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Polydopamine modified TiO2 nanotube arrays as a local drug delivery system for ibuprofen
Journal of Drug Delivery Science and Technology 56 (2020) 101537
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Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst
Polydopamine modified TiO2 nanotube arrays as a local drug delivery system for ibuprofen
T
Lifen Li, Chunling Xie∗∗, Xiufeng Xiao∗ Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, 350007, China
A R T I C LE I N FO
A B S T R A C T
Keywords: TiO2 nanotube arrays Polydopamine Drug delivery Modified
Dopamine with multifunctional groups exhibits excellent biological activity and self-polymerization ability, which provides active groups for secondary reaction on the different kinds of modified surface. In this study, using the ultrasonic method, dopamine polymer coatings functionalized on TiO2 nanotube arrays (TNTs) were successfully prepared. The obtained samples were characterized and evaluated using field-emission scanning electron microscopy (FESEM), transmission electron microscope (TEM) and atomic force microscopy (AFM), Fourier transform infrared (FT-IR) spectroscopy and thermogravimetric analysis (TGA). Upon dopamine selfpolymerization, due to the presence of multifunctional groups, it could interact with drug molecules to efficiently enhance drug loading, prevent drug sudden release and improve sustained-release performance of the carrier. TNTs were loaded with ibuprofen (IBU) via soaking method before and after modification and its release properties were investigated. The results showed that dopamine-modified TNTs remarkably improved the loading of IBU and prolonged drug release. Notably, the biomineralization ability of the sample was also tremendously enhanced through modification of the nanotubes with polydopamine. In conclusion, dopaminemodified TNTs may be a promising approach in promoting the loading of IBU and sustained the drug release that is noticeably essential for bone implant therapies.
1. Introduction The inherent limitations of current conventional drug delivery administration such as poor drug solubility lead poor bioavailability and biodistribution, poor drug selectivity, uncontrolled pharmacokinetics, and serious side effects in non-target tissues [1,2]. Therefore, local drug delivery systems have emerged as a potential solution to overcome these limitations. By increasing the surface specificity and degradability of carriers, the local drug delivery systems aim at releasing the optimal concentration of desirable drugs continuously at a controllable rate. Thus, these systems can provide increased therapeutic efficacy, decreased side effects, reduced the consumption of expensive drugs, and optimized use of drugs by avoiding rapid degradation and release of drugs. In the recent years, TiO2 nanotube (TNT) arrays have been increasingly recognized as one of the most exceptional drug-releasing materials for local drug delivery systems, owing to their controlled nanoporous or nanotube formation, high-specific surface area, tubular structure, and controllable size enhanced physical and chemical
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stability [3]. Moreover, much attention and scientific focus has been directed to TNT arrays for their promising applications in fields of drug delivery systems, antimicrobial agents, and medical implants [4–11]. As TNTs form weak interaction with drug molecules because of its smooth surface, making it difficult for drugs to enter the nanochannels, consequently, drugs get accumulated at the surface of the nanotubes. Therefore, surface functionalization of TNTs becomes essential to facilitate the interaction of TNTs with drugs through adsorption or covalent linking and to achieve controlled and sustained release of drugs. Most recently, Wang Z et al. used APTES to modify nanotubes and made them positively charged to adsorb negatively charged drugs and increased its drug loading. However, surface modification essentially requires materials with excellent biological characteristics. Dopamine has been known to promote proliferation, differentiation, mineralization, and gene expression of osteoblasts [12]. Furthermore, polydopamine (PDA), the final oxidation product of dopamine can serve as a versatile coating material that can be facilely deposited on a vast repertoire of the material surface with high binding strength [13]. When dopamine was self-polymerized, phenolic groups, amino groups,
Corresponding author. Corresponding author. E-mail address: [email protected] (X. Xiao).
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https://doi.org/10.1016/j.jddst.2020.101537 Received 22 August 2019; Received in revised form 14 January 2020; Accepted 22 January 2020 Available online 26 January 2020 1773-2247/ © 2020 Elsevier B.V. All rights reserved.
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Fig. 1. Samples characterization: SEM images of TNTs (A1) and TNTs-PDA (A2); tube diameter distribution of TNTs (B1) and TNTs-PDA(B2); TEM images of TNTs (C1) and TNTs-PDA (C2); AFM images of TNTs (D1) and TNTs-PDA (D2); (E) Z potential of TNTs, PDA, TNTs-PDA.
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2.3. Biomineralization experiment Biological activity of the prepared samples was evaluated by placing prepared samples into simulated body fluid (SBF) at 37 °C for an indicated time and SBF was replaced every day. The structure and morphology of the prepared samples were characterized by field emission scanning electron microscope (SEM). 2.4. Cell experiment Frozen mouse embryonic osteoblast cells (MC3T3) were thawed and seeded onto culture dishes containing in α-minimum essential medium (α-MEM) containing 10% (v/v) fetal bovine serum (FBS) and 1% (v/v) penicillin/streptomycin (P/S), cultured in an aseptic incubator of 5% CO2 at 37 °C. Once cells reached confluency, they were used for the following experiments. MC3T3 and growth medium were cultured onto TNTs, TNTs-PDA at an initial seeding density of 3 × 103 cells/cm2 and cultured for one and three days, respectively. Then, 10 μL CCK-8 were added to per well at 37 °C for 2 h. Finally, the solution was transferred to a 96-well plate and was measured at 450 nm using the enzyme labeling instrument.
Fig. 2. FTIR spectra of samples showing (a) TNTs; (b) TNTs-PDA.
and other reactive sites would remain on the PDA surface, which provided active groups for secondary reaction on the functionalized surface [14]. Therefore, dopamine was selected to modify the nanotubes in this study, it can promote loading and sustained release of the drugs due to its ability to enhance interactions between the nanotubes and the drugs.
2.5. Drug loading and release Solutions of ibuprofen (IBU; 30 mg/mL) with ethanol were prepared and transferred to reaction vessels. Subsequently, the TNTs-PDA samples were immersed in ibuprofen solutions. After 6 h, TNTs-PDA loaded IBU was rinsed with distilled water. Then samples were placed into 10 mL phosphate buffer solution (PBS) for 15 days. The release solutions were taken out by removing a certain volume of the solution and adding fresh PBS into tubes with the same volume. The concentration of released drug in PBS was measured using ultraviolet spectrophotometer at 264 nm and calibrated with the standards curve of known concentrations.
2. Experiments 2.1. Preparation of TNTs The titanium sheet was submerged into the electrolytic solution comprising of water (10 vol%), glycerol, and 0.5 wt% NH4F. The titanium sheet was served as the positive, and platinum as the cathode. The distance between the two was 1 cm and oxidized under a constant voltage of 60 V for 24 h. Subsequently, the pretreated titanium sheet was calcined at 450 °C for 2h in a muffle furnace.
