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Inner filter effect (IFE) as a simple and selective sensing platform for detection of tetracycline using milk-based nitrogen-doped carbon nanodots as fluorescence probe
⁎Corresponding author. khalid.omer@univsul.edu.iq (Khalid M. Omer)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
A simple, selective, and sensitive turn-off fluorescent assay for detecting of tetracycline in pharmaceutical dosage form based on inner filter effect (IFE) sensing platform has been described. In this IFE sensing strategy, N-doped carbon dots (CDs) were prepared by one-pot solvothermal synthesis using milk as a precursor and were directly used as a fluorophore in IFE. The prepared CDs were characterized by common spectroscopic and microscopic techniques. The CDs exhibited excitation-wavelength dependent emission with 10% as the fluorescence quantum yield. The fluorescence of CDs was decreased in correlation to the addition of absorber (tetracycline), as the excitation spectrum of the fluorophore (CDs) matches the absorption spectrum of the absorber. The present IFE-based sensing platform showed a good linear relationship from 2.0 µM to 200 µM (R2 = 0.9960) and provided a detection limit of 0.6 µM (signal-to-noise ratio of 3). Additionally, the cytotoxic effects of CDs were determined using normal healthy male Balb/C mice model treated with various doses of CDs and at the end of the study, no mortality or even no sign of toxicity was observed at oral doses of 100 and 200 mg/kg CDs in all treated animals. The proposed nanoprobe assay is a free from interferences, low-cost, biocompatible, and accurate for the detection of tetracycline in pharmaceutical formulation.
Keywords
Carbon nanodots
Nitrogen doped
Milk-based carbon dots
Tetracycline
Quenching
Hydrothermal
Cytotoxicity
Pharmaceutical analysis
1 Introduction
Tetracyclines are a group of broad-spectrum antibiotics that were discovered in 1940s (Chopra and Roberts, 2001). They are considered to be cheap and can be used for both human and animal infections to treat conditions caused by rickettsiae, mycoplasmas and chlamydiae (Bijan Zakeri, 2008; Daghrir and Drogui, 2013). This group includes many drugs such as doxycycline and minocycline; that share common structures but the most common one to be used in the medical field is tetracycline. TC offers advantages like low-cost, good oral absorption and being effective against a wide range of bacteria (Honrado et al., 1999; Agwuh and MacGowan, 2006). It can inhibit bacterial growth by inhibiting protein synthesis which is achieved by binding to the bacterial 30S ribosomal subunit (Brodersen et al., 2000). High doses of tetracycline can lead to serious side effects as photo-toxicity, superinfection and deposition in bone (Grossman, 2016; Toussaint and Gallagher, 2014).
Many techniques have been developed to detect and quantify tetracyline in the pharmaceutical products, include; high performance liquid chromatography (HPLC) (Oka et al., 2000), capillary electrophoresis (CE) (Kowalski, 2008), enzyme-linked immunosorbent assay (ELISA) (Zhang et al., 2014) and electrochemical sensors (Zhou et al., 2012). Despite the fact that these techniques can provide accurate results with high sensitivity, they suffer from some drawbacks like the expensive instruments required and high running costs (Hert et al., 2008; Levin, 2015; Konstantinou, 2017).
Carbon nanomaterials such as graphenes, carbon nanotubes, and carbon nanodots are being currently studied in many fields, such as biochemical sensing (Yue et al., 2013; Omer et al., 2019; Omer et al., 2018; Omer and Sartin, 2019), bioimging (Luo et al., 2013), photocatalysis (Xu et al., 2015; Omer et al., 2018; Mohammad et al., 2019), environmental and pharmaceutical analysis (Omer and Sartin, 2019; Luo et al., 2013). Recently, there has been an intense focus on utilizing carbon nanodots as a florescence probe in sensing applications due to low-cost precursors and facile preparation (Xu et al., 2015; Omer et al., 2018; Mohammad et al., 2019; Roy et al., 2015). Many methods have been developed to produce carbon nanodots such as, hydrothermal, chemical oxidation, laser ablation, microwave assisted and carbonization methods (Qu et al., 2016; Feng et al., 2015; Liu et al., 2017; Hou et al., 2016; Liu et al., 2014). Carbon nanodots offer advantages over other fluorophores for being water soluble, biocompatible and facile surface modification like surface passivation which can be used to enhance their properties (Jelinek, 2017; Yang, 2007; Pires et al., 2015).
