Abstract
Abstract
Context: Pirfinedone (PFD) is a novel agent which has the potential to prevent scarring in the eyes. The 0.5% PFD eye drops exhibits poor bioavailability. Whereas, the feasibility of using contact lens as ocular drug delivery device initiated novel possibilities.
Objective: To evaluate the delivery of PFD by soft contact lens (SCL) in vivo, we screened the most suitable lens material for PFD among various commercially available SCL materials in vitro.
Material and methods: Firstly, 11 different SCLs (−1.00 diopter) were respectively soaked in 2 ml of 0.05% PFD-loading solution for 24 h to fully absorb drug, and then placed in fresh phosphate buffered saline (PBS) to release the drug. PFD concentration in PBS was determined by ultraviolet absorbance at 310 nm. Secondly, by immersing in 2 ml of 0.5% PFD eye drops for 24 h, the polymacon lens (0.00 diopter) was then placed on the cornea of New Zealand rabbits. PFD concentrations were detected by high performance liquid chromatography (HPLC) in tears, aqueous humor, conjunctiva, cornea, and sclera at different time points.
Results: PFD showed some affinity for pHEMA-based lenses and the polymacon lens more slowly released more amount of PFD than any other lens in vitro (p < 0.001). Compared with eye drops, drug-loaded SCLs greatly enhanced the retention time and concentrations of PFD in cornea and aqueous humor and consequently improved the bioavailability of PFD.
Conclusion: Polymacon-based SCL is probably a promising vehicle to be an effective ophthalmic delivery system for PFD.
Introduction
Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone, PFD) is a novel broad-spectrum anti-fibrotic drug, which has played an important role in various organs such as the lung, kidney, and liver (Raghu et al., 1999; Hewitson et al., 2001; Di Sario et al., 2002; Azuma et al., 2005). Our research team had firstly developed ophthalmic solution of PFD for ocular administration (patent number: CN 201110228845). By local application, PFD had exhibited therapeutic activity in treating corneal chemical burns (Chowdhury et al., 2013) and preventing drainage channel obstruction following glaucoma filtration surgery (Zhong et al., 2011). However, as a consequence of epithelial membrane barriers, nonproductive absorption, and nasolachrymal drainage, only 1–7% of the actual medication in a drop is productively absorbed into the eye (Lang et al., 1995). In spite of its safety to eyes (Zhong et al., 2011), the 0.5% PFD eye drops exhibits short half-life and the same poor bioavailability as many other ophthalmic solutions (Sun et al., 2011).
As we all know, to improve the ocular bioavailability, it is apparently crucial to enhance the pre-corneal retention time of drug (Mahomed & Tighe, 2014). The feasibility of using contact lens as drug delivery system initiated novel possibilities (Gasset & Kaufman, 1970; Kompella et al., 2010). The use of contact lens for drug delivery can be traced back to 50 years ago (Gonzalez-Chomon et al., 2013). Being placed onto cornea, drug-loaded contact lens can increase the amount of drug passing through cornea and decrease the amount of drug inflowing into the nasolacrimal duct (Gonzalez-Chomon et al., 2013; Guzman-Aranguez et al., 2013). Therefore, contact lens is a promising potential vehicle for ocular drug delivery.
Nevertheless, not all contact lenses are suitable for drug delivery. The interaction between lens materials and drug was proved to be important to the uptake and release of contact lens (Gonzalez-Chomon et al., 2013; Phan et al., 2013; Mahomed & Tighe, 2014). The lens which shows a moderate affinity for the target drug will be a good vehicle for ocular delivery. The low affinity will decrease the uptake and release, whereas too strong affinity would increase only the uptake not the release (Gonzalez-Chomon et al., 2013).
We expect drug-loaded contact lens to improve the ocular bioavailability of PFD. Thus, the aim of this study was to select the most suitable lens material for PFD from 11 different commercially available soft contact lens (SCL) materials, and then, investigate the drug release of the selected lens material in vivo and the ocular distribution of PFD. Lastly, we could evaluate the practicality of ocular delivery of PFD by contact lens.
