Antibacterial and Cytotoxic Effects of Cyclodextrin-Triazole-Titanium Based Nanocomposite

Abstract

In this paper, the antibacterial activity of triazole functionalized cyclodextrin (CD.Click) and cyclodextrin-triazole-titanium based nanocomposite (CD.COM) was evaluated. The results indicated that CD.Click and CD.COM perform a wide range of antibacterial activity against both gram positive (Staphylococcus aureus and Bacillus subtilis) and gram negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. The cytotoxic effect of CD.COM was investigated in vitro on cancerous cell lines (cervical cancer, breast carcinoma and sarcoma osteogenic) and fibroblast cells by MTT assay. The cell viability evaluation confirmed that the growth of cancerous cells is inhibited in a dose and time dependent way without any significant effect on the normal fibroblast cells.

Keywords:
TiO₂; Triazole; β-Cyclodextrin; antibacterial; cytotoxic

GRAPHICAL ABSTRACT

HIGHLIGHTS

Observation of the antibacterial and cytotoxic effects of CD.COM due to the synergy between cyclodextrin, triazole and TiO₂ NPs.

The antibacterial activity of CD.COM against both gram positive and gram negative bacteria.

The CD.COM cytotoxicity against cancer cells and compatibility with fibroblast cells.

INTRODUCTION

Development of organic-inorganic nano-hybrids is an important research area in the field of nanotechnology. Biopolymers have been widely used in composite structures because of environmental and economic advantages containing renewable sources, compatibility, biodegradability and low cost. Polysaccharides, such as cellulose [¹,²], cyclodextrins (CDs) [³,⁴] and starch [⁵] proved to be good candidates to provide suitable substrates for metal oxide nano-fillers.

CDs are nontoxic, biodegradable, water-soluble cyclic oligosaccharides consisting of 6 (α-CD), 7 (β-CD) or 8 (γ-CD) D-glucose units linked together via α-1,4-glycosidic bonds to form torus-like structure [⁶]. β-cyclodextrin (β-CD), produced from enzymatic conversion of starch with moderate truncated cone-shaped hole, is low priced commercially available and has been extensively used in industry [⁷]. The ability of solubilization, extraction of phospholipids [⁸] and cholesterol [⁹] from cell membranes and lysis of red blood cells and blood coagulation [¹⁰] made the β-CD to be applied in medicine.

Among various kinds of metal oxides, titanium dioxide nanoparticles (TiO₂ NPs) have attracted significant attentions due to their excellent physical and chemical properties along with safe and broad-spectrum antibiosis [¹¹,¹²]. TiO₂ NPs are unique antibacterial agent because of their ability to disrupt bacterial cell walls as a result of their small size and large surface area [¹³,¹⁴]. TiO₂ NPs tend to agglomerate, so for solving this problem, they have been embedded on the support surface by chemical bonding. Modification of TiO₂ NPs with silane coupling agents is one way for creating the chemical binding with a support surface [¹⁵]. In addition, it provides the possibility of further chemical modifications to achieve more efficiencies [¹⁶].

The copper catalyzed alkyne-azide cycloaddition, known as click reaction, is a beneficial reaction for linkage of modified TiO₂ NPs with a support surface via triazole ring formation [¹⁷]. The triazoles are highly robust to metabolic degradation and capable to form hydrogen bonding enhancing their solubility and interacting with biomolecular targets [¹⁸,¹⁹]. So, triazole ring has significant biological properties such as antibacterial [²⁰], antifungal [²¹], anti-inflammatory [²²] antiviral [²³] and anticancer [²⁴-²⁶] activities, and have been utilized in medicinal chemistry to produce medicinally interesting drug candidates with a wide range of applications.

Given that the cancer is the second leading cause of death in humans, a great deal of interest has been recently devoted to the synthesis of new compounds with the potential to adapt with normal cells and reduce cancer cells [²⁷-²⁹]. At the same time, due to the resistance of bacteria to antibiotics, it is necessary to produce substances with effective antibacterial properties.

