Silver Nanoparticles Biosynthesized Using <i>Azadirachta indica</i> Fruit and Leaf Extracts: Optimization, Characterization, and Anticancer Activity

Alharbi, Njud S.; Alsubhi, Nehad S.

doi:https://doi.org/10.1155/2023/9916777

Journal of Nanomaterials

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Abstract Introduction Materials and Methods Results and Discussion Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 9916777 | https://doi.org/10.1155/2023/9916777

Silver Nanoparticles Biosynthesized Using Azadirachta indica Fruit and Leaf Extracts: Optimization, Characterization, and Anticancer Activity

Njud S. Alharbi¹and Nehad S. Alsubhi²

Academic Editor: Zhengwei Huang

Received07 Dec 2022

Revised06 Aug 2023

Accepted12 Oct 2023

Published26 Oct 2023

Abstract

Silver nanoparticles (AgNPs) are becoming increasingly important for various crucial applications, including antimicrobial, anticancer, catalytic, and anti-inflammatory. AgNPs biosynthesized from plant extracts have attracted considerable attention because of their eco-friendliness, simplicity, cost-effectiveness, and stability. This study investigated the potential of using fruit and leaf extracts of the medicinal plant Azadirachta indica as a capping and reducing agent for the biosynthesis of AgNPs. The size, shape, and optical properties of AgNPs significantly affect their chemical, physical, and biological activity. Therefore, this study optimized the biosynthesis conditions as a first attempt for A. indica fruit extracts to produce AgNPs with precise morphology. Subsequently, the biologically manufactured AgNPs were characterized using suitable techniques. Their potential anticancer activities were examined against in vitro human lung and breast cancer (H1975 and MCF-7) cell lines. The AgNPs were stable, with a high yield and a spherical shape, ranging in size from 14 to 19 nm and exhibiting an absorption band between 420 and 440 nm. The AgNPs biosynthesized using A. indica fruit and leaf extracts were shown to be highly toxic against in vitro H1975, with IC₅₀ of 62.2 and 91 µg/mL, respectively. The IC₅₀ values were 67.5 and 68.7 µg/mL when testing against the MCF-7 cells. These findings suggest that plant-derived nanoparticles have enormous potential for future biomedical applications, which warrants further investigation.

1. Introduction

Nanotechnology plays a crucial role in science and requires the manipulation of matter to give rise to new structures, devices, and materials. Notably, the manipulation of matter occurs at a near-atomic scale, which stipulates the number of particles required. Nanotechnology was first introduced in 1959 by Richard Feynman, a Nobel Prize winner, and gained considerable attention, leading to its development in 1974.

Nanoparticles (NPs) are small molecules ranging between 1 and 100 nm. Their different physical and chemical forms are not visible to the naked eye [1]. Based on the presence of a carbon atom, nanoparticles can be classified into two groups: organic and inorganic. Inorganic nanoparticles include metallic NPs, such as gold and silver, and semiconductor NPs, such as zinc oxide, titanium, and magnetic nanoparticles. Recently, inorganic nanoparticles have been widely used in many applications owing to their promising properties. For example, these metallic particles have been studied as medical agents for treating various diseases [2]. Currently, the most common types of nanoparticles are semiconductors, metals, carbon-based, ceramic, polymeric, and lipid-based nanoparticles.