Materials and methods
Materials
As described in Table 1, 11 different commercially available contact lenses (−1.00 diopter) were used in this study. Additionally, the polymacon lenses (0.00 diopter) were friendly supplied by the Hydron Contact Lens co., LTD (Shanghai, China). Pirfenidone and ethyl 4-aminobenzoate were purchased from Sigma- Aldrich Co. (St. Louis, MO). Phosphate buffered saline (PBS) was supplied by the Gino Biological Pharmaceutical Technology co., LTD (Hangzhou, China). With Pirfinidone dissolved in PBS at a concentration of 0.050% (w/v, 0.5 mg/ml), the uptake solution of SCLs in in-vitro studies was made. Furthermore, the 0.5% (w/v) PFD eye drops was made as reported by the manufactory laboratory of Zhongshan Ophthalmic Center (Sun et al., 2011). Methanol and acetonitrile were chromatographic grade (Burdick & Jackson, Morristown, NJ). Perchloric acid was supplied by Weijia Science and Technology Ltd. (Guangzhou, China). Water was ultra-pure (electric resistance ≥18.2Ω) which was made by Milli-Q Synthesis of the Millipore Company (Molsheim, France).
Table 1. Details of contact lenses used in this study.
Animals
Male and female albino rabbits weighting 2–2.5 kg were obtained from Medical Laboratory Animal Center, Guangdong Province, China (License number: SYXK 2010-0058). The experiment was conducted according to the ARVO (Association for research in vision and ophthalmology) statement for the use of animal in ophthalmic and vision research. And it was approved by the Ethics committee of animals in Zhongshan ophthalmic center, Guangzhou, China (the protocol number of the Ethics committee approval: SYXK 2015-013). All the animals were individually housed in clean cages at 20 °C and relative humidity of 50%. All animals were acclimatized for at least one week before use, and their eyes were carefully observed with a slit lamp to rule out observable ocular abnormalities. One week of washout period was incorporated in between any two successive studies.
Determination of PFD concentration in PBS
By muti-wavelength (200–600 nm) scan of 100 μl PFD-PBS solution with PBS as the blank control, the absorption maxima of PFD was found to be at 310 nm by UV-1601 spectrometer (Shimadzu, Kyoto, Japan). Therefore, the wavelength was used to determine the absorption values of PFD in PBS. The prepared uptake solution was diluted with fresh PBS to a range of concentrations (1.00, 5.00, 10.00, 15.00, 20.00, 25.00 μg/ml), and then a linear standard curve with R2 values of 0.999 was created by the correlation of absorbance readings and PFD concentrations.
In vitro uptake
The simple soaking method used in this study was reported to be very effective in drug loading (Tieppo et al., 2014). Three lenses of each type were removed from the packing and separately soaked in 5 ml fresh PBS with gently shaking (50 rpm/min) for five hours to remove any packing solution. And then, the lenses were removed out, partially dried on a blotting paper and placed respectively in an individual vial containing 2 ml of 0.05% PFD-PBS solution with gently shaking (50 rpm/min) to load PFD at room temperature. Lastly, after 24 h of uptake, 100 μl of the loading solution was diluted to obtain an absorbance reading by the UV spectrometer, and then the amount of uptake was calculated by the concentration difference of PFD between the initial and final loading solution.
In vitro release
According to the reported studies (Tieppo et al., 2014), the releasing solvent was replaced regularly by fresh PBS to reach a desired sink condition in our study. The details of the experiment were described as follows. After the uptake studies, the lens was removed into 5 ml fresh PBS shortly and partially dried on a blotting paper. Then the lens was placed into 2 ml fresh PBS with gently shaking (50 rpm/min) and was removed from the release solution at time points (15, 30, 60, 90 min). After being partially dried on a blotting paper, the lens was placed promptly into 2 ml fresh PBS again. All the experiments were performed in triplicate at room temperature. PFD concentration in the release solution was measured with the UV spectrometer at 310 nm.
Drug administration and sample collection in vivo
By soaking in 2 ml of 0.5% PFD eye drops for 24 h, the polymacon SCL (0.00 dioptor) was loaded with PFD. Then the SCL was removed from the drops and partially dried with blotting paper, the drug-loaded ploymacon SCL was applied quickly onto the cornea of right eye, and the 30 μl of 0.5% PFD eye drops was instilled into the conjuctival sac of the left eye as a control. At the following time intervals: 2, 15, 30, 45, 60, 90, 120, 150 min, 1 μl of tear fluid was collected from the lower marginal tear strip by glass capillary. The capillary was flushed three times in 40 μl ultra-pure water, and then, 10 μl of 10% perchloric acid was added to precipitate the protein. Tear samples were centrifuged at 12 000 r/min for 15 min and the supernatants were stored at −4 °C for high performance liquid chromatography (HPLC) analysis.
