Article pubs.acs.org/Langmuir
Formation of Controllable Hydrophilic/Hydrophobic Drug Delivery Systems by Electrospinning of Vesicles Wei Li,* Tian Luo, Yanjuan Yang, Xiuniang Tan, and Lifei Liu Department of Chemistry, Capital Normal University, Beijing 100048, China S Supporting Information *
ABSTRACT: Novel multifunctional poly(ethylene oxide) (PEO) nanofibrous membrane, which contains vesicles constructed by mixed surfactant cetyltrimethylammonium bromide (CTAB)/sodium dodecylbenzenesulfonate (SDBS), has been designed as dual drug-delivery system and fabricated via the electrospinning process. 5-FU and paeonolum, which are hydrophilic and hydrophobic anticancer model drugs, can be dissolved in vesicle solution’s bond water and lipid bilayer membranes, respectively. The physicochemical properties of the electrospun nanofibrous membrane were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and X-ray diffraction (XRD). Drug release behaviors of the electrospun nanofibrous membrane fabricated with different molar ratio of CTAB/SDBS vesicle solution were investigated. The result showed that the releasing amount of hydrophilic drug presented an ascending release manner, while the hydrophobic one showed a descending release behavior with increasing of the molar ratio of CTAB/SDBS. Moreover, the release amount of drugs from drug delivery system can be controlled by the molar ratio of CTAB/SDBS in the vesicle solution easily and conveniently. The distinct properties can be utilized to encapsulate environmental demanding and quantificational materials. pain during cancer treatment.18−20 Thus, medication combination treatment in clinical practice is common and useful in order to improve the cancer therapeutic value of medicinal drugs.21−23 Furthermore, high and durable drug content along with low toxicity in situ is supposed to be taken into account as an effective therapy. In practice, the targeted drugs for coadministration often include both hydrophilic and hydrophobic drugs, whose different properties would hinder the drug-loading process, leading to a challenge to encapsulate them into the same drug delivery simultaneously. On the other hand, to achieve a desirable level for improving the clinical effect, it is crucial to control the drugs loading amount in the delivery system but hard to achieve. The two main factors are bottlenecks in drug delivery system.24 It has been reported that polymer nanoparticles and liposomes can be applied as drug delivery to encapsulate both hydrophobic and hydrophilic anticancer drugs.25 In spite of the operational complexity brought by chemical conjugation during the lodaing process, the drugs loading amount and ratio still cannot be controlled. Development of a novel electrospun nanofibrous drug delivery system allowing for the loading of hydrophilic/hydrophobic drugs and a controlled release amount still remains a great challenge.
1. INTRODUCTION In recent years, continuous research interestingly has been directed to tissue engineering, especially drug delivery for its close relationship with human health.1−5 Because of their high surface-to-volume ratio and functional characteristics, nanofibrous membrane can be applied to drug delivery, which has theoretical and practical significance. Electrospinning as a novel nanofiber-producing technology has attracted attention over the past two decades.6−8 The nonwoven membrane of fibers with diameter ranging from a few microns to less than 100 nm has many advantages in drug delivery, such as its characteristic of three-dimensional structure, large surface area, small aperture, and biocompatibilityperfect mechanical properties. A variety of drugs and bioactive molecules9−11 have been verified to be loaded into electrospun nanofibrous membrane. For instance, the scaffolds produced from electrospun nanofibers have been applied in wound healing or implant in surgery, which offer site speicific delivery of drugs to the body. The electrospun nanofibrous drug delivery system can be designed to control the drug release, no matter whether the release mechanism focuses on diffusion alone or diffusion and scaffold degradation simultaneously.12 This drug delivery system has attracted much attention in the field of cancer clinical therapy in recent decades.13−17 It is well known that infection and pain are two headaches after surgery, so two or more different drugs should be released from the electrospun nanofibrous drug delivery system at the proper time and in appropriate doses to prevent infections and reduce the patient’s © XXXX American Chemical Society