In recent studies, silver nanoparticles (AgNPs) are the most popular metal nanoparticles [3]. AgNPs have gained immense importance, primarily because of their large surface area, which enables coordination with many ligands, a feature not commonly found in many other types of nanoparticles [4]. The chemical, biological, and physical properties of AgNPs make them good candidates for various applications in pharmaceuticals, water treatment, biolabeling, food industries, optics, textile coatings, catalysis, light emitters, energy science, integrated circuits, antimicrobial deodorant fibers, sensors, and drug delivery [5]. AgNPs have different shapes, including octagonal, diamond, and thin sheets, but a spherical shape is preferable in most applications [6]. AgNPs can be formulated chemically, physically, or biologically [7]. Chemical methods may result in AgNPs retaining toxins during the synthesis [8]. Physical methods may require high pressure and irradiation [9]. Biological methods that employ bacteria, fungi, and yeast to synthesize AgNPs ranging from 1 to 100 nm might be an alternative and are considered safe for humans and the environment [10]. Green or biological nanotechnology can improve the quality of life in several fields, including food, biomedical, and agricultural [11]. In addition, the nanoscale provides higher surface-to-volume ratios, which allow them to be applied in a wide range of fields, including antibacterial properties, medicine, diagnostics, anticorrosion, microelectronics, catalysis, biofertilizers, and nanosensors [12]. In addition, large-scale nanoparticles can be synthesized with green chemical processes, which can also be used to decrease pollution by absorbing environmental toxins and acting as a green corrosion inhibitor in acidic and basic media. It is also helpful for therapeutic applications, corrosion research, and cytotoxicity research [13]. The synthesis process mainly requires metal precursors (AgNO₃), reducing agents, stabilizing agents, and capping agents [14].

The use of medicinal plants to manufacture AgNPs has been previously studied [15–17]. Extracts from medicinal plants are economical, energy efficient, and environmentally friendly [18]. Using green chemistry to synthesize nanoparticles gave a hint for molecules consisting of biologically active plant extracts, which could reduce and stabilize the process [12]. The synthesis of AgNPs from plants is a simple two-step process. The first step involves the reduction of silver ions (Ag⁺) to Ag. The second step is stabilization and agglomeration, leading to AgNPs forming (Figure 1) [5]. The hydroxyl groups involved in phytochemicals in plants, including flavonoids, enzymes, tannins, alkaloids, amino acids, and proteins, are mainly responsible for stabilizing and reducing Ag⁺ to Ag⁰ [8]. Reducing the Ag⁰ further results in growing silver nuclei, hence forming AgNPs.

Biosynthesizing AgNPs from plant extracts is relatively easy, simple, and inexpensive (Figure 2). However, plant extract-based AgNP synthesis has a few limitations that must be addressed. For instance, phytochemicals may change during plant growth owing to internal/environmental exposure, affecting the reproducibility, homogeneity, and polydispersity of AgNPs. AgNPs may aggregate when synthesized with plant extracts, resulting in a large surface area. Furthermore, the diversity and complexity of plant extracts used in photochemical synthesis pose a significant challenge in understating their roles in regulating the shape and size of AgNPs under experimental conditions.

Azadirachta indica is a widely used medicinal plant in South and Southeast Asia and is grown in many parts of the world owing to its health benefits [19]. The extracts have been shown to cure various ailments and are used as fertilizers [20]. The biosynthesis of AgNPs employing leaf extract from A. indica has been reported in various studies [21, 22]. A. indica extract is vital for synthesizing AgNPs because of its flavanones and terpenoids, which stabilize AgNPs [22].

Cancer is a genetic disease caused by the mutation, amplification, or abnormal expression of essential genes involved in cell fate regulation [23]. Globally, breast cancer is the most common form of cancer, followed by lung cancer, as reported by the World Health Organization in 2020. Despite the significant investment of 5.5 billion dollars in breast cancer research over the past 20 years [24], the underlying causes of this disease are still unknown. Current medicines often prove fatal to patients because of their undesirable side effects. Thus, developing alternative tumor medicines with fewer side effects is necessary. In addition to other research areas, the natural manufacturing of products from medicinal herbs is the most successful. Nanotechnology applications in biological systems have recently been designated as a novel category in translational and reformative therapies. AgNPs have recently attracted considerable interest because of their ability to damage DNA, destroy tumor cells, generate reactive oxygen species (ROS), and regulate signaling pathways [25]. In our previous study, we synthesized AgNPs from A. indica fruit extracts, which exhibited a decrease in A549 cell viability [25]. This is the first study to optimize the biosynthesis of AgNPs using A. indica fruit extracts or assess their anticancer effects in lung and/or breast cancer (H1975 and/or MCF-7) cells. Therefore, this study aimed to biosynthesize AgNPs using A. indica fruit and leaf extracts and optimize the synthesis conditions to form AgNPs with precise morphologies. In addition, the study also examined the toxicity of the biosynthesized AgNPs against in vitro H1975 and MCF-7 cells, achieving significant results.

