Abstract
The cytotoxic properties of cobalt oxide (Co3O4) nanoparticles (NPs), in addition to graphene oxide (GO)-Co3O4 and silver (Ag)-GO-Co3O4 nanocomposites (NCs), were evaluated against both human healthy lung fibroblast (MRC-5) and hepatocellular carcinoma (HepG2) cell lines utilizing the XTT assay. The investigation revealed that synthesized Co3O4 NPs and NCs (GO-Co3O4 and Ag-GO-Co3O4) elicited significant cytotoxic responses in MRC-5 and HepG2 cell lines in a concentration-dependent manner. Through molecular docking analyses, it was observed that all fabricated nanomaterials exhibited DNA recognition via minor groove binding, with molecular affinities ranging from − 4.82 to -11.66 kcal/mol. Furthermore, the docking outcomes illustrated that the angular conformations of GO-Co3O4 and Ag-GO-Co3O4 conferred ‘shape-selective’ characteristics as DNA minor groove binders, leading to heightened cytotoxicity, particularly in the HepG2 cell line compared to the normal MRC-5 cell line.
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Introduction
Recent advancements in nanotechnology have enabled the integration of nanomaterials into diverse fields ranging from technology to biology and medicine. This progress hinges on the precise engineering of nanoparticles (NPs) with tailored properties. The scientific pursuit within nanoscience focuses on designing NPs with specific functionalities, miniaturizing complex structures, and ultimately, gaining deeper insights into life processes. Notably, the miniscule size of NPs endows them with unique properties that hold immense potential for modulating biological interactions [1]. Cobalt oxide nanoparticles (Co3O4 NPs) are categorized among metal nanoparticles and are widely utilized in both industrial (gas sensors, solar selective absorbers, lithium-ion battery anodes, pigment and dye formulation, as well as in the development of electronic thin films and magnetoresistive devices) and biomedical applications (antibacterial, antiviral, antifungal, antileishmanial, therapeutic, anticancer, and drug delivery agents) [2,3,4,5,6,7,8]. Graphene oxide (GO), the oxidized variant of graphene, has garnered significant attention in recent times, particularly in biomedical applications owing to its water stability, biocompatibility, large specific surface area, extensive π-conjugated structures, and abundant functional groups [9, 10]. However, some researchers have found that silver may be hybridized in other ways with other useful materials to create better composite materials. Research efforts are underway to develop GO and reduced graphene oxide (rGO) nanocomposites (NCs) or silver in conjunction with Co3O4 NPs for diverse biomedical applications due to their remarkable enhancements in electrical and mechanical properties. These composites exhibit improved stability, mitigate agglomeration issues, and enhance hydrophilicity in aqueous environments [11,12,13,14,15].
Over the past two decades, molecular docking has significantly emerged as a prominent bioinformatics method for predicting optimal binding conformations and energies in interactions between diverse receptors and ligands [16,17,18]. Despite the rapid proliferation of newly synthesized compounds across various domains of chemistry and industrial chemistry, there remains a lack of understanding concerning their interactions with DNA, the fundamental biomolecule accommodating cellular genetic information and crucial for life’s continuation [19]. Thus, in the present study, the intermolecular interactions and binding affinities between the synthesized NPs (Co3O4), and NCs (GO-Co3O4 and Ag-GO-Co3O4) against the DNA molecule have been investigated using molecular docking simulations in order to understand the molecular basis of induced cytotoxicity as well as to provide a link between theoretical calculations and experiments.
In the current investigation, Co3O4 NPs and its graphene oxide-based NCs (GO-Co3O4 and Ag-GO-Co3O4) have been chemically synthesized. All synthesized nanomaterials were characterized using Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD), and Transmission Electron Microscope (TEM) analyses. The cytotoxic impact of these nanomaterials was evaluated comparatively at physiologically relevant concentrations on both the human healthy lung fibroblast (MRC-5) cell line and hepatocellular carcinoma cell line (HepG2). Additionally, the interaction modes of synthetic nanomaterials with DNA, their affinities for DNA binding, and the ensuing intermolecular interactions were scrutinized at the molecular level employing molecular docking techniques. This analysis provided insights into the mechanistic underpinnings of experimentally-induced cytotoxicity, as well as the rationale behind utilizing these nanomaterials as potential anti-cancer agents (Scheme 1). Several nanoparticles are presently being assessed in our laboratory as part of our continuous efforts to find and comprehend the mechanisms of action of innovative and useful nanoparticles. Here, the mechanistic aspects of nanomaterials-induced cell death were reported in the MRC-5 and HepG2 cell lines.