The exploration of new agents with dual antibacterial and anticancer activities is necessary because of promising therapeutic potential due to their capability to decrease the threat of bacterial infections in the frequently immunocompromised cancer patient [³⁰-³²]. This class of compounds with dual antibacterial and anticancer effects not only controlling growth of cancer related bacterial infections but also protecting patients from the infection due to downplay of immune system [³³].

Nanocomposites can perform significant improvement in various fields due to their better efficiency than any of the organic and inorganic raw materials. In this regards, novel cyclodextrin-triazole-titanium based nanocomposite (CD.COM) was synthesized hoping to observe the synergy of cyclodextrin, triazole and TiO₂ moieties. The CD.COM was prepared from nucleophilic reaction of the amino modified TiO₂ NPs (TiO₂/AS) with the triazole modified cyclodextrin (CD.Click) [⁴]. The antibacterial activity of CD.Click and CD.COM was investigated against gram negative (E. coli; Escherichia coli and P. aeruginosa; Pseudomonas aeruginosa) and gram positive (S. aureus; Staphylococcus aureus and B. subtilis; Bacillus subtilis) bacteria. In addition the cytotoxic effect of CD.COM was evaluated on cancerous cell lines (MCF-7; breast carcinoma, Saos; sarcoma osteogenic and Hela; cervical cancer) and fibroblast cells.

EXPERIMENTAL

Material and methods

The tested bacteria included E. coli PTCC 1330, P. aeruginosa PTCC 1074, S. aureus ATCC 35923, and B. subtilis PTCC 1023 were purchased from Persian Type Culture Collection (Iran). The reference antibiotics of chloramphenicol and gentamicin were obtained from Padtan Teb (Iran). Cancer cell lines of HeLa, MCF-7 and Saos were purchased from Pasteur Institute of Iran (Tehran) and the fibroblast cell line was obtained by non-enzymatic method from newborn human foreskin at Amirkola children’s hospital (Babol, Iran). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was bought from Alfa Aesar (Lancashire, UK). Nutrient Muller Hinton Agar was obtained from Merck (Goettingen, Germany). Dulbecco’s Modified Eagle’s Medium (DMEM), penicillin and streptomycin were provided from Biowest (France). Fetal bovine serum (FBS) was obtained from Gibco (Germany). Dimethyl sulfoxide (DMSO) was obtained from Merck company (Germany). Cell viability was automatically measured by microplate reader (Rayto analyzer, CHINA) at wavelength of 570 nm.

Synthesis

The pathway of CD.COM synthesis is displayed in Scheme 1. The experimental details for synthesis of the CD.COM were reported in our previous paper [⁴]. The titania/γ-aminopropyltrimethoxysilane (TiO₂/AS) was synthesized via the reaction of 3-aminopropyltrimethoxysilane (AS) with anatase TiO₂ nanoparticles (TiO₂ NPs) [³]. The heptakis (6-bromo-6-deoxy)-β-cyclodextrin [CD-(Br)₇] was synthesized in the presence of triphenylphosphine (Ph₃P) by treating N-bromosuccinimide (NBS) with β-cyclodextrin (β-CD) [⁴]. Through the reaction of CD-(Br)₇ with sodium azide (NaN₃), the heptakis (6-azido-6-deoxy)-β-cyclodextrin [CD-(N₃)₇] was obtained [³⁴]. The heptakis [6-(4-bromomethyl-1H-[1,2,3]triazole-1-yl)-6-deoxy]-β-cyclodextrin (CD.Click) was prepared through a click reaction of CD-(N₃)₇ with propargyl bromide (P.Br) [⁴].

Scheme 1
Synthetic pathway for the CD.COM preparation.

