Release behavior and toxicity profiles towards A549 cell lines of ciprofloxacin from its layered zinc hydroxide intercalation compound
© Abdul Latip et al.; licensee Chemistry Central Ltd. 2013
Received: 8 March 2013
Accepted: 27 June 2013
Published: 12 July 2013
Layered hydroxides salts (LHS), a layered inorganic compound is gaining attention in a wide range of applications, particularly due to its unique anion exchange properties. In this work, layered zinc hydroxide nitrate (LZH), a family member of LHS was intercalated with anionic ciprofloxacin (CFX), a broad spectrum antibiotic via ion exchange in a mixture solution of water:ethanol.
Powder x-ray diffraction (XRD), Fourier transform infrared (FTIR) and thermogravimetric analysis (TGA) confirmed the drug anions were successfully intercalated in the interlayer space of LZH. Specific surface area of the obtained compound was increased compared to that of the host due to the different pore textures between the two materials. CFX anions were slowly released over 80 hours in phosphate-buffered saline (PBS) solution due to strong interactions that occurred between the intercalated anions and the host lattices. The intercalation compound demonstrated enhanced antiproliferative effects towards A549 cancer cells compared to the toxicity of CFX alone.
Strong host-guest interactions between the LZH lattice and the CFX anion give rise to a new intercalation compound that demonstrates sustained release mode and enhanced toxicity effects towards A549 cell lines. These findings should serve as foundations towards further developments of the brucite-like host material in drug delivery systems.
KeywordsDrug delivery Layered zinc hydroxide nitrate Ciprofloxacin Anion exchange Sustained release Release mechanisms Cytotoxicity
The application of nanotechnology to drug delivery is nowadays a growing research field. A wide variety of nano-sized drug carriers has found niche in the field, owing to their unique structures which give rise to new generations of therapeutic agents and medical devices . The main advantages of the nano-based drug delivery over the traditional ones are manifold: enhanced biodistribution and pharmacokinetics of drug , improved delivery of poorly water-soluble drugs , lowered systemic toxicity of drug while being concentrated on the target organ  and ability to optimize drug release rate towards achieving better patient compliance .
Layered hydroxides salts (LHS) is a layered inorganic compound which shares structural resemblance to anionic clay, layered double hydroxides (LDH). The structure of LDH is derived from that of brucite, [Mg(OH)2] and may be represented by the formula [M2+1-xM3+x (OH)2](An-)x/n.mH2O; where M2+ and M3+ are divalent and trivalent cations of the lattice, respectively, x is equal to the ratio [M3+/( M2+ + M3+)] and An- is an anion . In relation to LDH, its LHS sibling may undergo structural modifications based on different type of metal cation that is present in the compound lattice. It has been reported that nitrate group precursor are directly involved in the formation of LHS of Cu2(OH)3NO3, La(OH)2NO3.H2O and Mg2(OH)3NO3 via coordination with the lattice cation through one oxygen atom of the nitrate ion [7, 8].
In Zn5(OH)8(NO3)2.2H2O (denoted as LZH), the brucite-like lattice is modified wherein one-fourth of octahedrally coordinated Zn2+ cations are absent, thus creating empty octahedral sites. On either side of the empty octahedra are found tetrahedrally coordinated Zn2+ cations with the hydroxyl ions and water molecules. In this compound, the nitrate ion is not coordinated with the Zn2+ cations and located in the interlayer space of LZH .
LHS is currently gaining attraction due to its simple method of synthesis , as a precursor for a wide band gap ZnO , for the synthesis of layered double hydroxide salts  and anion exchange properties . A wide variety of guest molecules has been intercalated into the interlayer region of LHS, mainly via ion exchange process, ranging from anionic dyes , porphyrin sensitizers  and an anti corrosive compound . In particular, LHS has demonstrated the ability to extend the release period of bioactive molecules  and drug molecules , prompting more investigations towards potential applications of LHS in drug delivery systems.
Ciprofloxacin (CFX) is a wide spectrum antibiotic that belongs to the quinolone family . The antimicrobial activities of CFX are mainly achieved through the chlorine-substituted N–1 cyclopropyl group which enhances cell penetration and improves activity against DNA gyrase and topoisomerase IV enzymes . Although CFX is known as a safe drug, there are cases of side effects associated with CFX such as anaphylaxis and pulmonary edema [21, 22]. CFX suffers from moderate oral bioavailability , as it chelates with calcium-, magnesium- and aluminium-containing salts upon concomitant administration . In drug delivery systems, CFX has been used with various drug carriers such as polymeric nanoparticles [25–27], cyclodextrin , chitosan , montmorillonite  and calcium apatite .
