Palygorskite polypyrrole nanocomposite: A new platform for ...

Applied Clay Science 99 (2014) 119–124

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Research paper

Palygorskite polypyrrole nanocomposite: A new platform for electrically tunable drug delivery Yong Kong a,b,⁎, Hanli Ge a, Jianxin Xiong c, Shixiang Zuo a, Yong Wei a,d, Chao Yao a,⁎⁎, Linhong Deng a a

School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China Jiangsu Provincial Key Lab of Palygorskite Science and Applied Technology, Huaiyin Institute of Technology, Huaian 223003, China Pneumology Department, Changzhou Children's Hospital, Changzhou 213003, China d Xuyi Botu Palygorskite Clay Hi-Tech Development Co., Ltd., Xuyi 211700, China b c

a r t i c l e

i n f o

Article history: Received 23 January 2014 Received in revised form 15 June 2014 Accepted 17 June 2014 Available online 2 July 2014 Keywords: Polypyrrole Palygorskite Aspirin Drug-delivery Electrical stimulus

a b s t r a c t A clay polymer nanocomposite (CPN) based on aspirin-loaded palygorskite (Pal) modified polypyrrole (PPy) was prepared by in situ electropolymerization of pyrrole monomer in the presence of Pal as the modifier and aspirin as the drug source. This drug-loading approach was simple and convenient, since colloid templates such as polystyrene microspheres used in conventional drug-loading system were not needed. The resulting CPN was characterized by TEM, XRD, cyclic voltammetry (CV), chronocoulometry, electrochemical impedance spectroscopy (EIS) and FTIR. The CPN was used as a new platform for aspirin delivery, which could significantly enhance aspirin loading capacity of the system and control aspirin release by external electrical stimulus. The results indicated that the proposed novel drug-delivery system might be promising as an implantable device where drug release could be electrically tuned according to the patient's requirement. © 2014 Elsevier B.V. All rights reserved.

1. Introduction The past decades have seen the development of therapeutically effective, safe, and patient-compliant drug-delivery systems, and researchers still continue to design novel tools and strategies for improving such systems. Recently, conducting polymers have gained much attention as stimuli-responsive macromolecules for drug delivery because of their inherent electroactive properties (Abidian et al., 2006; Richardson et al., 2009; Svirskis et al., 2010a; Zeng et al., 2003). Among these polymers, polypyrrole (PPy) has emerged as a highly promising material due to its ability to switch between oxidation and reduction states in response to electrical potential, and its good biocompatibility (Cho and Borgens, 2011; Geetha et al., 2006; George et al., 2005). However, due to their quite small specific surface area (SSA), most conducting polymers are limited in the capacity to load drugs, which hinders their application as drug delivery system toward a range of disease states (Sharma et al., 2013). In order to enhance the drug-loading capacity of the drug-delivery system, a colloid template method was recently proposed (Kang

⁎ Correspondence to: Y. Kong, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China. Tel.: +86 519 86330256; fax: +86 519 86330167. ⁎⁎ Corresponding author. Tel.: +86 519 86330256; fax: +86 519 86330167. E-mail addresses: [email protected] (Y. Kong), [email protected] (C. Yao).

http://dx.doi.org/10.1016/j.clay.2014.06.020 0169-1317/© 2014 Elsevier B.V. All rights reserved.

et al., 2011; Pokki et al., 2012). However, this method requires complete removal of the colloid templates from the system, which is difficult and time-consuming (Yang et al., 2004). Alternatively, the drugloading capacity can be enhanced by increasing the SSA of the matrix. One approach is to use clay materials as the matrix because they exhibit not only excellent stability and high adsorption, but also large SSA (Fan et al., 2008; Kong et al., 2010). For example, the SSA of palygorskite (Pal) is as large as 119 m2 g−1 (Kong et al., 2009). This makes Pal a potential material for modification of the drugdelivery system based on conducting polymers (Aguzzi et al, 2007; Li et al., 2013). In the present work, PPy was modified with Pal by a simple in-situ electropolymerization technique free of colloid templates, and the resulting Pal PPy nanocomposite combined the advantages of both PPy and Pal. On one hand, PPy could be electrically tuned to efficiently release drug by adjusting the applied potential, on the other hand, Pal was anticipated to increase the overall drug-loading capacity of the developed system. To evaluate the performance of this clay polymer nanocomposite (CPN), aspirin, a commonly used anti-inflammatory drug that can be easily detected, was used as target drug molecule to be delivered (Gupta et al., 2010; Murtaza et al., 2011; Szostak and Mazurek, 2002). The results indicated that modification of PPy with Pal increased both drug-loading capacity and drugreleasing efficiency of the drug-delivery system as compared to PPy alone.