Received: December 10, 2014 Revised: April 18, 2015
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syringe was placed into a syringe pump (TJ-3A/W0109-1B, Baoding Longer Precision Pump Co., Ltd.) that delivered the solution at a controlled flow rate of 0.5 mL/h. A horizontal electrospinning setup was used in all experiments. For the PEO vesicle solution, the high voltage power supply source (HB-Z503-1AC, Tianjin Hengbo Co., Ltd.) maintained a voltage of 17.0 kV between the capillary tip and a grounded metal plate covered in aluminum foil, with an interelectrode distance of 18.0 cm. Dry nanofibers were collected directly from the aluminum-foil-covered plate and stored at room temperature. 2.4. Characterization of Electrospun Nanofibrous Membranes. A digital vacuum scanning electron microscope (SEM) (JSM5600 LV, JEOL) was used to examine the morphologies of electrospun nanofibrous membranes. Before it, the specimens were sputter-coated with gold to prevent charges from accumulating. The Fourier transform infrared (FTIR) spectrum of the electrospun nanofibrous membranes were recorded on a Bruker-Vector 22 FTIR spectrometer. The crystalline structures were analyzed by X-ray diffraction (XRD, PAN alytical, Model X’pert PRO) based on powder or fiber samples. The operating parameters are 40.0 kV and 40.0 mA, room temperature, ranged from 5.0° to 60.0° at a scanning rate of 5.0°/min. 2.5. Preparation of Silica Particles by Using the Electrospun Polymer Vesicle Solutions as Templates. To clarify the structure of vesicles in the electrospun composite fibers, the hollow silica spheres were prepared with the electrospun polymer vesicle solutions as templates. It was a universal method which used in the relevant study.34−36 A 10.0 mL store solution with the ratio of CTAB/SDBS at 3:7 was charged into a view vessel. The system was stirred to be homogeneous after 0.2 mL of TEOS was added. Meanwhile, hydrochloric acid was added and used as catalyst for the hydrolysis reaction of TEOS; the pH value of the solution was 3.0. After being stirred for 24.0 h at 25.0 °C, the prepared solution was electrospun into nanofibers with the above apparatus and procedures. The nanofibers were collected and adhered to the copper grid. The morphology of the obtained fibers was characterized by using TEM with a TECNAI 20 PHILIPS electron microscope. 2.6. Studies of the Drug Releasing. The drug-loaded electrospun nanofibrous membranes were incubated in 700 mL phosphate buffered saline solution (PBS, 0.2 mol/L, pH 7.4) at 37.0 °C and gently stirred at 60 cycles/min. At a certain time, 1 mL of the buffer was taken out, and an equal amount of fresh buffer was added. The release of 5-FU from the electrospun nanofibrous membranes was monitored by a UV−vis spectrophotometer (PerkinElmer, Lamboda Bio 40) at the wavelength of 265 nm and converted to the 5-FU concentration according to the calibration curve of 5-FU in the same buffer. Then the accumulative amount of the released 5-FU was calculated as a function of incubation time. The paeonolum concentration was measured on an Agilent 1100 Series high-pressure liquid chromatography (Agilent Technologies, Santa Clara, CA) equipped with a C18 reverse phase column (Cosmosil C18 AR-II; Nacalai, Tokyo, Japan). The analysis was taken at a flowing rate of 0.8 mL/min by using 60.0% of methanol/water solution (v/v) as mobile phase, and paeonolum was determined at the UV−vis adsorption wavelength of 274 nm and converted to the paeonolum concentration according to the calibration curve of paeonolum in the same buffer. Then the accumulative amount of the released paeonolum was calculated as a function of incubation time.