Inner filter effect (IFE) results from the absorption of the excitation or emission light by absorbers in the detection system when the absorption spectra of the absorbers overlaps with the fluorescence excitation or emission spectra of fluorophores. IFE has shown as an effective and efficient strategy tool for converting the analytical absorption signals into fluorescence signals, which has been proven to commendably enhance the sensitivity and selectivity compared to other fluorescence quenching mechanisms (e.g. photoinduced electron transfer (PET) and fluorescence resonance energy transfer (FRET) (Yang et al., 2014; Yan et al., 2015; Chang and Ho, 2015). Additionally, Meanwhile, IFE based sensors do not require covalent linking between a receptor and a fluorophore or surface modification of CDs, providing simplicity and flexibility in probe fabrication (He et al., 1993).
In this work, we developed an IFE based sensor using highly florescent carbon dots as a fluorophore and tetracycline as an absorber that can be used in the IFE based assay for tetracycline detection in pharmaceutical dosage forms. Fig. 1 shows a schematic diagram of the preparation of milk-based carbon dots and the selective quenching effect after adding tetracycline.
2 Materials and methods
2.1 Chemicals
Pure tetracycline was purchased from (Research Products International Corp, USA). Tetracycline capsules were obtained from the local pharmacy stores. Fat free milk was purchased from a local supermarket. Deionized water (18 MΩ) was used throughout the research works.
2.2 Synthesis of CDs
The carbon dots were prepared through a single step hydrothermal method. Briefly, 1.0 mL of milk was mixed with 10 mL of ultra-pure water with stirring for 10 min, then placed in 25 mL Teflon-lined stainless-steel autoclave. The mixture was then heated at 180 °C in a constant temperature for 4 h. After cooling down to room temperature, the resulting solution was filtered with 0.22 μm filter membrane, to remove large particles then centrifuged at 12000 rpm for 15 min. Finally, solvent extraction was used for further purification using chloroform as an organic solvent. The upper layer which contained green colored carbon dots was isolated further purified with dialysis membrane (1000 MWCO) and stored at ambient temperature.
2.3 Instrumentation
Fluorescence spectra were recorded with a Cary Eclipse Fluorescence Spectrophotometer (Agilent Technologies, USA), with excitation slit set at 5 nm and emission at 5 nm in a quartz cell. The ultraviolet–visible (UV–vis) absorption spectra are conducted on Cary 60 Spectrophotometer (Agilent Technologies, USA). X-Ray diffraction spectra (XRD) was performed using Empyrean X-ray diffractometer (PANalytical, Netherland). Sample preparation for XRD was done by casting few drops of CDs on a piece of well-cleaned glass, then drying overnight. Raman measurements were recorded on inVia Reflex Raman Microscope (Renishaw, UK). The sample of CDs were drop casted on a piece aluminum then waited until complete dryness. The sample was excited using 785 nm. The FTIR spectrometer used Nicolet iS50 FTIR Spectrometer (Thermo Scientific, USA). High resolution transmission electron microscopy (HR-TEM) images were obtained using TECNAI G2 F20 microscope (Ames Lab, USA) at 200 kV. XPS analysis was produced using Thermo Escalab 250 XI X-ray photoelectron spectrometer (Thermo Scientific, USA) (hv = 1486.6 eV).
2.4 Preparation of tetracycline samples
20 tetracycline capsules were taken, grinded and their powder content was collected. A quantity equivalent to 0.50 g of tetracycline of that powder was taken and dissolved in ultra-pure water. The resulting solution was then filtered with 0.22 μm filter membrane to remove any undissolved particles, then diluted with water for further analytical purposes.
2.5 IFE-based fluorescence assay
The IFE based fluorescence sensing assay was performed under the following procedures. 1 mL of CD solution (1 mg/mL) was mixed with 0.5 mL of various concentrations of tetracycline solution. The pH of the solution adjusted between 2 and 7 with HCl or NaOH solution. The fluorescence measurements were recorded after 5 min and the solutions were excited at 370 nm.
2.6 Quantum yield
The quantum yield was calculated using fluorescein as reference standard. The absorbance and emission spectra for both the sample and standard were plotted and the integration was calculated to determine the quantum yield using the formula: where × represents the sample while st represents the standard. ɸ stands for fluorescence quantum yield, η is the refractive index of the solvent (water = 1.33). Grad is the gradient of plot of fluorescence spectra against that of absorbance.