2. Materials and Methods

2.1. Materials

Harvest and collection of A. indica leaves, and fruits took place in Makkah City, Saudi Arabia, on October 14^th and March 13^th, 2020, respectively. The breast cancer line, MCF-7, was obtained from King Fahd Medical Research Center at KAU, Jeddah, KSA. The nonsmall cell lung cancer cell line, H1975, was obtained from King Faisal Specialist Hospital & Research Center, Jeddah, KSA. In addition, the following reagents were purchased from Solarbio, China: fetal bovine serum (FBS), Dulbecco’s modified Eagle medium (DMEM), phosphate-buffered saline (PBS), dimethyl sulfoxide (DMSO), 100 U/mL penicillin, 100 mg/mL streptomycin, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye.

2.2. Plant Preparation

As previously described [26], the fruits and leaves of A. indica were washed twice with tap water, rinsed twice with distilled water, and dried in the shade at 25°C (room temperature). The leaves and fruits were then powdered, kept in a sealed container, and stored at −20°C until use [27]. The preparation time for A. indica fruits and leaves was nearly identical.

2.3. Aqueous Plant Extraction

Plant extraction was performed as previously described [26]. Fruits and leaves (5 g) were suspended in 100 mL of deionized water in a 250 mL flask. The solution was boiled for 10 min at 100°C and then filtered using a coffee filter first to separate the large particles. Subsequently, further filtering was performed using Whatman No. 1 filter paper to obtain a clear solution. The extracts were then poured into an Erlenmeyer flask (250 mL) and refrigerated until further use. The A. indica leaves, fruits, and extracts are shown in Figure 3.

2.4. Synthesis of AgNPs

As described previously, 90 mL of 1 mM AgNO₃ solution was added separately to 10 mL of fruit and leaf extracts [28]. The mixture was placed at room temperature (25°C) until the sample color changed, centrifuged for 15 min at 12,000 rpm, the supernatant was removed, and the pellet was washed with deionized water. The centrifugation was repeated twice or thrice to remove any substances absorbed from the AgNPs. Figure 4 shows a schematic illustrating the synthesis of AgNPs using plant extracts. Finally, the samples were freeze-dried for further characterization and application.

2.5. Optimizing the AgNPs Synthesis

This study evaluated the effects of synthesis parameters, including extract concentration, temperature, pH, and light intensity, on the morphology and yield of AgNPs. The AgNO₃ solution (1 mM) remained constant despite all the conditions. The plant extracts and AgNO₃ solutions had a pH of 7. As previously described [29], AgNPs were synthesized using different extract concentrations: 10%, 20%, and 30% at a temperature of 25°C and a pH value of 7. As per a previous study [30], we synthesized AgNPs at various temperature values: 25, 40, 60, and 80°C using 10% extract concentration and pH 7. Moreover, acetic acid (CH₃COOH) and sodium hydroxide (NaOH) were added in small amounts to adjust various pH conditions (acidic at 4, neutral at 7, and basic at 9) that were employed to create AgNPs at 25°C and 10% extract concentration, as previously described [31]. The AgNPs were synthesized under different light conditions: dark, room light, and sunlight, using a 10% extract concentration at 25°C and pH 7, as previously described [32]. In addition, the AgNO₃ concentration and reaction time effect on the morphology of the AgNPs were extensively studied [21]. Although AgNPs can be synthesized using AgNO₃ concentrations ranging from 0.1 to 10 mM, 1 mM is the best AgNO₃ concentration for synthesizing AgNPs, as previously reported [33, 34]. Hence, this study used a 1 mM AgNO₃ concentration. Multiple reactions with different durations can increase the reduction rate and synthesize AgNPs with the appropriate morphology [35]. A previous study concluded that AgNPs were completely produced when plant extracts were incubated with AgNO₃ for 6 hr [36]. Hence, increasing the reaction time increases the reduction rate of AgNP synthesis.