In this paper, we prepared an inorganic drug carrier based on LZH host material intercalated with a model drug, CFX. Considering LZH possesses higher layer charge density compared to that of LDH counterpart , we are prompted to examine the release behavior of the intercalated CFX anions from LZH in phosphate-buffered saline solution, after which the corresponding release mechanisms was further established. In addition, the toxicity profile of the intercalation compound was evaluated against adenocarcinomic human alveolar basal epithelial cancer cell line to demonstrate synergistic effects between drug–host interactions towards cells growth inhibition .
Materials and methods
Ciprofloxacin, C17H18FN3O3 (1–cyclopropyl–6–fluoro–4–oxo–7–piperazin–1–yl–quinoline–3–carboxylic acid, molecular weight 331.34 g/mol) was purchased from Sigma Aldrich Co. Ltd. and was used as received. All solutions were prepared using deionized water.
Synthesis of LZH
Layered zinc hydroxide nitrate (LZH) was synthesized according to the modified version of previous report . An aqueous solution of 0.4 mol/L Zn(NO3)2.6H2O was prepared in 100 ml volumetric flask. To this solution, 0.8 mol/L NaOH solution was added dropwise, under vigorous magnetic stirring, until pH of the mixture reached pH 7.0. The resulting precipitates were aged at 70°C for 18 h, washed thoroughly with deionized water and dried in an oven at 60°C.
Synthesis of Z–CFX
The intercalation compound, Z–CFX was obtained via anion exchange between nitrate ion of precursor LZH and anionic ciprofloxacin (CFX) in a mixture solution of water:organic solvent. Approximately 0.2 g of finely ground LZH was dispersed in 25 ml of water:ethanol mixture solution containing 0.9 g of CFX under vigorous stirring. The pH of the exchange medium was adjusted by slow titration of 1.0 mol/L NaOH until pH 8.0 was achieved. The mixture was left under stirring for 24 h. The resulting product was collected by washing the precipitates thoroughly with deionised water and ethanol and was dried at 60°C for 24 h.
In vitro release
The release of CFX from the intercalation compound was conducted in phosphate-buffered saline solution (PBS) pH 7.4 wherein 0.6 mg of Z–CFX were immersed in the PBS solution and the accumulated release of CFX was measured at λmax = 276.3 nm using a Perkin Elmer UV–Vis Spectrophotometer Lambda 35.
Human lung alveolar carcinoma epithelial (A549) cells were cultured in RPMI 1640 medium under a humidified atmosphere (5% CO2 plus 95% air) at 37°C. The medium was supplemented with 10% heat-inactivated fetal bovine serum, 2 mM of L–glutamine, 100 units/ml of penicillin and 100 μg/ml of streptomycin.
MTT (3–(4,5–dimethylthiazole–2–yl)–2,5–diphenyltetrazolium bromide) cell viability assay was used to investigate the toxic effect of Z–CFX, ZLH and CFX. Cells (2 × 103 cells/100 μl) were seeded onto 96-well plates and incubated overnight at 37°C under a 5% CO2 atmosphere. After cells had stabilized, fresh medium containing either Z–CFX, ZLH or CFX at different concentrations (0.5, 5.0, 50.0 and 500.0 μg/mL) was added and incubation continued for 72 h. After the incubation, 10 μL of MTT solution was added to each well and incubated further for 4 h, the reaction was terminated by adding 100 mL of 10% SDS in 0.01 mol/L HCl solution. The absorbance was measured on a microplate reader at wavelength 570 nm.