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Y. Kong et al. / Applied Clay Science 99 (2014) 119–124

2. Materials and methods 2.1. Reagents and apparatus Pyrrole (Aldrich, 98%) was distilled under reduced pressure and stored at 4 °C prior to use. Pal was purchased from Jiangsu NDZ Technology Company (Changzhou, China) and washed with double distilled water to remove turbidity, and then dried at 80 °C. Aspirin and other chemicals were of analytical grade and obtained from Aladdin Chemicals Reagent Co., Ltd. (Shanghai, China). All solutions were prepared with doubly distilled water. The Pal, and the prepared CPN were examined for their morphologies by transmission electron microscopy (TEM) using JEM2000 (JEOL Corporation, Japan), XRD patterns by X-ray diffractometer (D/max 2500 PC, Rigaku Corporation, Japan) using Cu Kα radiation, FTIR analyses by FTIR-8400S spectrophotometer (Shimadzu Corporation, Japan), respectively. All electrochemical measurements were performed by using a CHI 660D electrochemical workstation. The content of aspirin was measured by using a UV-160A UV–Visible spectrophotometer (Shimadzu, Japan). 2.2. Preparation of aspirin-Pal PPy nanocomposites

PPy nanocomposites and a solution of 25 mL PBS was used as the media (pH 7.4). Aliquots were withdrawn from the working solution at specific time points, and replaced with the same amount of fresh media. The content of aspirin in each aliquot was measured by spectrophotometry and calculated by Lambert–Beer's law based on the absorbance at 205 nm. The release of aspirin by electrical stimulus was finished when no significant change was observed on the UV–Visible spectra. Spontaneous release of aspirin from the drug-loading system was measured in the same way but without applying the electrical stimulus, and used as control. 3. Results and discussion 3.1. TEM images of Pal and CPN TEM micrographs of Pal and CPN were shown in Fig. 1. Pal was fibrillar single crystal with a diameter ranging from 20 to 30 nm (Fig. 1A). The branching single crystal structure of Pal remained unchanged after its combination with PPy and clusters of Pal were embedded in the films of PPy, as can be seen in Fig. 1B. The effective coating of PPy on Pal formed a CPN with a core-shell structure. The resulting CPN combined the advantages of both PPy and Pal, which made the CPN an ideal candidate used in drug delivery by external electrical stimulus.

The preparation of aspirin-Pal PPy nanocomposites was carried out by in situ electropolymerization of pyrrole monomers in the presence of Pal as the modifier and aspirin as the drug source. The electrolytic cell consisted of a piece of indium–tin oxide glass (ITO) as the working electrode, a platinum foil as the auxiliary electrode and a saturated calomel electrode as the reference electrode. The whole procedure was carried out as follows. Firstly, 0.56 g Pal was dispersed in 25 mL phosphate buffer solution (PBS) containing 75 mg aspirin (pH 3.5) and sonicated for 1 h, then 0.34 mL pyrrole was added to this emulsion and dissolved with vigorous magnetic stirring for 30 min. The solution was deaerated by bubbling nitrogen for 10 min before the electropolymerization of pyrrole. Then, PPy was deposited onto the surface of ITO by a potentiostatic method, in which a positive potential of 0.80 V was applied at the ITO working electrode for 500 s. During the polymerization process, Pal and aspirin molecules were incorporated into the PPy film simultaneously. Subsequently, the prepared aspirinPal PPy nanocomposites was rinsed thoroughly with doubly distilled water and then dried. For comparison, aspirin-loaded PPy was synthesized by the same procedure except for the addition of Pal to the electrolyte.