Following the above-mentioned drug administration, four animals were killed by an intravenous injection of overdosed pentobarbital (100 mg/kg) at each of the regular time intervals: 8, 60, 90, 150, 240 min. The samples of conjunctiva, cornea, sclera, aqueous humor were immediately separated and weighted, and stored at −20 °C. Aqueous humor (100 μl) samples were mixed with 50 μl 10% perchloric acid, and centrifuged at 12 000 r/min for 15 min, and the supernatants were stored at −4 °C for HPLC analysis. Whole bulbar conjunctiva, whole cornea and sclera were homogenized with 0.8 ml methanol and 50 μl (20 μg/ml) ethyl 4-aminobenzoate (internal standard, IS). Each mixture was centrifuged at 12 000 r/min for 15 min. The supernatants were extracted, evaporated by flowing hot air, resolved with 0.2 ml methanol, and then centrifuged at 12 000 r/min for 15 min. Supernatants were used for HPLC analysis.
HPLC analysis of PFD concentration in samples
All the samples were measured by the same HPLC condition. The system consisted of a LC-20AT separation module (Shimadzu, Kyoto, Japan) and a SPD-20A UV detector (Kyoto, Japan). The HPLC separation was performed on a Luna 5-μm C18 column (150 mm × 4.6 mm; Phenomenex, Torrance, CA). Twenty microliters of each sample was injected into the column which was set at room temperature. The mobile phase consisted of a mixture of 35% (A) acetonitrile and 65% (B) ultra-pure water. The flow rate was set at 1 ml/min and the UV absorbance detector was set at 314 nm according to muti-wavelength scan. The retention time of PFD and IS were ∼4.3 and ∼7.4 min, respectively.
The standard curve of PFD in tear samples was linear over the concentration range from 0.392 to 39.216 μg/ml (R2 = 0.999). Similarly, the PFD concentration range of aqueous humor samples was 0.313–37.500 μg/ml (R2 = 0.999), and conjunctiva, cornea, sclera had the same concentration range of 0.500–37.500 μg/ml (R2 = 0.999).
Ocular irritation evaluation
Ocular irritation studies were performed on eight rabbits according to the Draize eye test (Wilhelmus, 2001). The drug-loaded ploymacon SCL was placed onto the cornea of right eye 6 h a day for one week, and the 30 μl of PBS was applied to the left eye as a control. The conjunctiva, cornea and iris were observed carefully with a slit lamp for any abnormalities at regular intervals.
Statistical analysis
If data comparisons were needed, statistical analysis was performed using a one-way ANOVA. If p ≤ 0.05, differences were considered significant. Unless mentioned, the results are presented as the mean ± standard deviation (SDs).
Results
In vitro studies
During the whole study, all of the 11 different lenses remained clear and transparent. The total uptake and release of PFD by the SCLs is exhibited in Figure 1. As shown in Figure 1, none of the lenses totally released the drug. Of all the lenses, both of the polymacon and etafilcon A lenses manifested the greatest uptake (p < 0.001), however, the polymacon material released more drug than the etafilcon A (p < 0.001). Similarly, compared with other lenses, the nelfilcon A and lotrafilcon A lenses demonstrated the significantly least uptake (p < 0.001), nonetheless, only the nelfilcon material released the least drug (p < 0.001). Additionally, the pHEMA-based SCLs (polymacon, hilaficon B, omafilcon A, ocufilcon A, etafilcon A) obviously released greater (p < 0.001) amount of PFD than the silicone hydrogel SCLs (lotrafilcon A, lotrafilcon B, balafilcon A, senofilcon A, galyfilcon A).
Published online:
17 July 2016Figure 1. PFD absorbed and desorbed by various lens materials in vitro. The data is plotted as the mean ± SDs (n = 3).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/idrd20/2016/idrd20.v023.i09/10717544.2016.1204570/20161201/images/medium/idrd_a_1204570_f0001_b.jpg"})
Figure 1. PFD absorbed and desorbed by various lens materials in vitro. The data is plotted as the mean ± SDs (n = 3).