2.6. Characterization of AgNPs

2.6.1. Ultraviolet–Visible Spectroscopy

As previously described [26], 3 mL of AgNP solution was placed in a UV glass cuvette cell and analyzed using ultraviolet–visible (UV–Vis) spectroscopy at wavelengths ranging from 300 to 600 nm with a 1 nm resolution at room temperature (∼25°C). Deionized water was used as a blank to calibrate the spectrophotometer.

2.6.2. Fourier Transform Infrared Spectroscopy

Fourier transform infrared (FTIR) spectroscopy (Thermo Fisher Scientific, Waltham, MA, USA) was used to examine the functional groups before and after the biosynthesis of AgNPs. Dried samples of plant extracts and AgNPs were analyzed by FTIR spectroscopy and scanned in the range of 600–4,000 cm⁻¹ and at 4 cm⁻¹ transmittances.

2.6.3. Field Emission Scanning Electron Microscopy

Field emission scanning electron microscopy (FESEM) was used to determine the shape and size of AgNPs. As previously described [37], a thin film of each biosynthesized AgNP sample was created by adding a few drops of the sample to a copper grid. The grid was allowed to dry at 25°C. The prepared samples were then examined using FESEM at magnifications of 250,000x and 120,000x (model Jeol 7600 F FESEM, Tokyo, Japan).

2.6.4. Dynamic Light Scattering and Zeta Potential

Dynamic light scattering (DLS) and zeta potential were used to measure the dynamic size distribution and surface charge of the synthesized AgNPs, respectively, using a Zetasizer (Malvern ZEN3600, Malvern Instruments, Malvern, UK). All nanoparticles were sonicated for 5 min before DLS and zeta potential analysis. As previously described [38], the AgNP solution was diluted with distilled water, and 1 mL of the sample was placed in a cuvette for analysis. The autocorrelation functions consist of an average of six runs of 10 s for each sample.

2.7. Anticancer Activity of AgNPs

The cytotoxicity of green-synthesized AgNPs against the cancer cell lines H1975 (lung cancer) and MCF-7 (breast cancer) was determined according to the methodology described in a previous study [39]. The cultivated cells were placed into 96-well microplates at 10,000 cells/well density for H1975 and 5,000 cells/well for MCF-7 in triplicate and incubated at 37°C with 5% CO₂. The cells were cultured in DMEM containing 10% FBS and 100 µg/mL penicillin/streptomycin. After reaching 70% confluence, the cells were exposed to variable concentrations of AgNPs ranging from 12.5 to 200 µg/mL, and 3% DMSO was used to dissolve powdered AgNPs. After 48 hr of incubation, the MTT assay was performed to determine the cytotoxicity of AgNPs by measuring absorbance at 570 nm using an enzyme-linked immunosorbent assay microplate reader. Cell cytotoxicity was determined by calculating the percentage of viable cells remaining using Equation (1):

3. Results and Discussion

3.1. Synthesis of AgNPs

As reported earlier, a change in the reaction solution (dark brown color) confirmed the formation of AgNPs. Surface plasmon resonance excitation and its bands, which result in the color change solution, are important for confirming the synthesis of AgNPs [40]. In addition, this indicates that the phytochemicals in the fruit and leaf extracts of A. indica magnificently reduced silver ions to Ag⁰ in solution. A. indica fruit and leaf extracts were used to stabilize AgNPs, as the color of the solution remained unchanged after 6 months. In previous studies, the stabilization of nanoparticles has been achieved using chitosan oligosaccharide lactate or sebacic acid [41, 42]. Figure 5 shows the AgNO₃ and AgNP solutions before and after synthesis, with the color changing from bright green to a stable dark brown, indicating a complete reduction of Ag⁺ into AgNPs [43].