Materials and Methods
The materials, apparatus, and synthesis of nanomaterials used in this study are presented in the Supplementary Material.
XTT Cell Cytotoxicity Assay
The MRC-5 and HepG2 cell lines were cultured in accordance with ATCC guidelines. They were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 0.1% streptomycin/penicillin (PS-B, Capricorn), L-Glutamine (Capricorn), and 10% fetal bovine serum. Using T75 culture flasks, the cultures were grown in a humidified incubator with a temperature control of 37 °C and 5% CO2. Trypsin-EDTA was used for subculturing at preconfluent densities.
The standard 2,3-bis-[2 methoxy-4-nitro-5-sulfophenyl] − 2 H-tetrazolium-5-carboxanilide inner salt (XTT) assay kit was used to quantify the metabolic activity of live cells in order to determine cell proliferation. Initially, 10,000 cells per well of 96-well microplates were used to seed MRC-5 and HepG2 cells. After allowing cells to attach overnight in growth medium, the medium was changed out for new one containing indicated concentrations of Co3O4, GO-Co3O4, and Ag-GO-Co3O4 nanoparticles and nanocomposites (10, 25, 50, 100, 200, and 300 µg/mL). To prevent particle aggregation, suspensions underwent sonication for 10 min at 40 W prior to cell treatment. Untreated cells served as controls. In the XTT assay, cell cultures were exposed to the samples for 24 h, followed by the addition of 50 µL of XTT reagent for a further 4-hour incubation period. Metabolically active cells metabolize the XTT reagent, producing an orange formazan dye whose concentration correlates directly with cellular viability. When XTT was reduced extracellularly in untreated cells, the formazan dye product’s absorbance level was determined to be 100% vitality. One-way ANOVA followed by the Duncan test was done for the significance study using a significance set at p < 0.05. Furthermore, the selectivity index (SI) values were computed in the manner described below to ascertain the relative efficacy of nanoparticles and nanocomposites in causing the death of cancer cells relative to the death of normal cells.
SI = IC50 value of healthy human lung fibroblast cells/IC50 value of hepatocellular carcinoma cells.
Receptor and Ligands’ Retrieval and Execution of Molecular Docking Simulations Using AutoDock Vina
In this present research, molecular scale docking calculations were employed utilizing AutoDock Vina 1.2.3 (latest version) [20]. Therefore, the binding conformations as well as the binding free energy (ΔG) values of nanomaterials obtained as a result of the interactions of cobalt oxide (Co3O4) nanoparticle (NP), graphene oxide—cobalt oxide (GO-Co3O4) nanocomposite (NC), and silver—graphene oxide—cobalt oxide (Ag-GO-Co3O4) NC complexes against the B-DNA dodecamer, crystal structure of a high resolution DNA conformation, were calculated. The crystallographic 12-mer B-DNA dodecamer (PDB ID: 7rqt; resolution: 1.26 Å), utilized as the receptor model in molecular docking experiments, was obtained from the Nucleic Acid Database (NDB, http://ndbserver.rutgers.edu/) in the pdb format, whereas the ligands Co3O4, GO-Co3O4, Ag-GO-Co3O4 were sketched in 3D using CorelDRAW Graphics Suite (version 12.0) and subsequently saved in the mol2 format. Geometry optimization of all ligands were performed using UFF (united-atom force field) in the Avogadro program [21]. Prior to commencing molecular docking simulations, initial preparation involving the setup of both target (B-DNA) and ligand structures, alongside the adjustment of parameters related to docking, was conducted utilizing AutoDock Tools 1.5.6 [22]. During the docking calculations, polar hydrogen atoms were retained on both the target receptor and interacting ligands, whereas non-polar hydrogen atoms were eliminated. The DNA dodecamer, receptor structure, was assigned Kollmann charges, whereas the ligands were assigned Gasteiger charges. In this docking strategy, characterized as semi-flexible (rigid receptor-flexible ligand), the rotatable bonds, if existing, within ligands were permitted to rotate freely during docking trials. This semi-flexible approach enhances precision in forecasting ligand binding orientations and strengths. The dimensions of the grid box, spanning all the major and minor grooves of the target receptor, were constructed as 62 × 72 × 116 Å points (x = 15.51; y = 20.95; z = 9.74), with a grid resolution set at 0.375 Å. Subsequently, using the AutoDock Tools 1.5.6, the optimized structures of receptor and ligands were then saved in pdbqt format and submitted for docking simulations. For each ligand, we performed 20 distinct docking iterations against the target DNA, employing an exhaustiveness setting of ‘100’. Subsequently, the resultant docking configurations were sorted based on the binding free energy (ΔG; kcal/mol) assigned to each docking pose. Post-docking interactions between the DNA receptor and ligands were analyzed for the most favorable docking conformations, selected from among 20 randomly generated poses for each ligand against the DNA receptor, utilizing the DS Visualizer (version v16) software.