Vesicles, like liposomes, with a broad size range can be obtained by using appropriate amphiphile molecules and preparation method. Vesicles exist in the form of sphere in the aqueous solution, which have a hydrophilic core and a hydrophobic layer formed by hydrophobic segments. Because of its unique structure, it is a perferct drug carriers in two aspects. First, vesicles are able to encapsulate both hydrophobic and hydrophilic drugs in their cavity. Thus, the discrete microstructure of vesicle makes it appliable in materials chemistry,26 gene delivery,27 gelation,28 and chemical reaction.29 Second, the structure of bilayer membrance, which is similar to cell membrane, makes the vesicle possess good biofilm compatibility and cell permeability. After the first report by Kaler et al.30 in 1989, the spontaneous formation of vesicle formed by mixture of cationic and anionic single chain surfactants have been thoroughly studied.31−33 Apart from the cheap materials and simple methods, the size and permeability of the vesicles can be controlled by varying the composition and ratio of different cationic and anionic surfactant.30 In this study, we developed a new strategy of coloading hydrophilic and hydrophobic drugs in the electrospun nanofibrous membrane with vesicles as carriers, which were based on spontaneous formation of vesicle from mixed cationic and anionic single chain surfactants. This novel dual drug delivery system has been successfully fabricated via electrospinning process with poly(ethylene oxide) (PEO), and a hydrophilic drug, 5-fluoro-2,4(1H,3H) pyrimidinedione (5-Fu), and a hydrophobic drug, paeonolum, were selected as the model drugs to be loaded within the drug delivery system. Interestingly, it is very easy and convenient to control the amount of different drugs in the vesicles by varying the ratio of anionic to cationic surfactant. Therefore, this new method can offer a desirable amount and ratio of hydrophilic and hydrophobic drugs to meet the requirements of clinical therapy.
2. EXPERIMENTS 2.1. Materials. PEO with a molecular weight of 600 kDa was purchased from Sigma-Aldrich. Cetyltrimethylammonium bromide (CTAB, 99.0%) and sodium dodecylbenzenesulfonate (SDBS, 99.0%) were supplied by Sinopharm Chemical Reagent Co. Ltd. 5-Fluoro2,4(1H,3H)pyrimidinedione (5-Fu, 99.9%) and paeonolum (99.5%), as model drugs, were purchased from Aladdin Chemistry Co. Ltd. Tetraethyl orthosilicate (TEOS, 99.5%), acetone (99.9%), and hydrochloric acid (99.9%) were purchased from Beijing Yili Fine Chemicals Co., Ltd. Analytical reagent sodium chloride, potassium chloride, and disodium hydrogen phosphate dodecahydrate, which were used to prepare the phosphate buffer solutions (PBS), were all purchased from Guangdong Xilong Chemical Co., Ltd. They were used without further purification. All solutions were prepared with deionized water. 2.2. Preparation of Polymer/Drug Vesicle Solutions for Electrospinning. A literature method for the preparation of spontaneous vesicle formation from mixed cationic and anionic single chain surfactants was adopted to prepare CTAB/SDBS vesicle solution.30 Then a suitable amount of PEO (2% w/v, w in g and v in mL) was added to the above CTAB/SDBS vesicle solution. 5Fluorouracil (5-FU) and paeonolum which were dissolved in acetone were added to get the store solution for electrospinning. After being stirred at room temperature, a bluish turbidity solution was obtained, which implied that vesicles in the CTAB/SDBS mixed solution were not destroyed with the addition of polymer and drugs. The prepared solutions were stored at room temperature before use. 2.3. Fabrication of Drug Delivery Fibrous Membranes via Electrospinning. The prepared PEO/drug vesicle solutions were loaded into a glass syringe with a 10 mL blunt-end tip capillary. The
3. RESULTS AND DISCUSSION This novel hydrophilic/hydrophobic drug delivery system has been successfully fabricated via the electrospinning process, and the electrospun nanofibrous membranes were obtained and characterized as follows. 3.1. SEM Characterization. Figure 1 shows the SEM images of electrospun nanofibrous membranes with vesicle solutions of different CTAB/SDBS molar ratio. It is clear that the morphology was different with different molar ratio, varying from nanofiber to the introduction of bead, which was mainly accounted for electrical conductivity and surface tension of the B
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Figure 2. TEM images of electrospun nanofibers with silica particles.
Figure 1. SEM images of electrospun nanofibrous membranes with vesicle solutions of different CTAB/SDBS molar ratio.
solution.12 Table 1 specifies the nanofiber diameter range in relation to Figure 1. It was varied from 140 to 380 nm. In the Table 1. Diameter of Nanofibers Shown in Figure 1 molar ratio of CTAB/SDBS
fiber diam range (nm)
8:2 7.5:2.5 7:3 3:7 2.5:7.5 2:8
120−450 160−380 bead 140−380 bead 120−330
mean fiber diam (nm) 240 ± 230 ± bead 280 ± bead 200 ±
80 20
Figure 3. FT-IR spectra of (a) 5-FU neat powder, (b) paeonolum neat powder, (c) PEO electrospun nanofibrous blank membrane, and (d) composite electrospun membrane loading two drugs.