2.6. Characterization The surface morphologies of the prepared samples were characterized using field emission scanning electron microscope (FESEM), transmission electron microscope (TEM) and atomic force microscopy (AFM). The potential of samples was detectived by zeta potential analyzer at room temperature. The vibration spectrum of the samples was measured by Fourier transform infrared (FTIR) spectra the resolution was 4 cm−1 and the scans times was 64. The hydrophobicity of the sample was analyzed by water contact angles (WCA); The phase composition of the samples was analyzed by X-ray diffraction (XRD), and the XRD test conditions was as follows: copper target
2.2. TNTs decorated with polydopamine (TNTs–PDA) To produce PDA-decorated TNTs, The above nanotubes were hydroxylated by submerging in 0.5 M NaOH solution for 30 min and led to the formation of TNTs-OH. Briefly, to facilitate dopamine solution diffusion inside the nanotubes, the treated nanotubes were immersed into dopamine hydrochloride (1 mg/mL) with Tris-HCl solution (1.2 mg/ mL, pH = 8.5) using an ultrasonic bath for 12 h. The prepared samples were designated as TNTs-PDA.
Fig. 3. WCA of samples showing (a) TNTs; (b)calcined TNTs; (c) TNTs-OH; (d)TNTs-PDA. 3
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Fig. 4. (A) The mechanism for self-polymerization of dopamine; (B) Scheme of the procedure for TNTs modification with PDA.
Fig. 5. XPS spectra of samples showing (A) wide-scan spectrum; (B,C,D) high resolution spectra of C1s, O1s, N1s: (a)TNTs-PDA; (b)TNTs.
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TNTs, the structure of TNTs-PDA was not changed obviously, while its surface was rougher (Fig. 1-D), the diameter and wall of the pipe all became smaller and thicker (Fig. 1-A, B). The average pore size of TNTs was 216 ± 10 nm, while TNTs-PDA was reduced to 158 ± 10 nm (Fig. 1-B). The zeta potential value of TNTs, PDA and TNTs-PDA were −3.74 mV, 5.38 mV, 2.5 mV, respectively. The zeta potential analysis, shown in Fig. 1-E. There was positive charge on the surface of TNTsPDA, attributing to the presence of the partial deprotonation when it was selfpolymerized. 3.1.2. FTIR analysis of samples Fig. 2 illustrates the infrared spectra of TNTs (Fig. 2 a) and TNTsPDA (Fig. 2 b). The broad absorption peak at 3436 cm−1 was attributed to the stretching vibration of –OH. The absorption peaks at 2919 cm−1 and 2852 cm−1 were assigned to –CH2 asymmetric stretching vibration and –CH2 bending vibration, respectively. And the sharp band at 1624 cm−1 [15,16] was the characteristic peak of PDA, ascribed to N–H stretching vibration. In addition, the absorption peaks at 1498 cm−1 were attributed to C]C bending vibration, which indicated that polydopamine was successfully and completely covered TiO2 nanotube arrays.
Fig. 6. TG curves of the samples showing (a) PDA; (b) TNTs-PDA.
(λ = 0.15406 nm), tube pressure 40 kV, tube flow 40 mA, scanning rate 3°/min, step 0.02°. The anode target of X-ray photoelectron spectroscopy (XPS) was Al target, the vacuum degree was 1486.6 eV, sample chamber was kept at 2 × 10−7 Pa, and the photoelectron incident angle was 20°. The surface element composition and chemistry of the samples were measured by X-ray photoelectron spectroscopy (XPS). 10°/min was chosen for the temperature raising rate of the thermogravimetric analyzer (TGA), and the change of the samples mass during the heating process was detected under the atmosphere of nitrogen. The amount of drug release in PBS was measured by UV–vis spectrophotometer (UV). The absorbance of the solution was measured at 450 nm using enzyme-labeled instrument (Bio-Rad, Japan), and the cell proliferation ability of the sample was analyzed.
3.1.3. Water contact angles analysis of samples Water contact angle (WCA) of TNTs (Fig. 3 A), calcined TNTs (Fig. 3 B), TNTs-OH (Fig. 3C) and TNTs-PDA (Fig. 3 D) were performed as illustrated in Fig. 3. TNTs (Fig. 3 A) was superhydrophilic materials and its WCA < 5°. After the calcination, the hydrophilicity of the TNTs decreased, owing to the dehydration and condensation of hydroxyl groups on the surface of the nanotubes. After hydroxylation of calcined TNTs (Fig. 3C), the WCA of the sample became smaller, indicating that the hydrophilicity of the sample was improved. This was mainly due to the large amount of hydroxyl groups on the surface of calcined TNTs after hydroxylation. Compared with the TNTs-OH, the hydrophilicity of polydopamine was weaker, and with the increase of the modification amount of polydopamine, the hydrophilicity of the samples decreases, while the WCA increases. The WCA of TNTs-PDA (Fig. 3 D) increased from 11.6° to 34.7°. The change of WCA on the surface of different
3. Results and discussion 3.1. Preparation of TNTs-PDA 3.1.1. Morphological analysis of samples The morphology of TNTs and TNTs-PDA was observed by SEM, TEM and AFM. Fig. 1 displays the morphology of the samples. Compared to
Fig. 7. SEM images of samples TNTs-PDA soaked in SBF for different time (A) 0 day; (B) 2 day; (C) 5 day; (D) 7 day. 5
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Fig. 8. SEM images of different samples immersed in SBF for 2 days showing (A) TNTs; (B) TNTs-PDA.
Fig. 10. Cell viabilities of MC3T3 cultured onto different substrates after one and three days of culture.
polymerized through deprotonation and intermolecular Michael addition to form physical trimer [17,18]. Thus, dopamine exhibited multiple functional groups during self-polymerization with the molecular driving forces of π-π bonding, hydrogen bonding, van der Waals to formed supermolecular polymers [19], which were facilely deposited onto TNTs with high binding strength[20.21], and further conjugated target molecules through simple chemistry [20–22]. Fig. 4 B schematically describes the deposition of PDA onto TNTs. With regard to the dopamine polymerization mechanism, amine groups, phenolic groups, and other reactive sites would remain on the PDA surface [23,24], which may interact with the TNTs or drugs through adsorption or covalent linking. XPS analysis displays the survey scan spectra of samples as shown in Fig. 5. An new peak of N1s at 401.6 eV was observed on the surface of TNT–PDA (Fig. 5 A-a), indicating that polydopamine was successfully introduced on TNTs. Fig. 5 B shows C1, C2, and C3 peaks appeared in C1s of TNTs (Fig. 5 B-b) spectrum, corresponding to CHx (284.53 eV), C–O (286.0 eV), C]O (288.4 eV) bonds, respectively. TNTs-PDA (Fig. 5 B-a) also presented three peaks at 284.57 eV, 286.1 eV, and 288.1 eV, belonging to C–H/C–C, C–O/C–H, and C]O bonds, respectively [25]. The characteristic peak strength and peak area of C1s enhanced remarkably, which may be attributed to the uniform modification of polydopamine on the surface of the samples to increase the content of the C element. Compared with TNTs (Fig. 5 C-b), new peaks of TNTsPDA (Fig. 5 C-a) appeared at 532.75 eV and 531.62 eV, corresponding to phenolic hydroxyl (-C-OH) and quinone (-C]O) of polydopamine, respectively. The binding energies of N 1s (Fig. 5 D-a) peaks were 399.7 eV and 401.6 eV, indicating that N on the surface of the prepared samples predominantly existed in the amino group and partially in amino protonation forms. Collectively, these results indicated that PDA was successfully modified on TNTs.