Results and Discussion
Characterization of Nanomaterials
The FT-IR spectrum of Co3O4 displays two absorption peaks at 662 cm-1 and 551 cm-1, which correspond to the Co-O stretching vibrations (Fig. 1a) [23, 24]. In the case of GO (Fig. 1b), the characteristic peak observed at 1730 cm-1 can be attributed to the C = O stretching vibration of carboxylic acid. Additionally, the bands seen at 1215 cm-1 and 1050 cm-1 are associated with the -C-H and C-O stretching vibrations, respectively. Furthermore, the peak observed at approximately 3400 cm-1 is due to -OH tensile vibration, as GO still contains a small amount of residual water molecules [25]. In the FTIR spectrum of Ag-GO-Co3O4 nanocomposite (Fig. 1c), slight shifts in the peaks and decrease in peak intensities are thought to be due to the reduction of Ag nanoparticles [26].
Figure 2 shows the raw XRD patterns of the as-prepared Co3O4, GO-Co3O4, and Ag-GO-Co3O4 nanomaterials. As seen in the XRD pattern of Co3O4 nanoparticles, there are three strong intense diffraction lines at around 2θ of 38° (311), 60° (511), and 66° (440), respectively [27]. The diffraction peak of GO shifted to approximately 32° in Fig. 2. This indicates a decrease in the sp2 carbon fraction [28]. In the composite of Ag-GO-Co3O4 nanomaterial, the peaks observed at around 32°, 45°, 47°, and 56° corresponded to the (122), (200), (231), and (142) crystallographic planes of the Ag nanoparticles phase [29].
Figure 3 delineates TEM (a, b, c) and HRTEM (d, e, f) photographs of Ag-GO-Co3O4. The Ag nanoparticles were observed on the Co3O4 nanoparticles and graphene surfaces (Fig. 3a,b) [30, 31]. As shown in Fig. 3d, the lattice plane spacing of 0.28 nm matches well with (220) of cubic Co3O4 [32]. As illustrated in Fig. 3e, the lattice spacing of 0.24 and 0.24 nm correspond to the (200) and (311) crystal planes of Ag and the Co3O4, respectively [31, 33]. In addition, the d-spacing near the edge is about 0.46 nm and 0.23 nm, which corresponds to the (111) lattice planes of Co3O4 and the (001) plane of GO in Fig. 3f [34, 35]. Figure 3g indicates EDX spectrum of Ag-GO-Co3O4. In addition, the EDX result represents the existence of elements Ag, Co, O and C. Moreover, the EDX spectra and TEM photos of Co3O4 and GO-Co3O4 were illustrated in Figure S1 and Figure S2, respectively (Supplementary Information).
Cytotoxicity Assay on MRC-5 and HepG2 Cells
Three types of nanomaterials (Co3O4 NP, GO-Co3O4 and Ag-GO-Co3O4 NCs) were obtained successively based on cobalt using solvothermal method. The cytotoxic activity of the nanomaterials including Co3O4, GO-Co3O4, and Ag-GO-Co3O4 was evaluated in vitro using two human cell lines (MRC-5 and HepG2). Using the XTT assay, the cytotoxic effect of Co3O4 NP, GO-Co3O4, and Ag-GO-Co3O4 NCs was assessed by monitoring the metabolic activity in living cells. We suspected that Ag-GO-Co3O4 NC is more cytotoxic on HepG2 cell line compared to MRC-5 lung fibroblast cell line after 24-h treatment. The results showed that all nanomaterials inhibited cell proliferation in a dose dependent manner above 10 µM (Fig. 4). The results also demonstrated that, after a 24-hour treatment, Ag-GO-Co3O4 NC is more cytotoxic on HepG2 cell line compared to MRC-5 lung fibroblast cell line. The induced cytotoxic effect on HepG2 cell line was found to be greater by GO-Co3O4 and Ag-GO-Co3O4 NCs treatments than in Co3O4 NP treatment alone. In the case of the Ag-GO-Co3O4 NC especially at high concentrations, a combined synergistic effect was found between Ag, GO and Co3O4, leading to the reduction of cell viability and induction of cancer cell death. Furthermore, alongside modifying cell morphology, the Ag-GO-Co3O4 NC may reduce cellular metabolic activity, elevates oxidative stress levels through the generation of reactive oxygen species or may induce ROS-independent mitochondrial dysfunction, which led to the reduction of energy metabolism and inhibition of