90 60
C−F stretching vibration), 640 and 550 cm−1 (out-of-plane bending vibration absorption of C−H in −CFCH−).39,40 All of these peaks can be detected in the composite electrospun membranes, which indicates that the 5-FU had been loaded in the membranes successfully. These peaks shifted to 1670, 1250, 642, and 551 cm−1, respectively. Furthermore, no new peak appears in the composite electrospun membranes, which reveals that the electrostatic interaction occurred between 5FU and PEO nanofibers. Regarding the FTIR spectrum of paeonolum neat powder, we can find the characteristic absorption peak in the composite electrospun membranes at the wavenumber of 3446 cm−1, which corresponds to the O−H stretching vibration, shifted to 3448 cm−1. The other characteristic peaks of neat paeonolum powder can also be found in the FTIR fingerprint spectroscopy (Supporting Information, Figure S1). The characteristic peaks at 1504 cm−1 shifted to 1502 cm−1, 1367 cm−1 shifted to 1342 cm−1, 1255 cm−1 shifted to 1250 cm−1, and 813 cm−1 shifted to 815 cm−1. It implies that the electrostatic interaction is the main intermolecular interactions within the membrane. 3.4. X-ray Diffraction (XRD) Analysis. To further demonstrate the physical properties and distribution of the two drugs in the fibers, neat powders and electrospun nanofibrous membranes were characterized by XRD. The result is shown in Figure 4. It was shown that 5-FU and paeonolum powders are crystal with many characteristic peaks. A weaker and wider peak at 2θ = 28.84° which attribute to 5FU in spectrum d was detected, suggesting that 5-FU had been loaded into the composite electrospun nanofibrous membrane
subsequent characterization, the vesicle solution of CTAB/ SDBS molar ratio at 3/7 was chosen to prepare the drugs delivery nanofibrous membranes. 3.2. Preparation of Silica Particles by Using the Electrospun Polymer Vesicle Solutions as Templates. Micelles and vesicles are commonly used templates to synthesize various kinds of materials.37,38 To confirm the structure of the vesicles in the mixed solution, the surfactant solution with polymer PEO was used as template to prepare silica particles. TEOS, which can be hydrolyzed to form silica, was used as a precursor and added to the mixed solution with hydrochloric acid. The mixed solutions were stirred and electrospun with the same technical parameters as used previously. TEM images of the obtained electrospun fibers are shown in Figure 2. The silica nanoparticles in the nanofibers are observed clearly. After removing the PEO which wrapped the silica nanoparticles with burning, the silica nanoparticles present the hollow structure, which approved the existence of vesicles in the solution. 3.3. Infrared Spectrum Characterization. The composition of the electrospun nanofibrous membrane was characterized by FTIR spectroscopy. Figure 3 illustrated the FTIR spectra of neat 5-FU, paeonolum powder, blank PEO nanofibrous membrane, and composite electrospun membrane loading two drugs. The characteristic peaks of 5-FU (Figure 3a) are clued at 1668 cm−1 (overlapped stretching vibration absorption of CO and CC), 1249 cm−1 (absorption of C
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Figure 4. XRD patterns of (a) 5-FU neat powder, (b) paeonolum neat powder, (c) PEO electrospun nanofibrous membrane, and (d) PEO electrospun nanofibrous membrane with 5-FU and paeonolum.