The XRD patterns of CPN, and Pal alone were shown in Fig. 2. Both spectra displayed a polycrystalline structure due to the presence of sharp reflections. The crystalline reflections at 8.3, 19.8, 24.2 and 27.5° (2θ value) on curve a were characteristic of Pal (Cao et al., 2008). The crystalline reflection at 8.3° was still observed clearly for the CPN (curve b), indicating that the incorporation of PPy did not alter the crystal structure of Pal. This unchanged crystal structure of Pal demonstrated that the PPy introduced by rapid electropolymerization acted only as a conducting coating layer of Pal. Liu and Tsai (2003) also reported that PPy played a role as a coating layer in the preparation of PPy/caprolactam-modified montmorillonite. It was noteworthy that a broad reflection ranging from 15.0 to 37.5° appeared on the XRD pattern of the CPN (curve b), which was attributed to the amorphous structure of PPy (Yang et al., 2002). The amorphous crystallinity of the electrodeposited PPy was further proven by the fact that no other obvious reflections for PPy were observed.

2.3. Release of aspirin from the drug-loading system

3.3. Electrochemical behaviors of the drug-loading system

The release of aspirin was triggered by external electrical stimulus, in which a negative potential of −0.6 V was applied at the aspirin-Pal

PPy was electrically conductive due to its uninterrupted and ordered π-conjugated backbone. As a result, the CPN could be regarded as a good

3.2. XRD characterizations of Pal and CPN

Fig. 1. TEM images of Pal (A) and CPN (B).


Fig. 2. XRD patterns of Pal (a) and CPN (b).

electrode material and used for drug-delivery by external electrical stimulus. Cyclic voltammetry (CV) was a useful technique by which important information on an electroactive material could be obtained. The cyclic voltammograms of aspirin-loaded PPy, PPy, CPN and aspirin-Pal PPy nanocomposites in 1.0 mol L−1 NaCl solution (pH 3.0) were shown in Fig. 3, where the scanning potential was set between − 1.0 and 1.0 V with a scan rate of 100 mV s− 1. The Faradic current at the aspirinloaded PPy was much larger than that at the PPy (curve a versus b), indicating that the conductivity of PPy was improved significantly when aspirin was doped into PPy films as the primary dopant. However, the current at the CPN decreased a lot as compared with PPy (curve c versus b), which was attributed to the addition of non-conductive Pal to the CPN. It was very interesting to find that the current at the aspirin-Pal PPy nanocomposites was the smallest (curve d), even smaller than that at the CPN free of aspirin (curve c). This change in current intensity was opposite to that at PPy electrode before and after aspirin was loaded, and was due to the obstruction of electron transfer in the system of aspirin-Pal PPy nanocomposites. In the presence of Pal, aspirin was loaded on the system by multi-actions, including doping, adsorption and ion-dipole interactions. However, the loading of aspirin on PPy alone as the drug-loading material was accomplished only by

Fig. 3. Cyclic voltammograms of aspirin-loaded PPy (a), PPy (b), CPN (c), and aspirin-Pal PPy nanocomposites (d).