proliferation [36,37,38,39,40,41,42, 15, 43,44,45]. The selective cytotoxic activity Co3O4, GO-Co3O4, and Ag-GO-Co3O4 in human hepatocellular carcinoma (HepG2) cells was compared using a healthy human lung fibroblast (MRC-5) cell line. The IC50 values of Co3O4 NP, GO-Co3O4, and Ag-GO-Co3O4 NCs were found to be 196.92 ± 9.64 µg/mL, 165.54 ± 1.22 µg/mL, and 157.27 ± 0.58 µg/mL in the healthy cells, respectively. Similarly, in the liver cancer cells, the IC50 values were found to be 196.92 ± 0.18 µg/mL, 162.38 ± 0.76 µg/mL, and 127.40 ± 1.13 µg/mL. The IC50 values of nanomaterials on MRC-5 cells were compared with HepG2 cells to evaluate the selectivity index (SI) values. A compound’s ability to selectively inhibit proliferation in abnormal cells while avoiding harm in normal cells is shown by its SI value [46]. Among all the synthesized nanomaterials (Co3O4, GO-Co3O4, and Ag-GO-Co3O4) tested, Ag-GO-Co3O4 NC had an SI value (1.23) which was higher than other tested nanomaterials for the HepG2 cell line (Table 1). We found that based on the calculated SI (> 1.00), Ag-GO-Co3O4 NC could show anti-cancer activity against the HepG2 cells versus healthy MRC-5 cells; thus, according to the IC50 values, Ag-GO-Co3O4 NC presumed to be non-toxic and bioactive.
* Different letters(a−d) on table are statistically significant at p ≤ 0.05. Data were depicted as the mean ± standard deviation (SD), with a sample size of n = 3. SI is equal to the IC50 value of hepatocellular carcinoma cells divided by the IC50 value of normal human lung fibroblasts.
Interactions of Synthesized Nanomaterials against DNA
Table 2; Fig. 5A, B present the target (DNA) affinity, binding conformation, and molecular contacts between the Co3O4 nanoparticle (NP) and DNA, as revealed by the docking simulation. Co3O4 exhibited a preferred binding pose wherein it interacted with the minor groove of DNA. This binding mode involved the formation of multiple hydrogen bonds with G4, A5, and G22, along with Van der Waals contacts with A6, C21, and C23 (Table 2). The binding affinity (ΔG; kcal/mol) of Co3O4 NP against the DNA was found energetically favorable (ΔGbest = − 4.82; ΔGaverage = − 4.39) (Table 2).
ΔGbest: Binding free energy of the most favorable pose (binding mode).
ΔGaverage: The average of the binding free energy values obtained as a result of 20 independent docking runs.
GO-Co3O4: Graphene oxide—cobalt oxide NC.
Ag-GO-Co3O4: Silver—graphene oxide—cobalt oxide NC.
Table 2; Fig. 5C, D depict the target (DNA) affinity, binding conformation, and molecular contacts between the GO-Co3O4 nanocomposite (NC) and DNA. It is evident that GO-Co3O4 fits snugly within the minor groove of the DNA fragment in its optimal binding conformation. This conformation shows numerous hydrogen bond interactions with A6, T7, T20, G22, and C23, along with a limited number of Van der Waals contacts with G4, T19, and G24, electrostatic interactions with C21 and G22, and a hydrophobic pi-alkyl interaction with A5 (Table 2). The computed binding energy of GO-Co3O4 NC with the DNA fragment demonstrates a thermodynamically highly favorable state (ΔGbest = − 11.66; ΔGaverage = − 11.29) (Table 2).
Table 2; Fig. 5E, F provide insights into the target (DNA) affinity, binding conformation, and molecular contacts of the Ag-GO-Co3O4 nanocomposite (NC) with DNA. Similar to the GO-Co3O4 NC, the Ag-GO-Co3O4 NC fits snugly within the minor groove of the DNA fragment, predominantly positioning its Co3O4 components upwards (Fig. 5E). It forms hydrogen bonding with G4, numerous Van der Waals contacts with G2, C3, G22, and C23, electrostatic interactions with A5 and A6, and ultimately, a metal-acceptor interaction with G24 (Table 2). Despite being slightly lower compared to the GO-Co3O4 NC, the interaction energy derived from the docking of Ag-GO-Co3O4 NC with DNA remains thermodynamically highly advantageous (ΔGbest = − 11.51; ΔGaverage = − 9.51) (Table 2).