All lenses were observed to finish the release of PFD within one hour and their release profiles are shown in the Table 2. Whereas, the polymacon lens more gradually released PFD than any other lens in the first 30 min (p < 0.001). The nelfilcon lens almost finished its release in the first 15 min and showed the sharpest release curve (p < 0.001).
Table 2. The details of the cumulative release of PFD by various lens materials with each lens soaked in 2 ml 0.50 mg/ml PFD-PBS solution.
In vivo studies
Because the polymacon material more gradually released more amount of PFD than any other commercially available SCLs materials, we selected it as the carrier to deliver PFD to eyes. By soaking in 2 ml of 0.5% PFD eye drops for 24 h, the polymacon lens with zero diopter was respectively prepared for the in vivo study. Every lens released the total of 1147.60 ± 73.19 μg PFD (according to “In vitro release”).
Six rabbits were studied the PFD concentration in tear fluid at different time points with the drug loaded lens onto the right eye and the 30 μl of 0.5% PFD eye drops to the left eye as a control. The concentrations of PFD in tear fluid are illustrated in Figure 2. Following administration of PFD eye drops, the PFD concentration in tear fluid rapidly dropped to 127.59 ± 31.15 μg/ml at 2 min and no PFD was further monitored at 15 min. On the other hand, the drug-loaded SCL exhibited a smoother concentration curve as shown in Figure 2. The PFD concentration was 865.94 ± 83.50 μg/ml at 2 min and decreased to 482.53 ± 83.50 μg/ml at 15 min, with 6.66 ± 2.97 μg/ml at 150 min.
Published online:
17 July 2016Figure 2. PFD concentrations in tear fluid. The data is plotted as the mean ± SDs (n = 6).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/idrd20/2016/idrd20.v023.i09/10717544.2016.1204570/20161201/images/medium/idrd_a_1204570_f0002_c.jpg"})
Figure 2. PFD concentrations in tear fluid. The data is plotted as the mean ± SDs (n = 6).
Compared with eye drops, the drug-loaded SCL largely enhanced the PFD concentrations of cornea, sclera and aqueous humor in 240 min as shown in Figure 3 (p ≤ 0.02). Excepting the lower concentration at the initial time point (p < 0.001), the PFD concentrations in conjunctiva were also upgraded when treated with SCL (p ≤ 0.02).
Published online:
17 July 2016Figure 3. PFD concentrations in various samples. (A) Cornea; (B) Aqueous humor; (C) Conjunctiva; (D) Sclera. The data is plotted as the mean ± SDs (n = 4).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/idrd20/2016/idrd20.v023.i09/10717544.2016.1204570/20161201/images/medium/idrd_a_1204570_f0003_c.jpg"})
Figure 3. PFD concentrations in various samples. (A) Cornea; (B) Aqueous humor; (C) Conjunctiva; (D) Sclera. The data is plotted as the mean ± SDs (n = 4).
As shown in Figure 4, the polymacon lenses were fit for the eyes of rabbits very well and no abnormalities were observed while they were worn. In the ocular irritation studies, the total value was zero according to the criterion of Draize eye test.
Published online:
17 July 2016Figure 4. Slit-lamp photography of eyes with or without polymacon lenses. (A) Before wearing drug-loaded ploymacon SCL; (B) Fluorescein staining of “A”; (C) With SCL on the cornea, after 10 min of wearing drug-loaded ploymacon SCLs; (D) Fluorescein staining of “C”; (E) Without SCL on the cornea, after wearing drug loaded ploymacon SCL 6 h a day for one week; (F) Fluorescein staining of “E”; (G) With SCL on the cornea, after wearing drug-loaded ploymacon SCL 6 hours; (H) Fluorescein staining of “G”.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/idrd20/2016/idrd20.v023.i09/10717544.2016.1204570/20161201/images/medium/idrd_a_1204570_f0004_c.jpg"})
Figure 4. Slit-lamp photography of eyes with or without polymacon lenses. (A) Before wearing drug-loaded ploymacon SCL; (B) Fluorescein staining of “A”; (C) With SCL on the cornea, after 10 min of wearing drug-loaded ploymacon SCLs; (D) Fluorescein staining of “C”; (E) Without SCL on the cornea, after wearing drug loaded ploymacon SCL 6 h a day for one week; (F) Fluorescein staining of “E”; (G) With SCL on the cornea, after wearing drug-loaded ploymacon SCL 6 hours; (H) Fluorescein staining of “G”.