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3.2. Characterization of AgNPs

3.2.1. UV–Vis Spectroscopy Analysis

AgNPs exhibit a high surface plasmon resonance in an aqueous solution and emit light between 400 and 500 nm, depending on their size, shape, and morphology [44]. Thus, as shown in Figure 6, since no peak appears in the 400–500 nm range for extracts or AgNO₃, the peak wavelengths observed in this range should be only for nanoparticles. The absorption spectra of AgNPs were evaluated at different parameters (extract concentration, temperature, pH, and light intensity), illustrating the impact of these parameters on the morphology and yield of AgNPs.

(1) Extract concentration. To study the influence of extract concentrations, we biosynthesized AgNPs at different extract concentrations: 10%, 20%, and 30% at 25°C and pH 7. Figure 7 shows that the absorption intensity of AgNPs increases with increasing extract concentration. The results showed that fruits produced AgNPs with a higher absorption intensity than those formed by leaves, indicating that the fruits yield more nanoparticles than leaves. In addition, increasing the concentration of A. indica leaf extract from 10% to 30% shifted the absorbance (silver peak) from 434 to 410 nm, forming a smaller particle size. However, the particle size was stable when using A. indica fruit extract, as the silver peak appeared at a wavelength of 424 nm, regardless of the extract concentration. Furthermore, the color of the solution slowly changed to brown as the extract concentration increased, illustrating the slow reduction of Ag⁺ to form Ag⁰. These findings are consistent with previous studies [29, 45].

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(2) Temperature. Figure 8 shows an increase in the growth of AgNPs with increasing temperature. For example, increasing the temperature from 25 to 80°C decreased the wavelength of the absorbance peak from 424 to 410 nm for the AgNPs synthesized using A. indica fruit extracts, forming small-sized nanoparticles. Similar results were observed for AgNPs synthesized using A. indica leaf extract. Hence, high temperatures could promote nanoparticle growth because the higher kinetic energy of the particles at high temperatures enables faster bioreduction of silver ions. These findings are consistent with previously reported results [46, 47].

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(3) pH. Different pH values (acidic at pH 4, neutral at pH 7, and basic at pH 9) were used to optimize the synthesis of AgNPs. Figure 9 shows that when the pH was increased to 9, higher absorption intensities were observed at 410 and 405 nm for AgNPs biosynthesized using A. indica fruits and leaves, respectively, illustrating the production of small nanoparticles. These findings confirm that pH can enhance the reduction rate of Ag⁺, resulting in a brown color after a few seconds of adding silver nitrate solution to the extracts. High pH can improve the bioavailability of the functional groups in plant extracts, and similar results have been reported [46]. However, Verma and Mehata [46] reported that high pH resulted in the agglomeration and instability of nanoparticles in storage. At pH 7, absorbance peaks appeared at 425 and 429 nm for AgNPs synthesized from leaves and fruits, respectively. A previous study [47] demonstrated that pH 7 is the most suitable for synthesizing AgNPs compared to the other pH values. These findings suggest that a neutral environment can help form appropriately sized nanoparticles. The difference in absorbance between pH 7 and pH 9 may result from the fact that pH 7 reactions take 20 min to occur while pH 9 reactions take just a few seconds. By contrast, AgNPs were slowly synthesized at a pH value of 4. They had broad wavelengths with increasing peak absorption, thus forming large nanoparticles.