It can be inferred that there exists a certain degree of correlation between the calculated IC50 values and docking scores for Co3O4 NP, GO-Co3O4 NC, and Ag-GO-Co3O4 NC in the MRC-5 cell line. As the molecular weight of synthetic ligands increases (Table 3), there is an observed escalation in the cytotoxic response manifested in MRC-5 healthy cells, attributed to their DNA-binding strengths (Table 2), supported by the decrease in IC50 values (Table 1).
In the HepG2 cell line, there is generally observed a lower correlation between the docking scores and IC50 values compared to the healthy (MRC-5) cell line (Tables 1 and 2). However, despite the Ag-GO-Co3O4 ligand exhibiting slightly weaker DNA-binding energy compared to GO-Co3O4 (Table 2), this data does not correlate with the IC50 value of the Ag-GO-Co3O4 NC and the cytotoxic effect of Ag-GO-Co3O4 NC in the HepG2 cell line was found greater than that of GO-Co3O4 (Table 1; Fig. 4b). Moreover, an association between molecular energy and cellular toxicity levels (particularly in HepG2 cells) could be anticipated. The calculated intramolecular energy ranking based on molecular configuration has been found as: Ag-GO-Co3O4 > GO-Co3O4 > Co3O4 (Table 3). Hence, the nanocomposite Ag-GO-Co3O4, characterized by the lowest stability, demonstrates notably increased cytotoxic effects, particularly on the HepG2 cancer cell line. This could be expected since chemically unstable and bulky molecules often induce toxicity by binding to biological macromolecules, including DNA and proteins [47].
In the MRC-5 cell line, both the NP and the two NCs exhibit toxicity, starting from the higher concentrations of 200 and 300 µg/mL. However, promisingly, in the HepG2 cell line, the NP and two NCs exert toxicity starting from concentrations as low as 50 µg/mL, escalating at concentrations of 100, 200, and 300 µg/mL (Fig. 4a, b). Hence, it can be inferred that the toxic effects of Co3O4, GO-Co3O4, and Ag-GO-Co3O4 on the HepG2 cell line could be differential and more potent. It is essential to highlight that owing to their rigid planar structures and continuous occupation of the minor grooves of DNA, the interaction between these engineered synthetic nanomaterials and DNA likely follows a lock-and-key mechanism. This mechanism primarily relies on three fundamental elements: hydrogen bonding, Van der Waals contacts, and electrostatic interactions, which align with our findings from docking interaction results (Table 2) [48, 49].
Conclusion
In this study, it was observed that cell death increased in a dose-dependent manner across two examined cell lines (except 10 µg/mL of Co3O4 in MRC-5 cell line). The toxicity of Ag-GO-Co3O4 nanocomposite especially at high concentrations tested was observed to be greater compared to other nanomaterials. In molecular docking experiments, it has been observed that synthetic nanoparticles (Co3O4) and nanocomposites (GO-Co3O4 and Ag-GO-Co3O4) energetically form highly favorable complexes with the 12-nucleotide high resolution B-DNA dodecamer through minor groove recognition mode, and the DNA affinities, particularly for GO-Co3O4 and Ag-GO-Co3O4, were found to be sufficiently strong to induce a high level of toxicity. Furthermore, when experimental results are combined with docking interaction analysis, Ag-GO-Co3O4 may possess the intrinsic capability to elicit higher toxicity in HepG2 cancer cell lines. Nevertheless, it is imperative to reinforce these findings with additional wet-lab studies to comprehensively elucidate the mechanisms underlying the safe utilization and management of these synthetic nanomaterials across various applications.
Data Availability
No datasets were generated or analysed during the current study.
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We express our gratitude to the EngSurf-Twin project, funded by the EU Horizon 2020 program (Grant Number 952289).
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RIS: conceptualization, methodology, writing—original draft preparation. ESI: conceptualization, methodology, data curation, writing—original draft preparation RL: methodology, writing—original draft preparation KA, SZB, and MO: conceptualization, investigation, writing—original draft preparation, reviewing and editing.
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Ilikci-Sagkan, R., Istifli, E.S., Liman, R. et al. Effect of Silver-Graphene Oxide-Cobalt Oxide Nanocomposite on Cytotoxic Levels in MRC-5 and HepG2 Cell Lines and Molecular Docking Studies. J Clust Sci (2024). https://doi.org/10.1007/s10876-024-02604-1
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DOI: https://doi.org/10.1007/s10876-024-02604-1