Discussions
To seek the fittest SCL material for ocular drug delivery of PFD, our study firstly investigated the uptake and release of PFD among 11 different lens materials in vitro. In the following in vivo studies, we selected the polymacon lens as the carrier of PFD. Finally, we found that the polymacon lens had the great potential for ophthalmic delivery of PFD.
The mention of contact lenses as ocular drug delivery device has the history of 50 years (Gonzalez-Chomon et al., 2013). Almost all of the commercially available lenses are made for correction of ametropia. However, this can not hinder investigators to study ocular drug delivery by these existing lens materials (Karlgard et al., 2003; Hui et al., 2008; Boone et al., 2009; Xu et al., 2011; Soluri et al., 2012; Phan et al., 2013; Mahomed & Tighe, 2014; Tieppo et al., 2014). SCLs can greatly increase the amount of drug released to the cornea, so the intraocular drug concentration is largely enhanced (Matoba & McCulley, 1985; Tieppo et al., 2012), which also was exhibited in our studies. Drug-loaded SCLs can simultaneously decrease the amount of drug released in the lachrymal fluid (Gonzalez-Chomon et al., 2013) and consequently lower the drug concentration in it. When treated with drug-loaded SCL, the drug concentration in tear fluid is very low at the original time, which is very different from the initial high level of drug in tear fluid by instillation of eye drops. Furthermore, the drug in the conjunctiva is mainly diffused from the tear fluid. As explained above, the loaded SCL resulted in the lower concentration of PFD in the conjunctiva, compared with PFD eye drops. As we all know that the drug delivery by eye drops has the problem of quickly elimination on the ocular surface (Lang et al., 1995). It was not unexpected to find that no PFD was detected in the tear fluid after 15 min instillation of PFD eye drops.
In spite of an initial burst release, the in vivo release of PFD illustrated a relatively smoother curve and was not the same as the in vitro release. The difference between the conditions of in vitro and in vivo release is so large that the results of the former cannot totally forecast the outcome of the latter (Pitt et al., 2011).
The affinity between drug and lens materials can greatly influence the uptake and release of drug (Karlgard et al., 2003; Hui et al., 2008; Soluri et al., 2012; Gonzalez-Chomon et al., 2013; Mahomed & Tighe, 2014). Moreover, the release percentage was varied in different lens materials, such as the polymacon and etafilcon A, or the nelfilcon A and lotrafilcon A. No matter how tiny the difference of lens materials was, it was critical to affect the drug uptake and release. The different factors mainly include the water content, the iconicity and porosity, and also the surface treatment of lenses (Karlgard et al., 2003; Hui et al., 2008).
Therefore, it is very important to select the lens materials suitable to the target drug in the design of SCL for ocular drug delivery. To seek the fittest SCL material as ocular drug delivery device for PFD, our study investigated the uptake and release of PFD among 11 different lens materials in vitro. All lenses released only a proportion of the absorbed drug which was similar to the previous studies (Karlgard et al., 2003; Hui et al., 2008; Soluri et al., 2012). Based on this, we speculated that PFD partially generated irreversible binding to lens materials. Like the natamycin (Phan et al., 2013), PFD showed greater affinity for the pHEMA-based lenses than the silicon hydrogel lenses in our studies. Similarly to other low molecular weight drugs (Wajs & Meslard, 1986; Karlgard et al., 2003; Hui et al., 2008; Gonzalez-Chomon et al., 2013), PFD was rapidly released by the majority of the lenses within the first hour. And yet, probably for its moderate affinity with PFD, the polymacon lens more slowly released more amount of PFD than any other lenses.
Although the pHEMA-based polymacon material was the fittest one to deliver PFD among the 11 different lenses in this study, the drug-eluting polymacon lens sustained drug release for just about 150 min in vivo. Considering the shorter retention time, we could develop the delivery of PFD by the viable single-day polymacon lens. Because, after all, the PFD retention time in ocular tissue was more than 240 min which was much longer than that of PFD eye drops. Nonetheless, to achieve a longer release time of days or weeks, based on this study, we should employ new approaches to develop new lenses specially for delivery of PFD, such as incorporation of drug-loaded colloidal particles (Gulsen & Chauhan, 2004; Gulsen & Chauhan, 2005; Ali et al., 2014) or molecular imprinting (White & Byrne, 2010).