Fig. 9. FTIR spectra and XRD patterns of the samples showing (a) TNTs-PDA; (b) TNTs-PDA-HA.
samples indirectly confirmed that the polydopamine layer was successfully uniformly introduced on the surface of TNTs [19]. 3.1.4. XPS analysis of samples The self-polymerization of PDA remains complex and the limitations of detection methods thus proposed different PDA formation mechanisms in the existing literature. Based on the experimental findings and theoretical conjecture, it is generally believed that the mechanism raised due to multiple physical and chemical interaction was more comprehensive [17]. Fig. 4 A presented the physical and chemical reaction behind the self-polymerization of dopamine. The polymerization began with the oxidation of dopamine to dobutamine with the subsequent nucleophilic addition reaction to form catecholamine. After rearrangement, the intermediate product (5, 6-dihydroxyindole) 6
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3.2. Mineralization experiment of samples In order to establish complete osseointegration, the implant must exhibit excellent biological activity and the ability to induce the formation of well-developed bone-like apatite formation. Fig. 7 presented the SEM images of TNTs-PDA soaked in SBF for 0, 2, 5, and 7 days, respectively. Apatite film was formed on the surface of TNTs-PDA,. With the increase of immersion days, the spherical hydroxyapatite became larger and more uniform, suggesting TNTs-PDA with excellent biomineralizationm ability. SEM images of TNTs and TNTs-PDA immersed in SBF for 2 days were shown in Fig. 8. There was only little hydroxyapatite film formed on the surface of TNTs (Fig. 8 A) for 2 days, while large hydroxyapatite was appeared on the surface of TNTs-PDA (Fig. 8 B), indicating that the biomineralization ability of the sample was greatly improved. Thanks to the surface of the sample with plenty of phenolic hydroxyl groups and amido, which was beneficial to the adsorption of Ca2+ and promoted the nucleation of hydroxyapatite on the surface of the sample, improving the biomineralization ability of the sample [27]. Furthermore, to study the apatite film formed on the surface of TNTs-PDA, the samples were characterized by FTIR and XRD, shown in Fig. 9. The absorption peaks appeared at 3425 cm−1 and 1636 cm−1 were corresponded to hydroxyapatite adsorbing water. The sharp band at 1036 cm−1 was ascribed to the stretching vibration absorption peak of PO43− and the bending vibration absorption peaks of PO43− were observed at 567 cm−1 and 604 cm−1. In the XRD (Fig. 9 B-b), the characteristic diffraction peak of the hydroxyapatite was presented at about 32°. Taken together, the findings indicated that hydroxyapatite fabricated on the surface of the prepared samples. 3.3. Samples cell test To examine proliferation of MC3T3 on the TNTs and TNTs-PDA, CCK-8 assay was employed in this study. Fig. 10 Shows the viability of MC3T3 grown on TNTs and TNTs-PDA after one and three days of culture. Compared to TNTs, the absorbance of TNTs-PDA showed higher after one and three days of culture, indicating that cells cultured on TNTs–PDA exhibited significantly higher cell viability.
Fig. 11. FTIR spectra and XRD pattern of samples showing (a) IBU; (b) TNTsPDA; (c) TNTs-PDA-IBU.
3.4. XRD and FTIR analysis of the samples after drug loading IR and XRD were employed to characterize the sample of TNTs-PDA loaded drugs, as shown in Fig. The strong peaks at 2871 cm−1, 2922 cm−1 and 2955 cm-1 were characteristic symmetric and asymmetric stretching vibrations of alkylchain of ibuprofen in Fig. 11 A-c. In addition, the absorption peaks appeared at 779 cm−1 and 1508 cm−1 corresponded to C–H and C]C on the benzene ring of IBU, and 1719 cm−1 was the telescopic vibration peak of the carbonyl group of IBU. In contrast to the XRD pattern of pure IBU, the XRD pattern of IBU loaded TNTs-PDA exhibited characteristic peaks at about 6.08°, 12.21°, 16.7°, 20.19°, respectively(JCPDS Card. 32–1723). Thus, confirming the successful loading of the drug on the prepared samples. The FTIR spectrum and XRD pattern of IBU loaded TNTs-PDA indicated that drugs were successfully loaded (Fig. 11).
Fig. 12. Drug release curves of the samples: (a) TNTs-IBU; (b) TNTs-PDA-IBU.
3.1.5. TG analysis of samples Thermogravimetric analysis of the prepared samples was performed in the range between 30 °C and to 600 °C, as shown in Fig. 6. Both the samples showed weight loss between 200 °C and 500 °C. TNTs-PDA (Fig. 6 b) exhibited a continuous weight loss from 30 °C to 300 °C, which was mainly caused due to desorption of adsorbed water on the samples surface, the condensation, and dehydration of hydroxyl groups on the sample surface. While between 300 °C and 450 °C, there was an apparent weight loss peak, which mainly corresponded to the decomposition of polydopamine [26], and the weight loss was near to 10 wt%.
3.5. In vitro release of IBU PBS (pH = 7.4) was used to investigate drug release profiles. The drug release curves of the samples were shown in Fig. 12. In the initial burst release stage, the drugs loaded in the upper part of the tubes and adsorbed on the surface were released rapidly into PBS. The physically adsorbed drugs on samples surface resulted in an initial burst release and followed by a sustained release. The released percentage of IBU from TNTs in the burst release stage was about 55.3% (Fig. 12a) (the drug accumulation of the sample released in PBS buffer solution for 15 days was taken as the total release amount). However, the released 7
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Fig. 13. Kinetic fitting of drug release at different stages: (A) initial stage; (B) slow release stage.