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doping. The complicated interaction between aspirin and the CPN decreased the mobility of electrons, and therefore the electron transfer became impaired. In addition to current intensity, the impedance changes at the electrode/electrolyte interface during the modification processes could be measured by electrochemical impedance spectroscopy (EIS). The value of the electron-transfer resistance (Ret) depended on the dielectric and insulating features at the electrode/electrolyte interfaces. The difference in the real part of the impedance between low frequency and high frequency could be used to evaluate the value of Ret. The EIS of different electrodes, including aspirin-Pal PPy nanocomposites, CPN, PPy and aspirin-loaded PPy, in 0.1 mol L−1 KCl solution containing 5 mmol L− 1 [Fe(CN6)]3 −/4 − were exhibited in Fig. 4. The frequency range was from 0.1 to 105 Hz, and the voltage amplitude was set as 5 mV. The impedance was measured at a bias potential of 0.2 V. The Ret of the aspirin-loaded PPy was only 44.8 Ω on account of the relatively high conductivity and fast responding ability of the films (curve a), which was much smaller than that of PPy (146 Ω) (curve b). However, the Ret values of the CPN and the aspirin-Pal PPy nanocomposites were increased to 1098 Ω and 1442 Ω, respectively (curves c and d). The EIS results agreed well with the cyclic voltammograms of different electrodes (Fig. 3), for the same reason as described above. 3.4. Electrochemical effective surface area (EESA) of CPN and PPy The EESA of the CPN and PPy could be calculated by the slope of the plot of Q versus t1/2 obtained by chronocoulometry using [Fe(CN)6]3− as an electroactive probe based on the following equation: Q = (2nFAD1/2 π−1/2C)t1/2 (Anson, 1964; Csiszar et al., 2001), where Q is the charge passed, n is the number of electrons during the reaction process (n = 1 for [Fe(CN)6]3 −/4 −), F is the Faraday constant, A is the surface area of the working electrode, D is the diffusion coefficient (D = 7.6 × 10−6 cm2 s−1 for [Fe(CN)6]3 −(Zheng et al., 2013)), C is the concentration of substrate (5 mmol L−1), and t is the time. From the slope of Q versus t1/2 (Fig. 5), A was calculated to be 4.04 cm2 and 0.72 cm2 for the CPN and PPy, respectively. The significant increase in the EESA of the CPN was due to the introduction of Pal. 3.5. FTIR analysis of the aspirin-Pal PPy nanocomposites The FTIR spectra of the CPN either or not loaded with aspirin were presented in Fig. 6. For a better comparison, the FTIR spectra of individual PPy, Pal, and aspirin were also provided. For PPy (curve c), the band

Fig. 4. EIS curves of aspirin-loaded PPy (a), PPy (b), CPN (c) and aspirin-Pal PPy nanocomposites (d) in 0.1 mol L−1 KCl containing 5 mmol L−1 [Fe(CN6)]3−/4−. Inset: enlargement of curves a and b.

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3.6. Drug release profile of the aspirin-Pal PPy nanocomposites

at 1544 cm− 1 was assigned to the stretching vibrations of C_C and C\C at pyrrole ring and the peak at 1460 cm−1 was associated with the C\N stretching vibration. The peak at 1172 cm− 1 was attributed to the in-plane vibrations of C\H and the peaks at 906 and 1037 cm−1 were due to the out-of-plane and in-plane vibrations of _C\H (Yang and Liu, 2010). Three characteristic peaks of Pal appeared at 1654, 1027 and 980 cm− 1 (curve d). The peak at 1654 cm−1 was assigned to the bending vibration of the deformation mode of water molecules in the channels of Pal, and the other two peaks at 1027 and 980 cm−1 were for the (Mg, Al)\Si\O (Zhang et al., 2010) and the perpendicular Si–nonbridging oxygen–Mg (Si\Onb\Mg) stretching vibrations (Yan et al., 2012). These characteristic peaks of both PPy and Pal could all be observed in the spectrum of the CPN (curve b), implying the effective combination of PPy and Pal. The interactions between PPy and Pal resulted in a small shift of these characteristic peaks compared with the individual PPy and Pal. For the spectrum of aspirin (curve e), the peak at 1753 cm−1 was attributed to the C_O vibrations of ester and the peak at 1689 cm−1 was due to the vibrations of C_O (carboxy) and O\H deformation vibrations (Boczar et al., 2003). As can be seen from the spectrum of the aspirin-Pal PPy nanocomposites (curve a), these two characteristic peaks of aspirin could still be observed only with a slight shift in position (1718 and 1685 cm−1), indicating the successful immobilization of aspirin to the drug-delivery system.