Figure 5. Cumulative 5-FU release profiles from electrospun nanofibrous membrane with different CTAB/SDBS molar ratio: (a) 2:8; (b) 3:7; (c) 7.5:2.5; (d) 8:2; (e) without surfactant.
time point in the case of 7:3 and 8:2 of CTAB/SDBS. The amount of 5-FU released from the composite fibers presented an ascending release manner as the molar ratio of CTAB/SDBS increased. The variation of release amount was attributed to the different content of bond water in the CTAB/SDBS vesicle, which can be adjusted by the molar ratio of CTAB/SDBS.30 Thus, the amount of hydrophilic drug which dissolved in the bond water of vesicles can be controlled with the molar ratio of the mixed surfactants. Fortunately, it was very easy and convenient to realize. 3.5.2. Paeonolum Release Properties of the Electrospun Nanofibrous Membrane. Paeonolum, a hydrophobic anticancer drug, was used as a model drug loaded into the vesicle. It would be dissolved into the lipid bilayer of the vesicle, thus, to be loaded into the electrospun nanofibrous membrane. The paeonolum concentration which released from the composite membrane could be calculated by [Rpaeonolum/Opaeonolum] × 100% (Opaeonolum is the original paeonolum content, and Rpaeonolum is the release paeonolum content of the membrane). The cumulative drug release profiles of the composite membrane as a function of the release time at 37.0 °C are shown in Figure 6. Paeonolum cannot dissolve in the aqueous
successfully. Meanwhile, the intensity of peak at 2θ = 28.84° which is attributed to 5-FU became weaker and wider in spectrum d. The result was similar to the electrospinning process in the literature.41,42 In addition, all peaks of paeonolum were not detected in the composite electrospun nanofibrous membrane, which suggested that paeonolum existed in the amorphous form, not the original crystal morphology, within the nanofibrous membrane. 3.5. Drug Releasing Study. To explore the capacity of electrospun nanofibrous drug delivery system for synchronously loading hydrophobic and hydrophilic chemotherapeutics, two model drugs’ release properties were examined. 5-FU was chosen as the hydrophilic model drug for its broad usage in first-line chemotherapy. Paeonolum, as a hydrophobic drug, is a routine anticancer agent broadly used in clinical treatment. The nanofibrous membranes which were electrospun with vesicle solution of different CTAB/SDBS molar ratio were prepared and investigated in the study. 3.5.1. 5-FU Release Properties of the Electrospun Nanofibrous Membrane. 5-FU, a hydrophilic anticancer drug, was used as a model drug loaded into the vesicle, and the release profile was determined by UV−vis characterization. 5-FU can be dissolved in the free water of the solution and bond water of the inner vesicle. To investigate the drug content wrapped in the bond water of the vesicle, a dialysis bag which was made up of a semipermeable membrane was employed in the vesicle solution for removing the 5-FU dissolved in the free water. The concentration of 5-FU which released from the electrospun nanofibrous membrane, that is the drug dissolved in the bond water of vesicles, can be calculated by [R5‑FU/O5‑FU] × 100% (O5‑FU is the original 5-FU content, and R5‑FU is the release 5FU content from the membrane). The cumulative drug release profiles of the composite membrane as a function of the release time at 37 °C are shown in Figure 5. Furthermore, 5-FU release profile from electrospun nanofibrous membrane without surfactant is also provided for comparison. Without the existence of vesicles in the scaffold, 5-FU will be completely released in a few minutes when added in the buffer solution. Other lines with surfactant in Figure 5 revealed a similar tendency, which implied that vesicle solutions with different CTAB/SDBS molar ratio almost have the same drug release property. Initially, for approximately the first 100 min, a rapid release of 5-FU could be observed in all systems. Subsequently, a stage of gradual release followed up to the cumulative release time of 400 min. For 2:8 and 3:7 (molar ratio) of CTAB/SDBS vesicle solutions, the 5-FU release amount reached 47.4% and 42.3% at 100 min from the electrospun nanofibrous membrane, whereas 29.4% and 20.2% of 5-FU were released at the same
Figure 6. Cumulative paeonolum release profiles from electrospun nanofibrous membranes with different CTAB/SDBS molar ratio: (a) 8:2; (b) 7.5:2.5 (c) 3:7; (d) 2:8.
electrospinning solution without surfactant due to its hydrophobicity and cannot be loaded into the electrospun nanofibrous membrane. So no paenolum has been detected in the buffer solution which is for the electrospun nanofibrous membranes without surfactant. Just as the cumulative 5-FU release profiles, the paeonolum release amount from electrospun nanofibrous membrane was different along with the variation of molar ratio of CTAB/SDBS. With the increasing of the molar ratio of CTAB/SDBS, the paeonolum amount showed a descending release behavior. It was also attributed to D
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desirable amount and ratio, as is often required in various industries, such as pharmaceuticals, food, and materials.