Declaration of competing interest
percentage from TNTs–PDA in this stage was about 28.16% (Fig. 12b). In the later stage of drug release, ibuprofen mostly released from the inner wall of the nanotubes. Furthermore, the released amount of ibuprofen significantly increased at this stage for TNTs–PDA. It was possible that the surface of TNTs-PDA existed active sites for amino radical, protonated amino group, which may form an electrostatic interaction with the drug ibuprofen. And it was beneficial to the adsorption of the drug molecules. The results showed that PDA modified TNTs contributed to reduce the sudden release and prolong the drug release. In order to study the release kinetics of drug release phase, the release curve was fitted with the zero-, first-order kinetic equations and Higuchi equation. The results indicated that the release of drugs from TNTs-PDA loaded system in the initial stage (before 12 h) was mainly attributed to the drugs loaded in the upper part of the tubes and adsorbed on the surface, and the fast release rate in accordance with the first-order kinetic equation
(
[ ln 1 −
Mt M∞
The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Acknowledgments This research was funded by National Natural Science Foundation of China of China(21805037), Fujian Province Nature Science Foundation (2016Y0025, 2017J01685,2018J01363), Fuzhou Science and Technology Project (2017-G-61, 2018-G-90). References
) = −0.19333x − 0.12309,
[1] M. Purvya, M. Meena, A review on role of nanostructures in drug delivery system, Rev. Adv. Mater. Sci. 32 (2011) 20–67. [2] B.P. Kumar, I.S. Chandiran, B. Bhavya, M. Sindhuri, D. Pharmaceutics, G. Krishna, Indian journal of pharmaceutical science & research microparticulate drug delivery system: a review, Indian J. Pharmaceut. Sci. Res. 1 (2011) 19–37. [3] A.Z. Wilczewska, K. Niemirowicz, K.H. Markiewicz, H. Car, Nanoparticles as drug delivery systems, Pharmacol. Rep. 64 (2012) 1020–1037. [4] N. Khoshnood, A. Zamanian, A. Massoudi, Effect of silane-coupling modification on bioactivity and in vitro properties of anodized titania nanotube arrays, Mater. Lett. 185 (2016) 374–375. [5] T.M. Tian, H. Dong, X. Tian, Y. Hao, Fabricated antibacterial and bioactive titania nanotube arrays coating on the surface of titanium, Saf. Sci. Technol. 20 (2013) 59–62. [6] K. Vasilev, Z. Poh, K. Kant, J. Chan, A. Michelmore, D. Losic, Tailoring the surface functionalities of titania nanotube arrays, Biomaterials 31 (2010) 532–540. [7] K.S. Mun, S.D. Alvarez, W.Y. Choi, M.J. Sailor, A. stable, label-free optical interferometric biosensor based on TiO2 nanotube arrays, Nano 4 (2010) 2070–2076. [8] H. Li, Q. Cui, B. Feng, J. Wang, X. Lu, J. Weng, Antibacterial activity of TiO2 nanotubes: influence of crystal phase morphology and Ag deposition, Appl. Surf. Sci. 284 (2013) 179–183. [9] N. Abbas, G.N. Shao, M.S. Haider, S.M. Imran, S.S. Park, S.J. Jeon, H.T. Kim, Inexpensive sol-gel synthesis of multiwalled carbon nanotube-TiO2 hybrids for high performance antibacterial materials, Mater. Sci. Eng. C 68 (2016) 780–788. [10] K. Gulati, M.S. Aw, D. Findlay, D. Losic, Local drug delivery to the bone by drugreleasing implants: perspectives of nano-engineered titania nanotube arrays, Ther. Deliv. 3 (2012) 857–873. [11] A. Roguska, M. Pisarek, A. Belcarz, L. Marcon, M. Holdynski, M. Andrzejczuk, M. Janik-Czachor, Improvement of the bio-functional properties of TiO2 nanotubes, Appl. Surf. Sci. 6 (2016) 354–378. [12] L. H, Mussel-inspired surface chemistry for multifunctional coatings, Science 318 (2007) 426–430. [13] B. M, The reduction of Ag+ in metallic silver on pseudomelanin films allows for antibacterial activity but does not imply unpaired electrons, J. Colloid Interface Sci. 10 (2018) 7649–7660. [14] X. M, Mussel-inspired bioactive ce-ramics with improved bioactivity cell proliferation differentiation and bone-related gene expression of MC3T3 cells, Biomater. Sci. 1 (2013) 933–941. [15] J.W. Fu, Z.H. Chen, M.H. Wang, Adsorption of methylene blue by a high-efficiency adsorbent (polydopamine microspheres): kinetics, isotherm, thermodynamics and mechanism analysis, Chem. Eng. 259 (2015) 53–61. [16] S.D. Ma, J. Feng, W.J. Qin, CuFe2O4@ PDA magnetic nanomaterials with a coreshell structure: synthesis and catalytic application in the degradation of methylene blue in water, RSC Adv. 5 (2015) 53514–53523.
R2 = 0.97135 Fig. 13A]. In the sustainable release stage (after 12 h), the cumulative release rate gradually increased, the release mechanism was weak diffusion, and the release effect was good in agreement with the Higuchi equation ( Mt =0.04513t1/2, R2 = 0.98451 Fig. 13B) [28], M∞ Where Mt denoted the amount released during the time, M∞ defined the total amount of complete release, Mt provided the released rate at inM∞ dicatedtime and k was the release constant.
4. Conclusions In this work, polydopamine was successfully modified TiO2 nanotube arrays by ultrasonic method. According to the mechanism of dopamine polymerization, amino groups, phenolic groups and other reactive sites would remain on the PDA surface during polymerization. These functional groups may increase drugs loading and prolong drug release by adsorption or covalent bond interaction with drugs. The experimental results demonstrated that the release curve was fitted with the first order kinetic equation at initial stage and the Higuchi equation at slow release stage. The results of biomineralization experiments showed that polydopamine promoted the nucleation of hydroxyapatite on the surface of samples, and improving biomineralization capacity of the samples. Finally, The cell viability of MC3T3 was enhanced by PDA functionalized TNTs.
CRediT authorship contribution statement Lifen Li: Conceptualization, Methodology, Writing - original draft. Chunling Xie: Formal analysis, Methodology, Investigation. Xiufeng Xiao: Supervision, Conceptualization, Writing - review & editing. 8
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[23] Y. Yang, P. Qi, Y. Ding, M.F. Maitz, Z. Yang, Q. Tu, K. Xiong, Y. Leng, N.A. Huang, Biocompatible and functional adhesive amine-rich coating based on dopamine polymerization, Mater. Chem. 3 (2015) 72–81. [24] R. Luo, L. Tang, S. Zhong, Z. Yang, J. Wang, Y. Weng, Q. Tu, C. Jiang, N. Huang, In vitro investigation of enhanced hemocompatibility and endothelial cell proliferation associated with quinone-rich polydopaminecoating, Appl. Mater. Interfaces 5 (2013) 1704–1714. [25] S. Syafiqah, C. Pascale, Polydopamine as an intermediate layer for silver and hydroxyapatite immobilisation on metallic biomaterials surface, Appl. Catal. 8 (2013) 0928-4931. [26] K. Negin, Z. Ali, Mussel-inspired surface modification of titania nanotubes as a novel drug delivery system, Appl. Catal. 10 (2017) 0928-4931. [27] Z.G. Wang, J.Q. Zeng, G.X. Tao, J.W. Liao, L. Zhou, J.Q. Chen, P. Yu, G.Y. Wang, C.Y. Ning, Incorporating catechol into electroactive polypyrrole nanowires on titanium to promote hydroxyapatite formation, Bioactive Mater. 3 (2017) 74–79. [28] A. Jain, S.K. Jain, In vitro release kinetics model fitting of liposomes: an insight, Chem. Phys. Lipids 201 (2016) 28–40.
[17] Y. Ding, L.T. Weng, M. Yang, Z. Yang, X. Lu, N. Huang, Y. Leng, Insights into the aggregation/deposition and structure of a polydopamine film, Appl. Catal. 30 (2014) 12258–12269. [18] J.S. Cai, J.Y. Huang, Immobilization of pt nanoparticles via rapid and reusable electropolymerization of dopamine on TiO2 nanotube arrays for reversible sers substrates and nonenzmatic glucose sensors, Appl. Catal. 13 (2017) 160–240. [19] Y. Yang, X.Y. Li, H. Qiu, Polydopamine modified TiO2 nanotube arrays for longterm controlled elution of bivalirudin and improved hemocompatibility, Appl. Catal. 10 (2018) 7649–7660. [20] Y. Liu, K. Ai, L. Lu, Polydopamine and its derivative materials: synthesis and promising applications in energy, environmental, and biomedical fields, Chem. Rev. 114 (2014) 5057–5115. [21] G. Pan, S. Zhang, W. Zhao, R. Cui, W. He, F. Huang, L. Lee, S. Shea, K.J. Shi, Q. Yang, Design of mussel-derived bioactive peptides for dual-functionalization of titanium-based, Biomaterials. Am. Chem. Soc. 138 (2016) 15078–15086. [22] L. Cheng, X. Sun, X. Zhao, L. Wang, J. Yu, G. Pan, B. Li, H. Yang, Y. Zhang, W. Cui, Surface biofunctional drug-loaded electrospun fibrous scaffolds for comprehensive repairing hypertrophic scars, Biomaterials 83 (2016) 169–181.