Conclusions
In general, among the 11 different commercially available lens materials investigated, the pHEMA-based polymacon lens is the most suitable carrier for PFD. By single-day use or being improved through new technology, the polymacon-based SCL is probably a promising vehicle to be an effective ophthalmic delivery system for PFD.
| Classification group | Polymer composition | Monomers | Brand name | Manufacturer | Water content (%) |
|---|---|---|---|---|---|
| I | Polymacon | pHEMA | clear38LE | Clearlab lntermational Pte Ltd | 38 |
| II | Nelfilcon A | modified PVA | DAILIES | CIBA Vision | 69 |
| II | Omafilcon A | pHEMA + MPC | Proclear 1 day | CooperVision Manufacturing Limited | 60 |
| II | Hilaficon B | pHEMA + AMA + NVP | Soflens-59 | Bausch&Lomb | 59 |
| IV | Ocufilcon D | pHEMA + MA | Easy day | HYDRON | 55 |
| IV | Etafilcon A | pHEMA + MA + PVP | 1-DAY ACUVEU MOIST | Johnson&Johnson | 59 |
| III/V | Balafilcon A | NVP + TPVC + NCVE + PBVC | Pure Vision | Bausch&Lomb | 36 |
| I/V | lotrafilcon A | DMA + TRIS + Siloxane | NIGHE & DAY | CIBA Vision | 24 |
| I/V | lotrafilcon B | DMA + TRIS + Siloxane | AIR OPTIX | CIBA Vision | 33 |
| I/V | Senofilcon A | HEMA + DMA + mPDMS + siloxane macromer + TEGDMA + PVP | ACUVEU OASYS | Johnson&Johnson | 38 |
| I/V | Galyfilcon A | HEMA + DMA + mPDMS + siloxane macromer + EGDMA + PVP | ACUVEU ADVANCE | Johnson&Johnson | 47 |
DMA: N,N-dimethylacrylamide; pHEMA: poly(hydroxyethyl methacrylate); mPPMS: monofunctional poly(dimethylsiloxane); MA: methacrylic acid; NCVE: N-carboxyvinyl ester; PVA: poly(vinyl alcohol); PVP: poly(vinyl pyrrolidone); PBVC: poly(dimethysiloxy)disilylbutanolbisvinylcarbamate; NVP: N-vinylpyrrolidone; TRIS: tris(trimethylsiloxy)sililpropyl-methacrylate; TPVC: tristrimethylsiloxysilylpropylvinycarbamate.
| Drug released(%) | ||
|---|---|---|
| Polymer composition | 15min | 30min |
| Polymacon | 74.5 ± 1.2* | 94.1 ± 0.5* |
| Hilaficon B | 82.1 ± 2.7 | 97.4 ± 1.3 |
| Omafilcon A | 86.2 ± 1.9 | 98.7 ± 0.5 |
| Nelfilcon A | 99.3 ± 0.6* | 100.0 ± 0.0 |
| Ocufilcon D | 86.8 ± 1.9 | 99.1 ± 0.5 |
| Etafilcon A | 81.0 ± 0.4 | 97.3 ± 0.4 |
| lotrafilcon A | 91.7 ± 1.2 | 99.5 ± 0.1 |
| lotrafilcon B | 86.9 ± 0.4 | 98.4 ± 0.2 |
| Balafilcon A | 89.0 ± 1.8 | 99.0 ± 0.2 |
| Senofilcon A | 85.4 ± 0.6 | 97.6 ± 0.1 |
| Galyfilcon A | 92.6 ± 0.8 | 99.5 ± 0.2 |
The data is plotted as the mean ± SDs (n = 3).
* p < 0.05.
Declaration of interest
The authors report that they have no declaration of competing interests.
This study was supported by Science and Technology Project of Guangdong Province (Grant No. 2012B031800461), Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120171130013) and Pearl River Nova Program of Guangzhou (Grant No. 2016-55), China.
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