The CD.COM characterization details were reported in our previous papers [³,⁴]. A summary of the characterization methods (FTIR; Fourier transform infrared spectroscopy, XRD; X-ray diffraction, TGA; thermogravimetric analysis, EDX; energy-dispersive X-ray spectroscopy and FESEM; field emission scanning electron microscopy) for identifying and determining the purity of CD.COM are provided in this section.

FTIR

The FTIR spectra of β-CD, TiO₂ and CD.COM are presented in Figure 1. For the β-CD [⁴], the stretching and bending vibrations of O−H groups are appeared at 3393 and 1647 cm^-1, respectively. The absorption peaks at 2926 and 1369 cm^-1 are related to the stretching and bending vibrations of -CH₂ groups. The absorption peaks for C−O stretching vibrations of the C−2/C−3, the C−O−C of glucopyranose unit and the C−O of C−6 are appeared at 1157, 1081 and 1029 cm^-1, respectively. Bands at 1419 and 942 cm^-1 are attributed to the bending vibrations of −CH₂ and C−H of six-membered ring, respectively.

In the spectrum of TiO₂ [¹], the absorbance peaks at 3200-3500, 1628, and 400-700 cm^-1 are associated to the stretching and bending vibrations of hydroxyl groups on the surface of TiO₂ NPs, and the stretching vibrations of Ti−O−Ti, respectively.

The FTIR spectrum of CD.COM [³,⁴] displays all the expected absorption peaks of TiO₂, triazole ring and cyclodextrin. The appearance of intense broad band of C=N stretching at 1634 cm^-1 could be ascribed to the triazole ring. A weak shoulder at ~3100 cm^-1 is assigned to the ꞊C-H stretching vibration of triazole ring.

Figure 1
The FTIR spectra of samples.

XRD

XRD patterns of β-CD, anatase TiO₂ NPs and CD.COM are displayed in Figure 2. The XRD pattern of β-CD exhibits diffraction peaks at 2θ = 9.5º, 10.9º, 12.9º, 13.5º, 16.8º, 18.3º, 19.0º, 24.2º, 24.7º and 35.6º in agreement with crystalline form [³,⁴]. The XRD pattern of TiO₂ NPs shows 2θ angle and miller indices (hkl) values at 25.3° [101], 37.9° [004], 48.1° [200], 53.92° [105], 55.1° [211], 62.8° [204], 68.8° [116], 70.89° [220] and 75.38° [215], respectively [¹]. The CD.COM XRD pattern indicates the presence of peaks for both constituents of the structure (TiO₂ and CD) [³,⁴]. The severity of cyclodextrin peaks in the composite pattern is very weak, which is probably related to the TiO₂ coating of the cyclodextrin surface.

Figure 2
The XRD patterns of samples.

TGA

The thermal stability of samples was analyzed by TGA (Figure 3). TGA curve of TiO₂ NPs shows the 7 wt% weight loss over the full temperature range relating to loss of physisorbed water as well as dehydration of the surface OH groups. Thermal degradation of β-CD is started at θ > 250 ºC and pyrolysis takes place at θ > 300 ºC. It is obvious that the presence of modified TiO₂ NPs in the functionalized cyclodextrin structure enhances the thermal stability of CD.COM (char yield = 59.5%) [³,⁴].

Figure 3
The TGA thermograms of samples.

EDX

The EDX spectra of TiO₂, β-CD and CD.COM are exhibited in Figure 4. The EDX spectra display the presence of appropriate elements for each sample. The existence of C, N, O, Si and Ti elements approves the presence of modified TiO₂ NPs with functionalized β-CD in the CD.COM structure [⁴].

Figure 4
The EDX spectra of samples.

FESEM

Figure 5 represents the FESEM images of β-CD, TiO₂ and CD.COM. The FESEM image of CD.COM exhibits not only the creation of rough surface and surface order reduction compared with β-CD, but also the capture of modified TiO₂ NPs into the network of functionalized cyclodextrin [³,⁴].

Figure 5
The FESEM images of samples.