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Polydopamine modified TiO2 nanotube arrays as a local drug delivery system for ibuprofen
T
Lifen Li, Chunling Xie∗∗, Xiufeng Xiao∗ Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, 350007, China
A R T I C LE I N FO
A B S T R A C T
Keywords: TiO2 nanotube arrays Polydopamine Drug delivery Modified
Dopamine with multifunctional groups exhibits excellent biological activity and self-polymerization ability, which provides active groups for secondary reaction on the different kinds of modified surface. In this study, using the ultrasonic method, dopamine polymer coatings functionalized on TiO2 nanotube arrays (TNTs) were successfully prepared. The obtained samples were characterized and evaluated using field-emission scanning electron microscopy (FESEM), transmission electron microscope (TEM) and atomic force microscopy (AFM), Fourier transform infrared (FT-IR) spectroscopy and thermogravimetric analysis (TGA). Upon dopamine selfpolymerization, due to the presence of multifunctional groups, it could interact with drug molecules to efficiently enhance drug loading, prevent drug sudden release and improve sustained-release performance of the carrier. TNTs were loaded with ibuprofen (IBU) via soaking method before and after modification and its release properties were investigated. The results showed that dopamine-modified TNTs remarkably improved the loading of IBU and prolonged drug release. Notably, the biomineralization ability of the sample was also tremendously enhanced through modification of the nanotubes with polydopamine. In conclusion, dopaminemodified TNTs may be a promising approach in promoting the loading of IBU and sustained the drug release that is noticeably essential for bone implant therapies.
1. Introduction The inherent limitations of current conventional drug delivery administration such as poor drug solubility lead poor bioavailability and biodistribution, poor drug selectivity, uncontrolled pharmacokinetics, and serious side effects in non-target tissues [1,2]. Therefore, local drug delivery systems have emerged as a potential solution to overcome these limitations. By increasing the surface specificity and degradability of carriers, the local drug delivery systems aim at releasing the optimal concentration of desirable drugs continuously at a controllable rate. Thus, these systems can provide increased therapeutic efficacy, decreased side effects, reduced the consumption of expensive drugs, and optimized use of drugs by avoiding rapid degradation and release of drugs. In the recent years, TiO2 nanotube (TNT) arrays have been increasingly recognized as one of the most exceptional drug-releasing materials for local drug delivery systems, owing to their controlled nanoporous or nanotube formation, high-specific surface area, tubular structure, and controllable size enhanced physical and chemical
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stability [3]. Moreover, much attention and scientific focus has been directed to TNT arrays for their promising applications in fields of drug delivery systems, antimicrobial agents, and medical implants [4–11]. As TNTs form weak interaction with drug molecules because of its smooth surface, making it difficult for drugs to enter the nanochannels, consequently, drugs get accumulated at the surface of the nanotubes. Therefore, surface functionalization of TNTs becomes essential to facilitate the interaction of TNTs with drugs through adsorption or covalent linking and to achieve controlled and sustained release of drugs. Most recently, Wang Z et al. used APTES to modify nanotubes and made them positively charged to adsorb negatively charged drugs and increased its drug loading. However, surface modification essentially requires materials with excellent biological characteristics. Dopamine has been known to promote proliferation, differentiation, mineralization, and gene expression of osteoblasts [12]. Furthermore, polydopamine (PDA), the final oxidation product of dopamine can serve as a versatile coating material that can be facilely deposited on a vast repertoire of the material surface with high binding strength [13]. When dopamine was self-polymerized, phenolic groups, amino groups,
Corresponding author. Corresponding author. E-mail address: [email protected] (X. Xiao).
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https://doi.org/10.1016/j.jddst.2020.101537 Received 22 August 2019; Received in revised form 14 January 2020; Accepted 22 January 2020 Available online 26 January 2020 1773-2247/ © 2020 Elsevier B.V. All rights reserved.
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Fig. 1. Samples characterization: SEM images of TNTs (A1) and TNTs-PDA (A2); tube diameter distribution of TNTs (B1) and TNTs-PDA(B2); TEM images of TNTs (C1) and TNTs-PDA (C2); AFM images of TNTs (D1) and TNTs-PDA (D2); (E) Z potential of TNTs, PDA, TNTs-PDA.
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2.3. Biomineralization experiment Biological activity of the prepared samples was evaluated by placing prepared samples into simulated body fluid (SBF) at 37 °C for an indicated time and SBF was replaced every day. The structure and morphology of the prepared samples were characterized by field emission scanning electron microscope (SEM). 2.4. Cell experiment Frozen mouse embryonic osteoblast cells (MC3T3) were thawed and seeded onto culture dishes containing in α-minimum essential medium (α-MEM) containing 10% (v/v) fetal bovine serum (FBS) and 1% (v/v) penicillin/streptomycin (P/S), cultured in an aseptic incubator of 5% CO2 at 37 °C. Once cells reached confluency, they were used for the following experiments. MC3T3 and growth medium were cultured onto TNTs, TNTs-PDA at an initial seeding density of 3 × 103 cells/cm2 and cultured for one and three days, respectively. Then, 10 μL CCK-8 were added to per well at 37 °C for 2 h. Finally, the solution was transferred to a 96-well plate and was measured at 450 nm using the enzyme labeling instrument.
Fig. 2. FTIR spectra of samples showing (a) TNTs; (b) TNTs-PDA.
and other reactive sites would remain on the PDA surface, which provided active groups for secondary reaction on the functionalized surface [14]. Therefore, dopamine was selected to modify the nanotubes in this study, it can promote loading and sustained release of the drugs due to its ability to enhance interactions between the nanotubes and the drugs.
2.5. Drug loading and release Solutions of ibuprofen (IBU; 30 mg/mL) with ethanol were prepared and transferred to reaction vessels. Subsequently, the TNTs-PDA samples were immersed in ibuprofen solutions. After 6 h, TNTs-PDA loaded IBU was rinsed with distilled water. Then samples were placed into 10 mL phosphate buffer solution (PBS) for 15 days. The release solutions were taken out by removing a certain volume of the solution and adding fresh PBS into tubes with the same volume. The concentration of released drug in PBS was measured using ultraviolet spectrophotometer at 264 nm and calibrated with the standards curve of known concentrations.
2. Experiments 2.1. Preparation of TNTs The titanium sheet was submerged into the electrolytic solution comprising of water (10 vol%), glycerol, and 0.5 wt% NH4F. The titanium sheet was served as the positive, and platinum as the cathode. The distance between the two was 1 cm and oxidized under a constant voltage of 60 V for 24 h. Subsequently, the pretreated titanium sheet was calcined at 450 °C for 2h in a muffle furnace.
2.6. Characterization The surface morphologies of the prepared samples were characterized using field emission scanning electron microscope (FESEM), transmission electron microscope (TEM) and atomic force microscopy (AFM). The potential of samples was detectived by zeta potential analyzer at room temperature. The vibration spectrum of the samples was measured by Fourier transform infrared (FTIR) spectra the resolution was 4 cm−1 and the scans times was 64. The hydrophobicity of the sample was analyzed by water contact angles (WCA); The phase composition of the samples was analyzed by X-ray diffraction (XRD), and the XRD test conditions was as follows: copper target
2.2. TNTs decorated with polydopamine (TNTs–PDA) To produce PDA-decorated TNTs, The above nanotubes were hydroxylated by submerging in 0.5 M NaOH solution for 30 min and led to the formation of TNTs-OH. Briefly, to facilitate dopamine solution diffusion inside the nanotubes, the treated nanotubes were immersed into dopamine hydrochloride (1 mg/mL) with Tris-HCl solution (1.2 mg/ mL, pH = 8.5) using an ultrasonic bath for 12 h. The prepared samples were designated as TNTs-PDA.
