 9.62 wt %), and antibiotic-loaded and silver-coreembedded MSNs against E. coli were 300, 75, and 40 μg mL−1, respectively. In comparison, the present HAPNWs@AgNPsCIP antibacterial paper displays lower MIC values and thus higher antibacterial activity. Furthermore, the antibiotic-loaded and silver-core-embedded MSNs are not suitable for reusable recycling in a convenient manner. In our previous study, a onestep solvothermal process was developed for the fabrication of AgNPs decorated HAPNWs paper.53 Herein, the as-prepared HAPNWs@AgNPs-CIP paper is demonstrated as an antibacterial material with low MIC value, high bactericidal efficiency, and long-term antibacterial activity.

Figure 9. In vitro cytotoxicity tests of four samples using human lung adenocarcinoma epithelial cell line A549: (a) HAPNWs, (b) HAPNWs@AgNPs, (c) HAPNWs@CIP, and (d) HAPNWs@ AgNPs-CIP.

with the samples at concentrations below 40 μg mL−1 for 24 h, more than 80% of cells survive. Even at a high concentration of 75 μg mL−1, the cell viabilities remain above 80% except the HAPNWs@AgNPs sample. This may be due to the higher silver content of HAPNWs@AgNPs relative to that of HAPNWs@AgNPs-CIP. The experimental results suggest that the HAPNWs@AgNPs-CIP paper is a promising antibacterial material with good biocompatibility.

4. CONCLUSION In this study, a new kind of ultralong hydroxyapatite nanowiresbased paper co-loaded with both silver nanoparticles and ciprofloxacin has been developed and demonstrated as a new kind of high-performance antibacterial material. A simple approach is adopted for the formation of Ag nanoparticles and subsequent loading of an antibiotic drug, and the contents of bactericides can be adjusted. The as-prepared HAPNWs@ AgNPs-CIP paper exhibits high flexibility, mesoporous pores (average 17.3 nm), high drug loading capacity (447.4 mg g−1), sustained and pH-responsive release properties (5.40−6.75% of Ag+ ions and 37.7−76.4% of CIP molecules at pH values of 7.4−4.5 at day 8, respectively), enhanced antibacterial efficiency (minimum inhibitory concentrations of 30 and 40 μg mL−1 against E. coli and S. aureus, respectively), and good biocompatibility. In addition, the experiments demonstrate the excellent recyclability (over 8 cycles) and long-term antibacterial activity (over 56 days). Given these advantages, we expect that the as-prepared HAPNWs@AgNPs-CIP antibacterial paper is promising for various biomedical applications. Furthermore, the synthesis strategy reported herein can also be extended for the efficient loading of multiple functional agents in the ultralong hydroxyapatite-nanowiresbased paper with advanced performance for environmental and energy applications. I


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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.7b05208. Characterization of the samples; structural formula of ciprofloxacin molecule; SEM images, XRD patterns, XPS patterns, DSC curves, digital images of the inhibition zones, and antibacterial test results of the as-prepared samples (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: 0086-21-52412616. Fax: 0086-21-52413122. ORCID

Zhi-Chao Xiong: 0000-0002-0216-5699 Ying-Jie Zhu: 0000-0002-5044-5046 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support from the Science and Technology Commission of Shanghai (15JC1491001), the National Natural Science Foundation of China (21601199), and the Shanghai Sailing Program (16YF1413000).

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REFERENCES

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Ultralong Hydroxyapatite Nanowires-Based Paper Co-Loaded with

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