the different content of lipid bilayer in the CTAB/SDBS vesicles, which can be easily and conveniently adjusted by the molar ratio of CTAB/SDBS.30 It was interesting that the amount of hydrophilic drug wrapped into the electrospun membrane increased while the amount of hydrophobic drug decreased with the molar ratio of CTAB/SDBS increasing. It provides us a versatile method to obtain a desirable amount and ratio of hydrophilic and hydrophobic materials loaded on the carriers. Thus, the amount of drugs in the vesicles can be controlled by varying the ratio of anionic to cationic surfactant. The formation and release process of electrospun composite fibers is schematically shown in Figure 7. Herein, cetyltrimethylammo-
4. CONCLUSION In summary, we have developed a novel hydrophilic/hydrophobic drug delivery system based on electrospinning with vesicle solution. 5-FU and paeonolum as the model drugs were dissolved into CTAB/SDBS vesicle solution and loaded into the PEO electrospun nanofibrous membranes successfully. The location and amount of the drugs in the composite fibers determined their individual release profiles. With the increasing of the molar ratio of CTAB/SDBS, the hydrophilic drug amount showed an ascending release, which attributed to the increasing content of bond water in the CTAB/SDBS vesicle, while hydrophobic drug presented a descending release behavior due to the smaller content of lipid bilayer membranes. Moreover, the release amount of drugs from the drug delivery system can be monitored and controlled by the molar ratio of CTAB/SDBS in the vesicle solution according to the mixed surfactant mechanism. This dual drug delivery system can be conveniently and easily controlled to offer a desirable amount and ratio of hydrophilic and hydrophobic drugs and has excellent potential applications in pharmaceuticals, food, and material.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
S Supporting Information *
FTIR fingerprint spectroscopy of Figure 3. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/la504796v.
Figure 7. Schematics of the preparation of hydrophilic/hydrophobic electrospun composite fibers.
Corresponding Author
*Tel +86-10-68903086, e-mail
[email protected] (W.L.).
nium bromide (CTAB) and sodium dodecylbenzenesulfonate (SDBS) were chosen as main components for constructing cationic−anionic surfactant vesicles to overcome the multidrug resistance. Moreover, CTAB can serve as chemosensitizer to enhance the drug efficacies43 whose anticancer activity has been proved exceptionally high.44,45 Additionally, the hydrophilic drug 5-Fu was wrapped into the aqueous interior, while the hydrophobic drug paeonolum was incorporated into the lipid bilayer membranes of the CTAB/SDBS vesicle for their solution property. The vesicle solution mixed with drugs and PEO was electrospun to fabricate the nanofibrous membranes. Consequently, hydrophilic and hydrophobic cancer therapeutic drugs have been simultaneous successfully loaded into the electrospun nanofibers to obtain the dual drug delivery system. Interestingly, it is very easy and convenient to control the amount of different drugs in the vesicles by varying the ratio of anionic to cationic surfactant. Meanwhile, these release rates were slow due to the existence of structure of vesicle. Therefore, this new method can offer a desirable amount and ratio of hydrophilic and hydrophobic drugs to meet the requirements of clinical therapy. Noticeably, besides CTAB, some other surfactants, such as dodecyl trimethylammonium bromide (DTAB), Tween 80, Triton X-100, P123, F127, Nonidet P-40, and sodium dodecylbenzenesulfonate (SDBS), are all well qualified as both anticancer active drugs and chemosensitizers for overcoming the multidrug resistance in cancer.44,46−48 Therefore, this versatile process can provide a unique delivery system for loading hydrophilic and hydrophobic materials on the carriers, in which different materials can be readily adjusted with a
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by Beijing Natural Science Foundation (2142011) and General Program of Science and Technology Development Project of Beijing Municipal Education Commission (No. KM201310028007).
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REFERENCES
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DOI: 10.1021/la504796v Langmuir XXXX, XXX, XXX−XXX