2.7 Animal study
Male Balb/C mice aged around 2 months and weighed about 20–25 g were obtained from the Animal House of College of Veterinary Medicine, University of Sulaimani. Before starting of the study, all mice were acclimatized to the laboratory situation at 25 ± 1.5 °C under the equal time of dark-light cycle for at least 1 week in wood chips matted plastic cages with free access to normal tap water. The Ethical approval for conducting this study was obtained at the College of Veterinary Medicine, University of Sulaimani (UNIVSUL/CVM/0011-2019).
2.8 Evaluation of acute toxicity
Eighteen mice were allocated randomly into 3 groups of 6 animals each. The first group acted as control negative and given tap water only, whereas group 2 and 3 drenched forcefully with 100 and 200 mg/kg CDs, respectively, using a standard method. Animals were starved for at least 12 h before daily dosing, exactly for 14 consecutive days (Rahman et al., 2014).
2.9 Clinical remarks and body weight measurement
All animals in 3 groups were ascertained for behavioural abnormalities, toxicological signs, and food intake twice a day throughout treatment. Body weights of mice were reported on days 0, 7, and 14 using the sensitive balance.
2.10 Haematological and biochemical tests
On day 15, blood samples were obtained by heart puncture under general anaesthesia, half of the blood put into an anticoagulant tube and another half was used for serum collection. Later on, the hepatic and renal function tests were performed on serum samples using optimized diagnostic kits while haematological tests including the total white blood cells (WBC), total red blood cells (RBC), haemoglobin (Hb), packed cell volume (PCV), and platelets (PLT) were determined using coulter counter.
2.11 Histopathology
Immediately after animal sacrificing and excising, fresh liver and kidney samples were collected, washed with normal saline, cut into small pieces and fixed in recently prepared formalin (10%). Exactly, after 2 days, tissue sections were transferred into a plastic cassette and directly put in an automated tissue processor for gradual dehydration. Next, tissue sections were embedded in paraffin wax and the blocks were sectioned using a semiautomated microtome and were mounted on glass slides using a hot plate. Subsequently, the slides were rehydrated gradually using various concentrations of ethanol, washed with normal tap water and finally, stained with Harris’s haematoxylin and eosin to be observed under a light microscope.
3 Results and discussion
3.1 Characterization of CDs
3.1.1 Size and surface composition
To determine the size and morphology of the prepared carbon dots transmission electron microscopy (TEM) was employed (Fig. 2A). The TEM images showed that the carbon dots are spherical in shape and have the average size of 10 nm.
The X-ray diffraction pattern (XRD) exhibits a noisy broad peak at 22.1 (Fig. 2B) which can be attributed to disordered carbon atoms and amorphous graphitic structure (Qu et al., 2012).
Infrared spectroscopy was used to identify the functional groups of the carbon dots (Fig. 3). The FTIR spectra showed a very broad peak at 3500–3000 cm−1 which can be attributed to O—H/N—H stretching (Moonrinta et al., 2018). C—H stretching and C⚌O were observed at 2930 cm−1 and 1640 cm−1 respectively (Mandava, 2019). The signal at 1550 cm−1 originated from C⚌C stretching while the signal at 1243 results from C—O Bending (Wartewig, 2005). The presence of these hydrophilic functional groups is in correlation with the fact that the carbon dots were water soluble. Raman spectrum was recorded as shown in Fig. 3B. Two characteristic peaks were observed, which correspond to D and G bands 1360 cm−1 and 1730 cm−1. The ratio of ID/IG is 1. 85, which is characteristic of the disorder extent and the ratio of sp3/sp2 carbon (Yang et al., 2014; Yan et al., 2015).
In order to further characterize the functional groups and elements on the surface of the carbon dots X-ray photoelectron spectroscopy (XPS) was used. The XPS spectra (Fig. 4) showed four main peaks: O 1s (529 eV), N 1s (397 eV), C 1s (285 eV), P 2p (131 eV). The O 1s spectrum can be deconvoluted to three peaks as shown in Fig. 4.C: Carbonyl oxygen (C⚌O, 532.2 eV), hydroxyl oxygen (C-OH, 533.7 eV) and (C—O, 530.9 eV) (Chen et al., 2014). While the C 1s spectrum can be deconvoluted to four peaks as shown in Fig. 4.B:sp2 carbon (C⚌C, 283.5 eV), sp3 carbon (C—O, 285.1 eV), (C—N, 286.5 eV) and carbonyl carbon (C⚌O, 287.9 eV) (Qu et al., 2014).