Fig. 3. WCA of samples showing (a) TNTs; (b)calcined TNTs; (c) TNTs-OH; (d)TNTs-PDA. 3
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Fig. 4. (A) The mechanism for self-polymerization of dopamine; (B) Scheme of the procedure for TNTs modification with PDA.
Fig. 5. XPS spectra of samples showing (A) wide-scan spectrum; (B,C,D) high resolution spectra of C1s, O1s, N1s: (a)TNTs-PDA; (b)TNTs.
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TNTs, the structure of TNTs-PDA was not changed obviously, while its surface was rougher (Fig. 1-D), the diameter and wall of the pipe all became smaller and thicker (Fig. 1-A, B). The average pore size of TNTs was 216 ± 10 nm, while TNTs-PDA was reduced to 158 ± 10 nm (Fig. 1-B). The zeta potential value of TNTs, PDA and TNTs-PDA were −3.74 mV, 5.38 mV, 2.5 mV, respectively. The zeta potential analysis, shown in Fig. 1-E. There was positive charge on the surface of TNTsPDA, attributing to the presence of the partial deprotonation when it was selfpolymerized. 3.1.2. FTIR analysis of samples Fig. 2 illustrates the infrared spectra of TNTs (Fig. 2 a) and TNTsPDA (Fig. 2 b). The broad absorption peak at 3436 cm−1 was attributed to the stretching vibration of –OH. The absorption peaks at 2919 cm−1 and 2852 cm−1 were assigned to –CH2 asymmetric stretching vibration and –CH2 bending vibration, respectively. And the sharp band at 1624 cm−1 [15,16] was the characteristic peak of PDA, ascribed to N–H stretching vibration. In addition, the absorption peaks at 1498 cm−1 were attributed to C]C bending vibration, which indicated that polydopamine was successfully and completely covered TiO2 nanotube arrays.
Fig. 6. TG curves of the samples showing (a) PDA; (b) TNTs-PDA.
(λ = 0.15406 nm), tube pressure 40 kV, tube flow 40 mA, scanning rate 3°/min, step 0.02°. The anode target of X-ray photoelectron spectroscopy (XPS) was Al target, the vacuum degree was 1486.6 eV, sample chamber was kept at 2 × 10−7 Pa, and the photoelectron incident angle was 20°. The surface element composition and chemistry of the samples were measured by X-ray photoelectron spectroscopy (XPS). 10°/min was chosen for the temperature raising rate of the thermogravimetric analyzer (TGA), and the change of the samples mass during the heating process was detected under the atmosphere of nitrogen. The amount of drug release in PBS was measured by UV–vis spectrophotometer (UV). The absorbance of the solution was measured at 450 nm using enzyme-labeled instrument (Bio-Rad, Japan), and the cell proliferation ability of the sample was analyzed.
3.1.3. Water contact angles analysis of samples Water contact angle (WCA) of TNTs (Fig. 3 A), calcined TNTs (Fig. 3 B), TNTs-OH (Fig. 3C) and TNTs-PDA (Fig. 3 D) were performed as illustrated in Fig. 3. TNTs (Fig. 3 A) was superhydrophilic materials and its WCA < 5°. After the calcination, the hydrophilicity of the TNTs decreased, owing to the dehydration and condensation of hydroxyl groups on the surface of the nanotubes. After hydroxylation of calcined TNTs (Fig. 3C), the WCA of the sample became smaller, indicating that the hydrophilicity of the sample was improved. This was mainly due to the large amount of hydroxyl groups on the surface of calcined TNTs after hydroxylation. Compared with the TNTs-OH, the hydrophilicity of polydopamine was weaker, and with the increase of the modification amount of polydopamine, the hydrophilicity of the samples decreases, while the WCA increases. The WCA of TNTs-PDA (Fig. 3 D) increased from 11.6° to 34.7°. The change of WCA on the surface of different
3. Results and discussion 3.1. Preparation of TNTs-PDA 3.1.1. Morphological analysis of samples The morphology of TNTs and TNTs-PDA was observed by SEM, TEM and AFM. Fig. 1 displays the morphology of the samples. Compared to
Fig. 7. SEM images of samples TNTs-PDA soaked in SBF for different time (A) 0 day; (B) 2 day; (C) 5 day; (D) 7 day. 5
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Fig. 8. SEM images of different samples immersed in SBF for 2 days showing (A) TNTs; (B) TNTs-PDA.
Fig. 10. Cell viabilities of MC3T3 cultured onto different substrates after one and three days of culture.
polymerized through deprotonation and intermolecular Michael addition to form physical trimer [17,18]. Thus, dopamine exhibited multiple functional groups during self-polymerization with the molecular driving forces of π-π bonding, hydrogen bonding, van der Waals to formed supermolecular polymers [19], which were facilely deposited onto TNTs with high binding strength[20.21], and further conjugated target molecules through simple chemistry [20–22]. Fig. 4 B schematically describes the deposition of PDA onto TNTs. With regard to the dopamine polymerization mechanism, amine groups, phenolic groups, and other reactive sites would remain on the PDA surface [23,24], which may interact with the TNTs or drugs through adsorption or covalent linking. XPS analysis displays the survey scan spectra of samples as shown in Fig. 5. An new peak of N1s at 401.6 eV was observed on the surface of TNT–PDA (Fig. 5 A-a), indicating that polydopamine was successfully introduced on TNTs. Fig. 5 B shows C1, C2, and C3 peaks appeared in C1s of TNTs (Fig. 5 B-b) spectrum, corresponding to CHx (284.53 eV), C–O (286.0 eV), C]O (288.4 eV) bonds, respectively. TNTs-PDA (Fig. 5 B-a) also presented three peaks at 284.57 eV, 286.1 eV, and 288.1 eV, belonging to C–H/C–C, C–O/C–H, and C]O bonds, respectively [25]. The characteristic peak strength and peak area of C1s enhanced remarkably, which may be attributed to the uniform modification of polydopamine on the surface of the samples to increase the content of the C element. Compared with TNTs (Fig. 5 C-b), new peaks of TNTsPDA (Fig. 5 C-a) appeared at 532.75 eV and 531.62 eV, corresponding to phenolic hydroxyl (-C-OH) and quinone (-C]O) of polydopamine, respectively. The binding energies of N 1s (Fig. 5 D-a) peaks were 399.7 eV and 401.6 eV, indicating that N on the surface of the prepared samples predominantly existed in the amino group and partially in amino protonation forms. Collectively, these results indicated that PDA was successfully modified on TNTs.