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(4) Light Intensity. The AgNPs were synthesized under different light conditions (dark, room light, and sunlight), and the results are discussed in Figure 10. When exposed to sunlight, the absorbance intensity of the narrow peak increased, indicating the complete formation of AgNPs. A previous study using A. indica leaves reported that exposure to sunlight accelerated the formation of smaller AgNPs [48]. Owing to photon promotion, AgNPs are rapidly biosynthesized under sunlight. Furthermore, under both room light and sunlight conditions, the biosynthesized AgNPs had absorbance peaks at the same wavelengths, confirming that sunlight does not affect nanoparticle size but only catalyzes the reaction to obtain high yields of AgNPs. However, no nanoparticles were produced under dark conditions when leaf extract was used. By contrast, the fruit extract could produce nanoparticles, which may be attributed to the difference in the phytochemicals in fruits and leaves. These results suggest that light plays a critical role in accelerating AgNP synthesis. A previous study reported that small AgNPs could be produced using pomelo peel extracts under direct sunlight [49].

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The synthesis parameters (30% extract concentration, 80°C, pH 9, and room light) with the best results were used to synthesize the AgNPs, and the results are shown in Figure 11. Biosynthesized AgNPs with broad absorption peaks were observed, indicating particle aggregation. A previous study reported similar results [50]. The aggregation and growth of AgNPs accelerate at high temperatures upon adding plant extracts to the AgNO₃ solution, resulting in unstable AgNPs, which may lead to the degradation and loss of bioactive compounds [51]. Furthermore, AgNPs were synthesized at 10% extract concentration, pH 7, and sunlight, providing high yields and narrow peaks, as shown in Figure 11. These results optimized the synthesis parameters (10% extract concentration, pH 7, and sunlight light) for further investigations in this study.

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3.2.2. FTIR Analysis

In the FTIR analysis, the AgNPs spectrum displayed several bands across the 600–4,000 cm⁻¹ measurement range. Figure 12 shows the FTIR spectra of the biosynthesized AgNPs and the A. indica fruit and leaf extracts. The results show equal performance from both A. indica leaf and fruit extracts to bind and reduce Ag⁺ through functional groups, owing to the similarity of the absorbance bands. The absorbance bands of the leaf extract were in the range of 3,300–3,340, 2,920–2,940, 1,600–1,630, 1,400–1,430, and 1,020–1,050 cm⁻¹. The bands around 3,300, 2,900, 1,600, 1,400, and 1,020 cm⁻¹ correspond to the functional groups present in the sample. They also correspond to OH-bonding, confirming the existence of phenol, CH alkyl, C = N, NH, and CO stretching, respectively [52]. The band at 2,345 cm⁻¹ was only observed in the fruit extract, corresponding to CH alkenes [53]. However, the peaks observed in both A. indica extracts disappeared in the AgNPs, suggesting that amino groups are partly utilized for stabilizing and encapsulating the nanoparticles. In addition, the band around 2,900 cm disappeared when synthesizing AgNPs from fruit extract, and it appeared when using leaf extract, suggesting that CH groups are also involved in nanoparticle synthesis. These findings agree with previously reported results [54] and [55]. A. indica extracts contain phenolics, flavonoids, and other bioactive compounds, which react to form AgNPs [56].

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3.2.3. FESEM Analysis

Figures 13 and 14 show the spherical shapes with uniform distributions for both biosynthesized AgNPs. In addition, the average size of AgNPs synthesized from A. indica fruit and leaf extracts are 14.5 and 18.7 nm, respectively. An earlier study of A. indica leaf extract synthesized larger AgNPs with sizes of approximately 20–50 nm [21]. The FESEM images also showed a small aggregate of nanoparticles, possibly due to sample preparation for FESEM analysis, which agrees with this study [57]. The spherical nanoparticles interact better with cell surfaces, facilitating the uptake of these particles by cells and thus increasing their cytotoxicity [58]. Furthermore, AgNPs have size-dependent activity, with small-sized AgNPs more toxic to the cells [59].