PPy had been widely explored for drug delivery purpose since it could undergo controllable, reversible redox reactions accompanied with simultaneous changes in its charge, conductivity and volume (Miller et al., 1987; Svirskis et al., 2010b). In this study, aspirin was doped into the CPN films as anions during the preparation of this CPN at pH 3.5. Since PPy is a typical organic semiconductor, electrical stimulation could be used to control the release of aspirin from the CPN by altering the redox states of PPy, i.e., aspirin anions could be de-doped into solution from the reduced PPy initiated by a negative potential, and vice versa. According to the calibration plot of the absorbance of aspirin to its concentration (Fig. 7), the drug release profile of the aspirin-Pal PPy nanocomposites at an external electrical stimulus (− 0.6 V) was shown in Fig. 8. Two important observations could be made from Fig. 8. First, the cumulative release of aspirin at −0.6 V from the CPN and the unmodified PPy, as calculated from curves a and b, were 61.1 and 37.2 μg mL−1 at 160 min, respectively, indicating that Pal played a key role in the enhancement of drug loading capacity. This was attributed to the large EESA of the CPN and the ion-dipole interactions between the cations (Mg2+, Al3+ and Fe3+) in Pal and the loaded aspirin anions, i.e., the interactions between cations in Pal and the electronegative carbonyl groups of aspirin molecules (Scheme 1). The importance of Pal could also be reflected by comparing the cumulative release of aspirin without the electrical stimulus from the CPN and the unmodified PPy, in which the release amounts of aspirin were calculated from curves c and d, to be 28.8 and 17.0 μg mL−1, respectively. Second, it was obvious that compared with the spontaneous release of aspirin from the CPN, the release amount of aspirin was significantly improved by an external electrical stimulus at −0.6 V (curve a versus curve c). Since the doped aspirin is negatively charged, electrostatic repulsion between aspirin anions and the CPN resulted in a rapid release of aspirin compared with the release of aspirin without electrical stimulus. The above results demonstrated that the CPN exhibited satisfactory drug loading capacity and drug release profile compared to the unmodified PPy. More importantly, a facile and simple modulation of aspirin release could be accomplished electrochemically. Thus, the proposed CPN might be a useful material used as a promising drug-delivery platform meeting requirements of different patients. The loading amount of aspirin into the CPN was calculated to be 1.87 mg based on the calibration plot in Fig. 7, and thus the aspirin loading capacity of the CPN was calculated to be 2.5% using the following equation: loading capacity (%) = 100 (mass of drug in the substrate)/ (mass of the dry substrate) (Liu et al., 2004). Although the loading capacity of the proposed CPN was much lower than that of the polystyrene

Fig. 6. FTIR spectra of aspirin-Pal PPy nanocomposites (a), CPN (b), PPy (c), Pal (d) and aspirin (e).

Fig. 7. The calibration plot of the absorbance of aspirin to its concentration.

Fig. 5. Plots of Q versus t1/2 of CPN (a) and PPy (b) based on the data from the chronocoulometric experiments.


Fig. 8. Cumulative aspirin release versus time. Release of aspirin from CPN (a) and PPy (b) by an electrical stimulus at −0.6 V; natural release of aspirin from CPN (c) and PPy (d) without electrical stimulus. Error bars in this figure indicate standard error of the mean (n = 3).

microspheres-based nanocomposite (19%) (Han et al., 2008), it circumvented the tedious process of preparing block copolymer and post-treatment of dialysis. More important, the release of aspirin could be electrically tuned by applying an external electrical stimulus on the CPN. Further, the obtained data during the release process from the CPN and PPy alone were fitted to the Higuchi model (Higuchi, 1961). The Higuchi model could be presented as the following equation: Q/A = (2C0D1/2 π−1/2)t1/2, where Q/A is the cumulative aspirin release per unit area, C0 is the initial concentration of aspirin, D is the apparent diffusion coefficient of aspirin, and t is the time. For both CPN and PPy alone, a linear relationship was obtained when the cumulative release of aspirin was graphed versus the square root of time (Fig. 9), indicating

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Fig. 9. Fitting cumulative aspirin release from CPN (a) and PPy (b) by an electrical stimulus at −0.6 V; natural release of aspirin from CPN (c) and PPy (d) without electrical stimulus to the Higuchi model.

that the Higuchi model gave good descriptions of the release of aspirin from the CPN and this release was matrix-controlled. 4. Conclusions Aspirin-Pal PPy nanocomposites were prepared by in situ electropolymerization of pyrrole in the presence of Pal and aspirin, and the resulted CPN was evaluated as a drug-delivery platform. This novel drug-delivery system was likely to offer high loading capacity as well as advanced release ability of the entrapped drug molecules due to its large EESA and the tunable electrical parameters. The as-prepared CPN indeed exhibited better drug loading capacity and drug release profile

Scheme 1. Schematic representation of the ion-dipole interactions between Pal and aspirin.