Biological studies

Antibacterial investigation

Antibacterial effects of CD.Click and CD.COM were assessed using a disk diffusion method [³⁵]. The CD.Click and CD.COM tablets (0.1 g, diameter: 13 mm) were placed on Muller-Hinton agar dishes infected with bacteria. The antibacterial activity of CD.Click and CD.COM was investigated against E. coli and P. aeruginosa as gram negative bacteria and S. aureus and B. subtilis as gram positive bacteria. The incubated bacteria in nutrient media at 37 °C for 24 h, led to bacterial concentration in the seeding culture of about 10⁸ colony forming units (CFU)/mL. Afterwards, the prepared tablets of CD.Click and CD.COM were put on the seeded agar plate in a 37 °C incubator for 24 h. Discs of chloramphenicol (30 mg per disc) and gentamicin (10 mg per disc) antibiotics were applied as references for comparison. The diameter of clear zone inhibition (mm) around the samples after 24 h incubation was measured to evaluate the antibacterial efficiency. All samples/standards were run in triplicate.

Cytotoxicity investigation

Cytotoxicity assay is widely used to screen the cytotoxic effects of synthesized compounds to cells via the cell viability assessment. This is the simplest in vitro technique that was introduced for biocompatibility study of the new synthesized materials. This can be of vital importance during finding new pharmaceutical compounds to warrant the safety of users. The cytotoxicity assay assessing the cell viability by using the MTT. The MTT is a trustworthy and sensitive indicator for the metabolic activity of cells that measures the reducing potential of cell using a colorimetric reaction. The assay relies on the yellow water-soluble tetrazolium dye reduction of MTT to purple colored formazan crystals by the mitochondrial dehydrogenases. The produced formazan after dissolution in DMSO is examined spectrophotometrically, and the amount of cytotoxicity is estimated from the spectra of nanoparticle-treated and untreated cells. The CD.COM cytotoxicity was investigated in vitro against Hela, MCF-7, Saos and fibroblast cells by MTT. The cells (8×10³ cells/well onto 96-well) were cultured in complete growth medium [DMEM; 10% FBS, 100 IU/mL penicillin and 100 μg mL^-1 streptomycin] and then incubated at 37 °C in 5% CO₂ atmosphere for 24 h to permit cell attachment. Then cells were treated with the CD.COM at different concentrations (7.8-500 mg L^-1) within 24 to 48 h, along with replacing of the cell culture medium by a renewed medium and further incubated for 24 h. The cells without any treatment were served as a control and grown on each plate under the same conditions as treated cells. After incubation, the medium was removed, washed with PBS and then MTT reagent (50 μL; 5 mg L^-1 in PBS) was added to each well and further incubated at 37 °C for 4 h. The cell viability is calculated from the following equation [³⁶]:

$\%CellViability=\frac{ExperimentalOD}{ControlOD}\times 100$ (1)

Where experimental OD (OD: Optical density) is obtained by measuring the absorption of formazan solution in DMSO using microplate reader at 570 nm.

RESULTS AND DISCUSSION

Antibacterial evaluation

Nanoscience and nanotechnology by employing biomaterials as novel biocidal agents have shown promising potential for preventing bacterial colonization. Antibacterial activity of compounds has important applications in biomedicine and pharmacology area. Therefore, the CD.Click and CD.COM in vitro antibacterial operations were assessed against gram positive: B. subtilis and S. aureus, and gram negative: P. aeruginosa and E. coli bacteria. The images are shown in Figure 6, and Table 1 tabulates the inhibition of bacteria compared to conventional chloramphenicol and gentamicin antibiotics as controls. The synthesized compounds showed a wide-range of activity against gram positive as well as gram negative bacteria. E. coli's growing (the most prevalent intestinal contaminant) is more inhibited than S. aureus. The crucial process for disinfection is the destruction of exterior wall and bacteria membrane [³⁷]. Microorganisms have different outer membrane [³⁸], for example, the cell wall of E. coli is thinner than S. aureus which can be easily distorted [³⁹]. It is worth mentioning that the antibacterial efficacy measured as region of bacterial growth inhibition halos revealed comparable activity between CD.Click and CD.COM. The antibacterial activity of CD.Click is likely related to the presence of cyclodextrin [⁴⁰,⁴¹] and triazole rings [⁴²], while in the CD.COM, the antibacterial effect depends on TiO₂ NPs [⁴³] along with cyclodextrin and triazole rings participation. Although the composition of CD.Click in the CD.COM structure is ~75% (CD.Click: TiO₂/AS = 3:1), antibacterial activity has relatively increased which could be attributed to the antimicrobial properties of TiO₂ NPs.