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3.2.4. DLS and Zeta Potential

DLS measurements revealed that AgNPs biosynthesized using A. indica fruit extract had a size of 245 nm, as shown in Figure 15(a). By contrast, a particle size of 160 nm was observed when using A. indica leaf extract, as shown in Figure 16(a). The particle sizes measured by DLS appear larger than those measured by FESEM because DLS includes bioorganic molecules encapsulating AgNPs [60]. Moreover, Van der Waals forces may increase the particle size of the solution. Furthermore, the results showed that AgNPs biosynthesized using A. indica fruit and leaf extracts had a polydispersity index (PDI) of 0.24 and 0.29, respectively, which is satisfactory for drug delivery applications [61]. PDI is an indicator of the stability and dispersity of nanoparticles; thus, nanoparticles with a PDI less than 0.5 are considered monodispersed and stable [62]. A previous study [63] reported similar particle sizes of AgNPs synthesized from Rheum palmatum root extracts.

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The zeta potential evaluates the stability and surface charge of AgNPs. AgNPs synthesized from A. indica fruit extract exhibited a zeta potential of −35 mV (Figure 15(b)). By contrast, those synthesized from A. indica leaf extracts had a zeta potential of −23 mV (Figure 16(b)). An extract capped by nanoparticles has a negative zeta potential [64]. Generally, nanoparticles with zeta potentials ranging from −20 to −30 mV are moderately stable [65]. Hence, AgNPs synthesized from A. indica fruit were more stable than AgNPs synthesized from leaf extract. These findings are significant compared to previous findings [55]. This study suggests that A. indica fruit extract can produce stable AgNPs with precise morphologies and yields, supporting various applications, including antibacterial, antiviral, antifungal, anti-inflammatory, and anticancer activities.

3.3. Anticancer Properties of AgNPs

Recent studies have suggested that AgNPs may act as therapeutic agents for cancer treatment because of their unique properties [66]. This study was conducted to test the anticancer activity of AgNPs in breast (MCF-7) and lung (H1975) cancer cell lines. Figure 17 shows images of the cells obtained using an inverted microscope (Leitz, Wetzlar, Germany). As observed with an inverted microscope, treatment with AgNPs caused the MCF-7 and H1975 cells to lose their typical morphological characteristics, and many shrinkage and necrotic cells were detected following exposure to AgNPs compared to untreated control cells (Figure 17). The results demonstrated a decrease in cell viability for both cancer cell lines with increasing concentrations of AgNPs, suggesting the cytotoxicity of the nanoparticles against cancer cells (Figure 18). A previous study reported that AgNPs could be cytotoxic to breast and lung cancer cells, depending on their concentration [67]. AgNPs’ anticancer properties are due to their induction of ROS in the cells, which stimulates apoptosis, autophagy, and necrosis [68]. The results of the MTT assay showed that AgNPs biosynthesized from A. indica fruit extract had more cytotoxic effects on H1975 lung cancer cells than AgNPs produced using A. indica leaf extract, with IC₅₀ of 62.2 and 91 µg/mL, respectively. This difference in cytotoxicity may be attributed to the fact that fruit extract contains more phytochemicals than leaves. The apoptotic action of small nanoparticles appears to be mediated by their uptake into nuclei within the intracellular membrane, which varies from the uptake of larger particles. A previous study reported that nanoparticles with a size of 50 nm could be rapidly and efficiently incorporated by mammalian cells via endocytosis compared to other sizes [69]. However, cells had a much lower uptake of nanoparticles larger than 50 nm. The researchers also demonstrated that smaller AgNPs are more capable of causing apoptosis in MC3T3-E1 cells than larger AgNPs. Small AgNPs are more toxic because of their larger surface areas, which release silver ions faster, activating ROS and resulting in apoptosis. The larger surface area of nanoparticles allows for better penetration and metal activity [28].