Fig. 9. FTIR spectra and XRD patterns of the samples showing (a) TNTs-PDA; (b) TNTs-PDA-HA.
samples indirectly confirmed that the polydopamine layer was successfully uniformly introduced on the surface of TNTs [19]. 3.1.4. XPS analysis of samples The self-polymerization of PDA remains complex and the limitations of detection methods thus proposed different PDA formation mechanisms in the existing literature. Based on the experimental findings and theoretical conjecture, it is generally believed that the mechanism raised due to multiple physical and chemical interaction was more comprehensive [17]. Fig. 4 A presented the physical and chemical reaction behind the self-polymerization of dopamine. The polymerization began with the oxidation of dopamine to dobutamine with the subsequent nucleophilic addition reaction to form catecholamine. After rearrangement, the intermediate product (5, 6-dihydroxyindole) 6
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3.2. Mineralization experiment of samples In order to establish complete osseointegration, the implant must exhibit excellent biological activity and the ability to induce the formation of well-developed bone-like apatite formation. Fig. 7 presented the SEM images of TNTs-PDA soaked in SBF for 0, 2, 5, and 7 days, respectively. Apatite film was formed on the surface of TNTs-PDA,. With the increase of immersion days, the spherical hydroxyapatite became larger and more uniform, suggesting TNTs-PDA with excellent biomineralizationm ability. SEM images of TNTs and TNTs-PDA immersed in SBF for 2 days were shown in Fig. 8. There was only little hydroxyapatite film formed on the surface of TNTs (Fig. 8 A) for 2 days, while large hydroxyapatite was appeared on the surface of TNTs-PDA (Fig. 8 B), indicating that the biomineralization ability of the sample was greatly improved. Thanks to the surface of the sample with plenty of phenolic hydroxyl groups and amido, which was beneficial to the adsorption of Ca2+ and promoted the nucleation of hydroxyapatite on the surface of the sample, improving the biomineralization ability of the sample [27]. Furthermore, to study the apatite film formed on the surface of TNTs-PDA, the samples were characterized by FTIR and XRD, shown in Fig. 9. The absorption peaks appeared at 3425 cm−1 and 1636 cm−1 were corresponded to hydroxyapatite adsorbing water. The sharp band at 1036 cm−1 was ascribed to the stretching vibration absorption peak of PO43− and the bending vibration absorption peaks of PO43− were observed at 567 cm−1 and 604 cm−1. In the XRD (Fig. 9 B-b), the characteristic diffraction peak of the hydroxyapatite was presented at about 32°. Taken together, the findings indicated that hydroxyapatite fabricated on the surface of the prepared samples. 3.3. Samples cell test To examine proliferation of MC3T3 on the TNTs and TNTs-PDA, CCK-8 assay was employed in this study. Fig. 10 Shows the viability of MC3T3 grown on TNTs and TNTs-PDA after one and three days of culture. Compared to TNTs, the absorbance of TNTs-PDA showed higher after one and three days of culture, indicating that cells cultured on TNTs–PDA exhibited significantly higher cell viability.
Fig. 11. FTIR spectra and XRD pattern of samples showing (a) IBU; (b) TNTsPDA; (c) TNTs-PDA-IBU.
3.4. XRD and FTIR analysis of the samples after drug loading IR and XRD were employed to characterize the sample of TNTs-PDA loaded drugs, as shown in Fig. The strong peaks at 2871 cm−1, 2922 cm−1 and 2955 cm-1 were characteristic symmetric and asymmetric stretching vibrations of alkylchain of ibuprofen in Fig. 11 A-c. In addition, the absorption peaks appeared at 779 cm−1 and 1508 cm−1 corresponded to C–H and C]C on the benzene ring of IBU, and 1719 cm−1 was the telescopic vibration peak of the carbonyl group of IBU. In contrast to the XRD pattern of pure IBU, the XRD pattern of IBU loaded TNTs-PDA exhibited characteristic peaks at about 6.08°, 12.21°, 16.7°, 20.19°, respectively(JCPDS Card. 32–1723). Thus, confirming the successful loading of the drug on the prepared samples. The FTIR spectrum and XRD pattern of IBU loaded TNTs-PDA indicated that drugs were successfully loaded (Fig. 11).
Fig. 12. Drug release curves of the samples: (a) TNTs-IBU; (b) TNTs-PDA-IBU.
3.1.5. TG analysis of samples Thermogravimetric analysis of the prepared samples was performed in the range between 30 °C and to 600 °C, as shown in Fig. 6. Both the samples showed weight loss between 200 °C and 500 °C. TNTs-PDA (Fig. 6 b) exhibited a continuous weight loss from 30 °C to 300 °C, which was mainly caused due to desorption of adsorbed water on the samples surface, the condensation, and dehydration of hydroxyl groups on the sample surface. While between 300 °C and 450 °C, there was an apparent weight loss peak, which mainly corresponded to the decomposition of polydopamine [26], and the weight loss was near to 10 wt%.
3.5. In vitro release of IBU PBS (pH = 7.4) was used to investigate drug release profiles. The drug release curves of the samples were shown in Fig. 12. In the initial burst release stage, the drugs loaded in the upper part of the tubes and adsorbed on the surface were released rapidly into PBS. The physically adsorbed drugs on samples surface resulted in an initial burst release and followed by a sustained release. The released percentage of IBU from TNTs in the burst release stage was about 55.3% (Fig. 12a) (the drug accumulation of the sample released in PBS buffer solution for 15 days was taken as the total release amount). However, the released 7
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Fig. 13. Kinetic fitting of drug release at different stages: (A) initial stage; (B) slow release stage.