3.2 Optical properties
UV–Vis spectra and steady state fluorescence emission were recorded in order to examine the optical properties of the CD. Fig. 5 shows the absorption and emission spectra of CD. The aqueous solution of carbon dots showed blue-greenish color when exposed to UV light, while it appeared pale yellow under daylight.
The UV–Vis spectra shows broad absorption peak at 240 nm which can be attributed to π to π* transition of C⚌C bonds in the graphene layers (Bera et al., 2010). Another weak and broad peak is observed between 400 and 450 nm which can be attributed to n to π* of the C⚌O group (Pan et al., 2010).
The maximum fluorescence emission was observed at 450 nm upon excitation at 370 nm (Fig. 5A). Excitation spectrum of CDs (the fluorophore) is same as the absorption spectrum of the tetracycline (the absorber), providing an efficient model for establishing IFE-sensing platform (Fig. 5B). Since the absorption of the absorber matches the excitation of the fluorophore, the IFE mode is primary inner filter effect (pIFE). Upon changing excitation wavelength, the fluorescence spectra of the CDs exhibited excitation wavelength-dependent fluorescence emissions (Fig. 5C), which is common in carbon nanodots due to difference origins of fluorescence emission such as surface defects and functional groups.
3.3 Pharmaceutical application
The CDs were tested against some common pharmaceuticals such as tetracycline, diazepam, ibuprofen, aspirin and Paracetamol. It was noticed that, tetracycline quenches the fluorescence emission of the CDs, while the others did not show any quenching effect. This is attributed to the fact that maximum peak of absorption spectra of the other pharmaceuticals, diazepam 240 nm, ibuprofen 265 nm, and aspirin 275 nm do not match the excitation spectrum of the prepared CD (Dinç, 1999; Ali et al., 2012; Salem et al., 2004).
This led to fabricate a nanoprobe for quantitative determination of tetracycline in the dosage form. Fig. 6 shows the fluorescence intensity of CDs after addition of different concentrations of tetracycline. The graph showed linearity from 2.0 μM to 200 μM with a detection limit 0.6 μM.
3.4 Assay of tetracycline capsules
The prepared carbon dots were used for quantitative analysis for the determination of tetracycline content in capsule dosage forms. The capsules contain excipients like starch and magnesium stearate that show no interference with the carbon dot fluorescence. Reference standard material of tetracycline was used to prepare a series of standard solutions. The average calculated content of tetracycline in capsule samples was 0.501 g (Spike Recovery 100.2%) which is within the acceptable limit of the British pharmacopeia (95.0–105.0% of the stated amount) (Towers, 2009). The experimental results were in a good agreement as compared with a reference method such as HPLC with 0.5% as error between both methods.
The results demonstrated that this method can be used as an economic and accurate alternative to other methods that are currently being used in quality control centers, as it provided high accuracy and selectivity.
Table 1 shows a comparison of different methods from the literature that used carbon dots for determination of tetracycline comparing the carbon sources, limit of detection and linearity range.
| Materials | LOD (μM) | Linearity range (μM) | Ref |
|---|---|---|---|
| Citric acid CD | 0.05 | 0.001–30 | Hou et al. (2013) |
| Tobacco CD | 5.18 | 0.04–6 | Miao et al. (2018) |
| Citric acid CD | 0.52 | 2–150 | Lin et al. (2016) |
| Europium CD | 0.3 | 0.5–200 | Liu et al. (2017) |
| milk-CD | 0.6 | 2–200 | This paper |
3.5 Cytotoxicity
The majority of mice did not show any signs of toxicity such as segregation and ruffled hair or behavioural abnormalities such as aggressiveness and cannibalism. Also, a significant (P < 0.05) body weight gain was noted in all animals during the test period (Table 2) which means CD is not affecting the growth of the animals.
| Animal group | Day 0 | Day 7 | Day 14* |
|---|---|---|---|
| Control | 20.10 ± 1.1 | 24.3 ± 0.7 | 28.9 ± 1.2 |
| Low dose | 20.33 ± 1.3 | 25.1 ± 0.55 | 29.2 ± 1.4 |
| High dose | 21.0 ± 1.7 | 28.3 ± 0.69 | 29.6 ± 0.9 |
Values are mean ± SD (n = 6) and have been analyzed using post hoc comparison test one way ANOVA. Data revealed a significant (P < 0.05) difference in body weight after treatment.