Zhang and coauthors established that CDs can disrupt cell membranes and lyse the bacterial cells. One of the known physiological properties of CDs is their high binding affinity to form an inclusion complex with cholesterol molecules. Although the cell membrane of prokaryotes and associated strains do not contain cholesterol or cholesterol-like molecules, but genome sequencing of strains has many genes for flotillin-like proteins. It is supposed that the flotillin-like proteins form a complex with unknown lipid molecules in the cell membranes, and this complex plays a significant role in the building and stabilization of their structures. This suggests that strains possessing the flotillin-like proteins are affected by CDs via trapping the unknown lipid molecules [⁴⁰].

The toxicity of TiO₂ NPs towards bacteria has been not only confirmed photochemically but also by a different mechanism in the dark [⁴⁴]. NPs with positive or neutral zeta potentials carry the positive charges while the microorganisms carry negative charges; this causes electrostatic attraction between microorganisms and NPs leading to physical attachment and contact with cell [⁴⁵]. NPs could create holes in the bacterial cell wall that associated with increased permeability, releasing the cell component and eventually cell death [⁴⁶]. Therefore, TiO₂ NPs with high level of interaction with the bacterial cells surface due to their small size and high surface to volume ratio, perform good antibacterial activity [⁴⁷].

The triazole rings with metabolic degradation stability and capability to hydrogen bond formation could favor binding to biomolecular targets and improve solubility [¹⁸]. The antibacterial activity of triazole rings with these favorable properties is related to inhibit the synthesis of cell membrane, cell wall and nucleic acids of bacteria [⁴⁸].

According to literature review [⁴⁹,⁵⁰], it is assumed that in the CD.COM structure, active sites of -OH and -NH capture bacteria, TiO₂ NPs create cavities in the bacteria cell and cause permeability and disruption of bacterial cell walls, as well as CD disrupt and lyse the bacterial cell walls. The triazole ring moieties also degrade the cell membrane, cell wall and DNA, and finally cause the cell death. Thus the ability of CD.COM to bacterial inactivation was attributed to synergy between the cyclodextrin, TiO₂ NPs and biocidal triazole rings.

Figure 6
The images of antibacterial test.

Table 1
Antibacterial activity of the compounds using Kirby-Bauer test

Test Strain	Zone of growth inhibition (mm)
	CD.COM1	CD.Click1	Gentamicin (10 μg/disc)	Chloramphenicol (30 μg/disc)
E. coli	48.5±1.3	45.0±1.4	19.6±1.1	20.7±1.5
P. aeruginosa	39.8±1.4	37.0±1.4	15.6±0.5	NE*
S. aureus	45.5±0.7	44.5±0.6	20.3±1.5	21.7±0.6
B. subtilis	50.5±0.7	49.5±0.9	26.0±1.7	22.3±1.2

• ¹
  Film diameter: 13 mm & Film weight: 100 mg
• * No Effect

Li and coauthors reported the inhibition zone of cellulose-TiO₂ hybrid (disc shape with 1.4 cm diameter) against S. aureus and E. coli bacteria that were 5.5 mm and 2.5 mm, respectively [⁵¹]. Tan and coauthors investigated the antibacterial effect of 1,2,3-triazole containing starch derivatives against E. coli and S. aureus by disc diffusion method [⁵²]. All the triazole containing starch compounds exhibited a moderate antibacterial activity, and 6-carboxyltriazole-6-deoxy starch (CBTST) displayed the highest inhibition zone for E. coli = 10.27 ± 0.28 mm and S. aureus = 10.76 ± 0.44 mm. Antibacterial activity of cyclodextrins against Bacillus strains was reported by Zhang and coauthors using a diffusion method with filter paper disks (diameter 6 mm). The obtained results established the antibacterial effect of methyl-β-CD [⁴⁰].