Powder x-ray diffraction (PXRD) patterns were recorded on an ITAL APD 2000 powder diffractometer using CuKα radiation (λ = 1.5418 Å) at 40 kV and 30 mA. The data was collected from 2–60° at a dwell time of 2° per minute. Fourier transform infrared (FTIR) spectra were recorded in the range 400–4000 cm-1 at a 4 cm-1 resolution on a Perkin–Elmer 1752X (Boston, MA) spectrophotometer using the potassium bromide (KBr) pellet technique; approximately 1% sample was mixed in 100 mg of spectroscopic grade KBr and the pellet was pressed at 10 tons. The atomic weight percent of carbon, hydrogen and nitrogen was determined using CHNS–932 (LECO Instruments St Joseph, MI). The zinc ion composition was determined using a Perkin–Elmer inductively coupled plasma-atomic emission spectrometry (ICP–AES) model Optima 2000DV under standard conditions. Thermogravimetric and differential thermogravimetric analyses (TGA/DTG) were carried out in 150 μL alumina crucibles using a Metter–Toledo instrument model TGA851e (Greifensee, Switzerland) at a heating rate of 10° per minute in the range of 25–900°C with the sample amount being 5–10 mg in nitrogen atmosphere. The surface morphology of the samples was observed by a field emission scanning electron microscope (FESEM), FEI Nova Nanosem 230 with an acceleration voltage of 25 kV. Prior to analysis, the samples were mounted on aluminum stub over double-coated carbon film. Textural characterisations were carried out using a nitrogen gas adsorption–desorption technique at 77 K using a Micromeritics ASAP2000. The sample was degassed in an evacuated heated chamber at 100°C overnight. Pore size distributions were calculated using the Barrett-Joyner-Halenda (BJH) model on the desorption branch.
Results and discussions
X-ray diffraction analysis
Fourier transform infrared spectroscopy
For CFX (Figure 4b), an absorption band at 3375 cm-1 is attributed to the stretching vibrations of amine group. Intense bands at 1711 and 1624 cm-1 are characteristic of the stretching vibrations of carbonyl group of carboxylic acid and ketone, respectively. Bands centered at 1310, 1269 and 1048 cm-1 are assigned to the stretching modes of C–N, C–C–C of ketone and C–F, respectively.
The FTIR spectrum of Z–CFX features main characteristic absorption bands of CFX anions which indicate that the anions were successfully intercalated into the LZH interlayers. Figure 4c depicts the stretching bands of asymmetric and symmetric of carboxylate group of the CFX anions, observed at 1576 and 1385 cm-1, respectively. Generally, difference in wavenumber between the carboxylate stretching bands (∆υ = υasym – υsym) gives information about the coordination environment of the functional group. Li et al.  mentioned that carboxylate group adopting unidentate coordination mode has a larger ∆υ value compared to that of bridging carboxylate; 200 and 150 cm-1, respectively. Since the ∆υ of COO– of CFX anions is 191 cm-1, we would suggest that the intercalated CFX is coordinately bonded to Zn2+ units of the lattice via one oxygen atom of the functional group.
Assignment of FTIR absorption bands of Z-CFX, CFX and LZH
υ(OH) of lattice, υ(O–H) COOH, υ(N–H) NH
3670 – 3200
3670 – 3200
δ(OH) of H2O
υ(C = O) ketone
Elemental analysis data, chemical formula and textural properties of LZH and Z-CFX
Sample proposed formula
Weight percentage (%)
BET surface area (m2/g)
Pore volume (cm3/g)
Average pore diameter (nm)
Zn 5 (OH) 8 (NO 3 ) 1.02 (CO 3 ) 0.07 .2.93H 2 O
Z-CFX (Molecular weight: 872.53 g/mol)
Zn 5 (OH) 8 (C 17 H 18 FN 3 O 3 ) 0.93 (NO 3 ) 0.14 (CO 3 ) 0.07 · 4.92H 2 O
Table 2 summarizes the specific surface area (SSA), the pore volume and the average pore diameter for LZH and Z–CFX as determined from the Brunaeur, Emmett and Teller (BET) method and the Barrett, Joyner and Halenda (BJH) method. It is worth mentioning that the CFX-intercalated LZH shows a larger surface area of 27 m2/g compared to that of the host with nitrate as the counter anion, LZH which is 14 m2/g. This finding is dissimilar from another group which observed the decreased in surface area value of LDH after being intercalated with organic anions . Moreover, reports on the N2 adsorption–desorption of LZH intercalated with drug anions are rather scarce for comparison purposes with our aforesaid findings .