* Increasing of body weight after 14 days in both treated groups when compared to that of the untreated control.
Additionally, the serum liver enzymes (ALP, ALT, and AST) and kidney components of urea, and creatinine levels in the treated groups were almost same to that of control negative mice without significant (P > 0.05) changes (Table 3). Moreover, we found normal levels of total red blood cells, white blood cells, haemoglobin, platelet counts as well as packed cell volume in the peripheral blood (Table 4). Thus, anaemia, thrombocytopenia, leucopenia, and pancytopenia was not predicted in the treated animals which are collectively indications of bone marrow suppression and toxicity.
| Animal group | ALP (U/L) | ALT (U/L) | AST (U/L) | Urea (mmol/L) | Creatinine (µmol/L) |
|---|---|---|---|---|---|
| Control | 111.5 ± 0.8 | 60.9 ± 1.3 | 144.5 ± 1.5 | 8.0 ± 0.9 | 30.8 ± 0.85 |
| Low dose | 112.7 ± 0.85 | 61.6 ± 1.22 | 145 ± 0.9 | 8.24 ± 1.1 | 29.9 ± 1.2 |
| High dose | 112.9 ± 0.65 | 60.7 ± 1.25 | 144.9 ± 0.77 | 7.9 ± 1.4 | 29.5 ± 1.5 |
| Animal group | Total RBC (×1012/L) | Hb (g/L) | PCV (L/L) | PLT (×105/L) | Total WBC (×103/µL) |
|---|---|---|---|---|---|
| Control | 8.5 ± 0.25 | 140 ± 1.2 | 0.4 ± 0.5 | 6.5 ± 0.9 | 2.7 ± 0.11 |
| Low dose | 8.3 ± 1.6 | 142 ± 1.33 | 0.41 ± 0.48 | 6.4 ± 0.85 | 2.5 ± 0.5 |
| High dose | 8.0 ± 0.9 | 139 ± 1.25 | 0.39 ± 0.39 | 6.1 ± 0.22 | 2.4 ± 0.45 |
Furthermore, microscopic examination of the liver of treated animals exhibited normal cellular details and binucleation and was without any distortions and oedema. The hepatocytes were ordered in cords and visible. The cross-section of the liver displayed no lyses in the blood cells, neutrophil, lymphocyte, or macrophage infiltration (Fig. 7). Additionally, there were no morphological changes in the kidneys of mice from all treated groups and the glomerular details displayed normal appearance similar to the control groups. The cross-sections of the glomeruli, distal, and proximal tubules showed normal architecture in all treated mice. Degeneration, bleeding, or necrosis was not observed in nephron cells as well as nephrons showed normal and visible nucleoli (Fig. 8). Therefore, the study suggests that the LD50 of CDs value in male mice might be greater than 200 mg/kg.
Values are mean ± SD (n = 6) and have been analyzed using post hoc comparison test one way ANOVA. Data revealed nonsignificant (P > 0.05) difference in liver and kidney function parameters after 14 days of treatment when compared with the untreated control group. ALP: alkaline phosphatase, ALT: alanine aminotransferase, and AST: aspartate aminotransferase.
Values are mean ± SD (n = 6) and have been analyzed using post hoc comparison test one way ANOVA. Data revealed nonsignificant (P > 0.05) difference in haematological parameters after 14 days of treatment when compared with the untreated control group. RBC: red blood cell, Hb: haemoglobin, PCV: packed cell volume, PLT: platelet, and WBC: white blood cell.
4 Conclusion
In summary, a fluorescence probe based on primary IFE sensing platform was fabricated for detection of tetracycline in pharmaceutical dosage form. The fluorophore, carbon nanodots, were prepared from a readily available source with a simple, green, and single step hydrothermal method. The nanodots were selectively quenched via addition of tetracycline leading to fabricate a nanoprobe for detection of tetracycline in dosage forms. The nanodots showed high accuracy and selectivity in the detection of tetracycline in pharmaceutical dosage forms with a detection limit of 0.60 µM. We confirmed that CDs has no cytotoxic effects on vital organs, serum biochemistry and blood parameters in vivo. This work proved that prepared carbon nanodots derived have potentials in pharmaceutical analysis and quality control as a low cost and accurate alternative method.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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