Studies conducted by our research group have demonstrated that the CD.COM showed higher antibacterial activity in comparison with cellulose-triazole-titanium based nanocomposite (Cell.Com; E. coli = 27.0 ± 1.4 mm, P. aeruginosa = 20.0 ± 1.4 mm, S. aureus = 26.0 ± 0.7 mm and B. subtilis = 21.5 ± 0.7 mm) [¹⁷]. This result is related to this fact that pure microcrystalline cellulose has not antibacterial activity [⁵¹], in spite of cyclodextrin. Comparing the results of our research work with those reported in the literature indicates that the synergistic effects of TiO₂ NPs, triazole ring and cyclodextrin have improved the CD.COM antibacterial activity.

Cytotoxicity evaluation

Considerable attention has been given on the synthesis of novel compounds with capability of biocompatibility with normal cells and killing cancerous cells. So, the cytotoxic effect of CD.COM was screened in vitro on cancerous cell lines (Hela, MCF-7 and Saos) and fibroblast cells by MTT assay. As can be seen in Figure 7, the CD.COM has no cytotoxic effect on fibroblast cells at concentration range of 7.8-500 mg L^-1 over period of 24 h, while its toxicity is significant on the MCF-7 and Saos cancerous cell lines in concentrations above 15.6 mg L^-1. This toxicity is observed at a concentration dependent way in all three cancerous cell lines over a period of 48 h, while no significant toxicity is observed on fibroblast cells. These results show the promising properties of CD.COM against cancer cells and low toxicity to normal cells. The cytotoxic effect of CD.COM is mostly related to the triazole rings, because the 1,2,3-triazole moiety was reported to possess anticancer activity [⁵³].

Figure 7
The cell viability of studied cell lines after exposure to increasing concentrations of the CD.COM.

CONCLUSIONS

In this manuscript, we investigated the antibacterial activity and cytotoxic effect of new triazole functionalized cyclodextrin (CD.Click) and cyclodextrin-triazole-titanium based nanocomposite (CD.COM). The antibacterial effects of CD.Click and CD.COM were explored against gram negative and gram positive bacteria. The antibacterial assay showed that the CD.Click due to the cyclodextrin and triazole rings, and the CD.COM because of the synergistic effects of cyclodextrin, TiO₂ NPs and triazole rings exhibited a broad variety of activity against both gram positive and negative bacteria. In addition, MTT assay assessed in vitro the cytotoxic effect of CD.COM on cancer cell lines of HeLa, MCF-7, Saos and fibroblast. The CD.COM did not show toxicity in fibroblast cells at a range of 7.8 to 500 mg L^-1 at 24 h, whereas at concentrations higher than 15 mg L^-1, it exhibited significant cytotoxicity against cancer cell lines of Saos and MCF-7. The toxicity was observed as concentration-dependent in all three cancer cell lines after 48 h, but, no significant change was detected in fibroblasts. These findings verify the promising properties of CD.COM against cancer cells and low toxicity to normal cells.

Acknowledgments

This research was partially supported by University of Mazandaran and research council of Shahrood University of Technology.

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Edited by

Editors-in-Chief:

Paulo Vitor Farago

Associate Editor:

Andressa Novatski

Publication Dates

• Publication in this collection
  12 May 2021
• Date of issue
  2021

History

• Received
  11 Dec 2019
• Accepted
  07 Oct 2020