Recently, Hussein and co-workers reported that surface area of hippurate–LZH intercalation compound was decreased compared to that of the starting material, ZnO . Hippuric acid was first dissolved in dimethyl sulfoxide before it was added to the ZnO suspension. On the contrary, in this work, CFX was dissolved in a mixture of water:ethanol solution to solubilize the drug prior to its intercalation into LZH since the drug CFX has poor solubility in aqueous solution. In a related finding, Malherbe et al.  showed that the surface area of hexacyanoferrate-intercalated LDH had increased when the intercalation compound was obtained via anion exchange in water-organic solvent mixtures. The group concluded that the inherent properties of organic solvents were responsible for the increased surface area of the obtained materials. We would attribute the increased in surface area of Z–CFX compared to LZH is due to different pore texture of the resulting material, which is very much depending on the method of synthesis.
- 1.First-order model which demonstrates the release system where dissolution rate depends on the amount of drug present in the intercalation compound and can be mathematically expressed as :
- 2.Parabolic diffusion model which describes the diffusion-controlled release of a drug from a medium and is generally written as :
- 3.The modified Freundlich model which explains experimental data on ion exchange and diffusion-controlled process following the equation :
- 4.The Bhaskar model which deals with the diffusion-controlled release of drug from particles and is summarised in the form :
In equations 1 – 4, Co and Ct are the amount of drugs in the LZH matrix at release time 0 and t, respectively, K is the rate constant, and a and b are the constants whose chemical significance is not clearly understood .
The fitting of release data is best achieved with the modified Freundlich model (R2 = 0.98), followed by parabolic diffusion (R2 = 0.96) which suggest that the release process is of diffusion-controlled. Note that high R2 value of the latter model is due to the “grouping” of the data towards low values on the x-axis, which is often observed upon applying this model for the kinetic analysis in layered hydroxides [18, 53]. Generally, there are two governing mechanisms in the release system of layered double hydroxides (LDH); anion diffusion through particles and dissolution of the LDH particles . The modified Freundlich model which concerns with the heterogeneous diffusion from flat surfaces via ion exchange would describe better the release process in Z–CFX; surface CFX anions diffused first into the PBS medium and underwent exchange with phosphate ions in the medium. The process was followed by diffusion from the interlayer anions. The latter process being designated as the rate limiting step . We would attribute the sustained release of CFX anions due to the strong coordination bond which occurred between the anions and the Zn ions of the LZH lattice.
Al Ali et al.  found that zinc layered hydroxides intercalated with hippuric acid possessed synergistic effects with tamoxifen towards HepG2 cells in which the IC50 value significantly decreased than that of tamoxifen and hippuric acid alone. Li et al.  pointed out that decreased viability of HeLa cancer cells was due to LDH intercalation with folic acid which protected the anticancer drug from degradation and enhanced its permeability into the target cells. Considering the sustained release behavior of Z–CFX, we would attribute the enhanced antiproliferative effects observed in Z-CFX is due to the strong interactions occurred between LZH and CFX; the host would facilitate the cell uptake and further protect the guest from degradation so that the anions were slowly released and “killed” the A549 cells .
CFX was successfully intercalated into the interlayers of layered zinc hydroxides via anion exchange mechanism in water:organic solvent mixture solution. The basal spacing of LZH was expanded to maximize the drug–host interactions in the intercalation compound, Z–CFX in which the intercalated CFX anions were bonded to tetrahedral Zn2+ moieties of the lattice in a unidentate coordination mode. Due to strong coordination bond between drug–host lattice, the intercalated anions were slowly released, following diffusion–anion exchange mechanisms in which diffusion from the interlayer anions being the rate limiting step. The antiproliferative towards A549 cells were enhanced due to the synergistic effects between CFX and LZH. These findings should serve as strong foundations in further development of biocompatible LZH-based drug carrier.
Prof. Dr. Mohd Zobir Hussein is professor of chemistry at the Institute of Advanced Technology, Universiti Putra Malaysia. His major research areas include layered organic–inorganic nanohybrid for gene and drug delivery, nanoparticles and nanostructured materials, their design, synthesis and applications. He has contributed to more than 200 technical papers. He is the assignor of 1 granted patent on the preparation method of nanomaterial for controlled release formulation and co-assignor of another 2 granted patents. In December 2012, he was awarded as one of Malaysia’s top scientist researcher by the government of Malaysia.
Layered hydroxide salts
Layered zinc hydroxide nitrate
Layered zinc hydroxide nitrate intercalated with ciprofloxacin
Powder x-ray diffraction
Fourier transform infrared
This work is financially supported by the Ministry of Higher Education, Malaysia through the ERGS grant No. ERGS/1/11/STG/UPM/01/18. AFL is thankful for the ASTS fellowship from Universiti Sains Malaysia.
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