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compared to those of the unmodified PPy. In this sense, this novel drugdelivery system might prove to be a good candidate material for implantable device where drug release could be electrically tuned according to the patient's requirement. Acknowledgments This work was supported by Natural Science Foundation of China (21275023, 11172340), Natural Science Foundation of Jiangsu Province (BK2012593), Jiangsu Provincial Key Lab of Palygorskite Science and Applied Technology (HPK201203), Changzhou Key Lab of Respiratory Medical Engineering (CM20133005), Science & Technology Program of Huaian (HG201303, HAM201306), Graduate Research Innovation Program for Universities of Jiangsu Province (KYZZ_0302) and PAPD. References Abidian, M.R., Kim, D.H., Martin, D.C., 2006. Conducting-polymer nanotubes for controlled drug release. Adv. Mater. 18, 405–409. Aguzzi, C., Cerezo, P., Viseras, C., Caramella, C., 2007. Use of clays as drug delivery systems: possibilities and limitations. Appl. Clay Sci. 36, 22–36. Anson, F., 1964. Application of potentiostatic current integration to the study of the adsorption of cobalt(III)-(ethylenedinitrilo(tetraacetate) on mercury electrodes. Anal. Chem. 36, 932–934. Boczar, M., Wójcik, M.J., Szczeponek, K., Jamróz, D., Zieba, A., Kawałek, B., 2003. Theoretical modeling of infrared spectra of aspirin and its deuterated derivative. Chem. Phys. 286, 63–79. Cao, J.L., Shao, G.S., Wang, Y., Liu, Y., Yuan, Z.Y., 2008. CuO catalysts supported on attapulgite clay for low-temperature CO oxidation. Catal. Commun. 9, 2555–2559. Cho, Y., Borgens, R.B., 2011. Biotin-doped porous polypyrrole films for electrically controlled nanoparticle release. Langmuir 27, 6316–6322. Csiszar, M., Szucs, A., Tolgyesi, M., Mechler, A., Nagy, J.B., Novak, M., 2001. Electrochemical reactions of cytochrome c on electrodes modified by fullerene films. J. Electroanal. Chem. 497, 69–74. Fan, Q.H., Shao, D.D., Hu, J., Wu, W.S., Wang, X.K., 2008. Comparison of Ni2+ sorption to bare and ACT-graft attapulgites: effect of pH, temperature and foreign ions. Surf. Sci. 602, 778–785. Geetha, S., Rao, C.R.K., Vijayan, M., Trivedi, D.C., 2006. Biosensing and drug delivery by polypyrrole. Anal. Chim. Acta. 568, 119–125. George, P.M., Lyckman, A.W., LaVan, D.A., Hegde, A., Leung, Y., Avasare, R., Testa, C., Alexander, P.M., Langer, R., Sur, M., 2005. Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics. Biomaterials 26, 3511–3519. Gupta, V.K., Jain, R., Shrivastava, M., Nayak, A., 2010. Equilibrium and thermodynamic studies on the adsorption of the dye tartrazine onto waste “coconut husks” carbon and activated carbon. J. Chem. Eng. Data 55, 5083–5090. Han, J.T., Silcock, P., McQuillan, A.J., Bremer, P., 2008. Preparation and characterization of poly(styrene-alt-maleic acid)-b-polystyrene block copolymer self-assembled nanoparticles. Colloid Polym. Sci. 286, 1605–1612. Higuchi, T., 1961. Rate of release of medicaments from ointment bases containing drugs in suspension. J. Pharm. Sci. 50, 874–875.

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