Declaration of competing interest
percentage from TNTs–PDA in this stage was about 28.16% (Fig. 12b). In the later stage of drug release, ibuprofen mostly released from the inner wall of the nanotubes. Furthermore, the released amount of ibuprofen significantly increased at this stage for TNTs–PDA. It was possible that the surface of TNTs-PDA existed active sites for amino radical, protonated amino group, which may form an electrostatic interaction with the drug ibuprofen. And it was beneficial to the adsorption of the drug molecules. The results showed that PDA modified TNTs contributed to reduce the sudden release and prolong the drug release. In order to study the release kinetics of drug release phase, the release curve was fitted with the zero-, first-order kinetic equations and Higuchi equation. The results indicated that the release of drugs from TNTs-PDA loaded system in the initial stage (before 12 h) was mainly attributed to the drugs loaded in the upper part of the tubes and adsorbed on the surface, and the fast release rate in accordance with the first-order kinetic equation
(
[ ln 1 −
Mt M∞
The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. Acknowledgments This research was funded by National Natural Science Foundation of China of China(21805037), Fujian Province Nature Science Foundation (2016Y0025, 2017J01685,2018J01363), Fuzhou Science and Technology Project (2017-G-61, 2018-G-90). References
) = −0.19333x − 0.12309,
[1] M. Purvya, M. Meena, A review on role of nanostructures in drug delivery system, Rev. Adv. Mater. Sci. 32 (2011) 20–67. [2] B.P. Kumar, I.S. Chandiran, B. Bhavya, M. Sindhuri, D. Pharmaceutics, G. Krishna, Indian journal of pharmaceutical science & research microparticulate drug delivery system: a review, Indian J. Pharmaceut. Sci. Res. 1 (2011) 19–37. [3] A.Z. Wilczewska, K. Niemirowicz, K.H. Markiewicz, H. Car, Nanoparticles as drug delivery systems, Pharmacol. Rep. 64 (2012) 1020–1037. [4] N. Khoshnood, A. Zamanian, A. Massoudi, Effect of silane-coupling modification on bioactivity and in vitro properties of anodized titania nanotube arrays, Mater. Lett. 185 (2016) 374–375. [5] T.M. Tian, H. Dong, X. Tian, Y. Hao, Fabricated antibacterial and bioactive titania nanotube arrays coating on the surface of titanium, Saf. Sci. Technol. 20 (2013) 59–62. [6] K. Vasilev, Z. Poh, K. Kant, J. Chan, A. Michelmore, D. Losic, Tailoring the surface functionalities of titania nanotube arrays, Biomaterials 31 (2010) 532–540. [7] K.S. Mun, S.D. Alvarez, W.Y. Choi, M.J. Sailor, A. stable, label-free optical interferometric biosensor based on TiO2 nanotube arrays, Nano 4 (2010) 2070–2076. [8] H. Li, Q. Cui, B. Feng, J. Wang, X. Lu, J. Weng, Antibacterial activity of TiO2 nanotubes: influence of crystal phase morphology and Ag deposition, Appl. Surf. Sci. 284 (2013) 179–183. [9] N. Abbas, G.N. Shao, M.S. Haider, S.M. Imran, S.S. Park, S.J. Jeon, H.T. Kim, Inexpensive sol-gel synthesis of multiwalled carbon nanotube-TiO2 hybrids for high performance antibacterial materials, Mater. Sci. Eng. C 68 (2016) 780–788. [10] K. Gulati, M.S. Aw, D. Findlay, D. Losic, Local drug delivery to the bone by drugreleasing implants: perspectives of nano-engineered titania nanotube arrays, Ther. Deliv. 3 (2012) 857–873. [11] A. Roguska, M. Pisarek, A. Belcarz, L. Marcon, M. Holdynski, M. Andrzejczuk, M. Janik-Czachor, Improvement of the bio-functional properties of TiO2 nanotubes, Appl. Surf. Sci. 6 (2016) 354–378. [12] L. H, Mussel-inspired surface chemistry for multifunctional coatings, Science 318 (2007) 426–430. [13] B. M, The reduction of Ag+ in metallic silver on pseudomelanin films allows for antibacterial activity but does not imply unpaired electrons, J. Colloid Interface Sci. 10 (2018) 7649–7660. [14] X. M, Mussel-inspired bioactive ce-ramics with improved bioactivity cell proliferation differentiation and bone-related gene expression of MC3T3 cells, Biomater. Sci. 1 (2013) 933–941. [15] J.W. Fu, Z.H. Chen, M.H. Wang, Adsorption of methylene blue by a high-efficiency adsorbent (polydopamine microspheres): kinetics, isotherm, thermodynamics and mechanism analysis, Chem. Eng. 259 (2015) 53–61. [16] S.D. Ma, J. Feng, W.J. Qin, CuFe2O4@ PDA magnetic nanomaterials with a coreshell structure: synthesis and catalytic application in the degradation of methylene blue in water, RSC Adv. 5 (2015) 53514–53523.
R2 = 0.97135 Fig. 13A]. In the sustainable release stage (after 12 h), the cumulative release rate gradually increased, the release mechanism was weak diffusion, and the release effect was good in agreement with the Higuchi equation ( Mt =0.04513t1/2, R2 = 0.98451 Fig. 13B) [28], M∞ Where Mt denoted the amount released during the time, M∞ defined the total amount of complete release, Mt provided the released rate at inM∞ dicatedtime and k was the release constant.
4. Conclusions In this work, polydopamine was successfully modified TiO2 nanotube arrays by ultrasonic method. According to the mechanism of dopamine polymerization, amino groups, phenolic groups and other reactive sites would remain on the PDA surface during polymerization. These functional groups may increase drugs loading and prolong drug release by adsorption or covalent bond interaction with drugs. The experimental results demonstrated that the release curve was fitted with the first order kinetic equation at initial stage and the Higuchi equation at slow release stage. The results of biomineralization experiments showed that polydopamine promoted the nucleation of hydroxyapatite on the surface of samples, and improving biomineralization capacity of the samples. Finally, The cell viability of MC3T3 was enhanced by PDA functionalized TNTs.
CRediT authorship contribution statement Lifen Li: Conceptualization, Methodology, Writing - original draft. Chunling Xie: Formal analysis, Methodology, Investigation. Xiufeng Xiao: Supervision, Conceptualization, Writing - review & editing. 8
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[23] Y. Yang, P. Qi, Y. Ding, M.F. Maitz, Z. Yang, Q. Tu, K. Xiong, Y. Leng, N.A. Huang, Biocompatible and functional adhesive amine-rich coating based on dopamine polymerization, Mater. Chem. 3 (2015) 72–81. [24] R. Luo, L. Tang, S. Zhong, Z. Yang, J. Wang, Y. Weng, Q. Tu, C. Jiang, N. Huang, In vitro investigation of enhanced hemocompatibility and endothelial cell proliferation associated with quinone-rich polydopaminecoating, Appl. Mater. Interfaces 5 (2013) 1704–1714. [25] S. Syafiqah, C. Pascale, Polydopamine as an intermediate layer for silver and hydroxyapatite immobilisation on metallic biomaterials surface, Appl. Catal. 8 (2013) 0928-4931. [26] K. Negin, Z. Ali, Mussel-inspired surface modification of titania nanotubes as a novel drug delivery system, Appl. Catal. 10 (2017) 0928-4931. [27] Z.G. Wang, J.Q. Zeng, G.X. Tao, J.W. Liao, L. Zhou, J.Q. Chen, P. Yu, G.Y. Wang, C.Y. Ning, Incorporating catechol into electroactive polypyrrole nanowires on titanium to promote hydroxyapatite formation, Bioactive Mater. 3 (2017) 74–79. [28] A. Jain, S.K. Jain, In vitro release kinetics model fitting of liposomes: an insight, Chem. Phys. Lipids 201 (2016) 28–40.
[17] Y. Ding, L.T. Weng, M. Yang, Z. Yang, X. Lu, N. Huang, Y. Leng, Insights into the aggregation/deposition and structure of a polydopamine film, Appl. Catal. 30 (2014) 12258–12269. [18] J.S. Cai, J.Y. Huang, Immobilization of pt nanoparticles via rapid and reusable electropolymerization of dopamine on TiO2 nanotube arrays for reversible sers substrates and nonenzmatic glucose sensors, Appl. Catal. 13 (2017) 160–240. [19] Y. Yang, X.Y. Li, H. Qiu, Polydopamine modified TiO2 nanotube arrays for longterm controlled elution of bivalirudin and improved hemocompatibility, Appl. Catal. 10 (2018) 7649–7660. [20] Y. Liu, K. Ai, L. Lu, Polydopamine and its derivative materials: synthesis and promising applications in energy, environmental, and biomedical fields, Chem. Rev. 114 (2014) 5057–5115. [21] G. Pan, S. Zhang, W. Zhao, R. Cui, W. He, F. Huang, L. Lee, S. Shea, K.J. Shi, Q. Yang, Design of mussel-derived bioactive peptides for dual-functionalization of titanium-based, Biomaterials. Am. Chem. Soc. 138 (2016) 15078–15086. [22] L. Cheng, X. Sun, X. Zhao, L. Wang, J. Yu, G. Pan, B. Li, H. Yang, Y. Zhang, W. Cui, Surface biofunctional drug-loaded electrospun fibrous scaffolds for comprehensive repairing hypertrophic scars, Biomaterials 83 (2016) 169–181.
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