Besides the nanoparticles’ size, the surface charge is considered one of the most critical factors governing AgNPs’ toxicity [70]. The AgNPs cytotoxicity mechanism combines the effects of surface charge and a release of silver ions from nanoparticles. The surface charge of AgNPs is crucial for the development of responses of cells to stress action. It plays a significant role in binding proteins, changing the AgNPs’ physical and chemical properties. As the surface charge increases, the toxicity of nanoparticles increases. AgNPs biosynthesized from fruits and leaves showed similar cytotoxic effects on MCF-7 cells, with IC₅₀ values of 67.5 and 68.7 µg/mL, respectively. In this study, AgNPs from A. indica leaf extract show better toxicity against MCF-7 cells than previously reported [71]. Moreover, plant-derived AgNPs’ toxicity levels may vary depending on the target cells, extraction solvents, collection site, and study period. Media ionize AgNPs differently, influencing their cytotoxicity on cancer cells. A previous study dissolved AgNPs in three diffusion media (PBS, deionized water, and cell culture medium), and silver ions were detected at high concentrations in deionized water [72]. A recent study investigated the stability of AgNPs by measuring absorbance at 100–900 nm in PBS buffer, distilled water, complete medium, DMEM, and NaCl (0.9%) over 28 days [73], and the results showed shelf stability of AgNPs in distilled water.

The cytotoxicity of AgNPs against cancer cells could be determined by activating lactate dehydrogenase and ROS, leading to the induction of apoptosis [29]. The apoptosis of cancer cells was confirmed in the host by the resulting nuclear fragmentation, in which the accumulation of ROS and oxidative stress causes physiological and cellular events, including stress, mitochondrial disruption and destruction, apoptosis, inflammation, and DNA damage. ROS levels illustrate the induction of apoptosis and are involved in DNA damage. AgNPs were shown to efficiently induce cell death in HeLA cells by arresting their cell cycle at Sub G1 [53]. Figure 19 shows the mechanism of the anticancer activity of AgNPs. The ability of a treatment to selectively cause apoptosis in cancer cells while sparing healthy cells is an essential requirement for effective cancer treatment. In this regard, earlier investigations reported that AgNPs were less toxic to healthy cells than cancer cells, highlighting the potential application of AgNPs as an anticancer treatment. For instance, Singh et al. [74] demonstrated a deficient level of toxicity of the AgNPs produced from papaya leaf extract against normal HaCaT cells and Farahani et al. [75] also reported less toxicity of the AgNPs biosynthesized using Amigdalus spinosissima against normal L929 cells.

Tables 1 and 2 summarize several important properties of AgNPs biosynthesized from A. indica based on recent studies and this study. The tables highlight that this study was able to fabricate AgNPs with smaller sizes and higher toxicity against cancer cells than those reported in previous studies.

4. Conclusions

In recent years, there has been an extensive effort toward developing safer ways to synthesize AgNPs. Different characterization techniques were used to estimate the morphology of AgNPs, prepared from various medicinal plants, with varying shape and size distributions, which poses a severe challenge in their application. In this context, the plant extract volume, reaction temperature, silver salt concentration, reaction time, and pH value may play a vital role in achieving the desired shape and size of AgNPs. Hence, the AgNPs in this study were synthesized using the extracts of A. indica leaves and fruits. The synthesis was optimized to synthesis nanoparticles with the desired morphologies. In addition, AgNPs were characterized using UV−Vis spectroscopy, FTIR, FESEM, DLS, and zeta potential measurements. The cytotoxicity of green-synthesized AgNPs against lung and breast cancer cell lines was assessed using the MTT assay. The findings suggest that A. indica fruit and leaf extracts are suitable for synthesizing AgNPs with high yields and short production times. In addition, this study found that bioAgNPs are effective against lung and breast cancer; however, further research is needed to evaluate the effect of AgNPs on healthy cells.

Data Availability

The data used to support the findings of this study are included in the article.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Authors’ Contributions

Nehad S. Alsubhi contributed to performing the literature search, experiments, and data analysis and preparing and writing the manuscript. Njud S. Alharbi had the idea for the article and contributed to supervising, critically editing, revising the manuscript, and approving its final version.

Acknowledgments

This research work was funded by Institutional Fund Projects under grant no. (IFPIP: 240-247-1443). The authors gratefully acknowledge the technical and financial support provided by the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.

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Copyright © 2023 Njud S. Alharbi and Nehad S. Alsubhi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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