Glutamic Acid-Coated Zinc Oxide Nanoparticles: Synthesis, Characterization, and Anticancer Activity

Glutamic Acid-Coated Zinc Oxide Nanoparticles: Synthesis, Characterization, and Anticancer Activity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Glutamic Acid-Coated Zinc Oxide Nanoparticles: Synthesis, Characterization, and Anticancer Activity Nguyen Thi Huong, Nguyen Ngoc Son, Vu Minh Thanh, Ninh Duc Ha This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3922581/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract This paper presents a method to enhance the compatibility of zinc oxide nanoparticles (ZnO NPs) produced from guava leaf extract by modifying the nanoparticle surface with L-glutamic acid. The Glu-coated ZnO material was subjected to characterization using Fourier transform infrared spectroscopy (FTIR), X-ray scattering spectroscopy (XRD), UV-Vis spectroscopy, and electron energy scattering spectroscopy (EDS). The results corroborated the attachment of glutamic acid to the surface of the nanoparticle. The thermal density analysis (TGA) results indicate that the Glu-coated ZnO material contains around 8.998% organic content. The morphology and size of nanoparticles were assessed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering spectroscopy (DLS) both before and after modification. The findings demonstrate that the bare ZnO nanoparticles had an average size of around 25.32 nm, but the Glu-coated ZnO nanoparticles measure 41.88 nm. Their zeta values are − 9.05 mVs and − 18.6 mV, respectively. The anti-cancer effect of ZnO nanoparticles coated with glutamic acid was evaluated on various cell lines including HeLa (cervical cancer), A549 (lung cancer), and MCF7 (breast cancer). The findings demonstrated a significant enhancement in the anti-cancer efficacy of ZnO NPs with the application of Glu coating on their surface. The IC50 values of Glu-coated ZnO for the Hela, A549, and MCF7 cancer cell lines are 40.43 µg/mL, 37.20 µg/L, and 44.23 µg/mL, respectively. The findings indicate that the utilization of Glu-coated ZnO material holds significant promise in the field of cancer treatment. L-Glutamic acid Zinc oxide nanoparticles Ancticancer Guave leaf Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Zinc oxide is a semiconductor material with incredible application potential, used in many different fields, including agriculture, industry, electronics, chemicals, rubber, catalysis, and even biomedicine. ZnO is a wide-bandgap semiconductor with an energy gap of 3.37 eV at room temperature. They have the ability to absorb ultraviolet radiation with wavelengths around 366 nm [ 1 , 2 ]. Therefore, ZnO has been used as a UV inhibitor for fabric or skin protection products or applications in the photocatalyst field. Interestingly, although there have been many studies on the synthesis and applications of ZnO NPs, the properties and activities of these nanoparticles seem to be unstable. These depend greatly on the chemicals used and the procedure used to synthesize ZnO NPs [ 2 , 3 ]. In the biomedical field, ZnO has been used since ancient times as a friendly antibacterial agent thanks to its antibacterial, antifungal, and skin-protecting activities [ 4 ]. Recently, ZnO NPs have found more applications in this field. They have been shown to have significant anti-cancer activity against some cancer cell lines, such as A549 cells [ 5 – 7 ], human colon cancer cells (LoVo cells) [ 8 – 10 ], human head and neck squamous carcinoma cells [ 11 ], myeloblastic leukemia cells (HL60) [ 12 ], acute myeloid leukemia (AML) cells [ 13 ], and MCF7 cells [ 14 – 16 ]. Their mechanism of killing cancer cells has been studied, and many researchers have agreed that the penetration of ZnO NPs into cancer cells triggers the mass production of reactive oxygen species (ROS), which leads to the apoptosis of cancer cells [ 17 , 18 ]. It is known that when a foreign body enters a cell, the cell's defense mechanism starts to make ROS. But with ZnO NPs, the unique properties of the nanoparticle surface act as oxidation-reduction reaction centers, causing a lot of ROS to be made, which leads to the apoptosis of cancer cells [ 19 ]. ZnO NPs are also found to hold potential in various applications in the field of biomedicine, including diabetes treatment [ 20 , 21 ], bioimaging [ 22 , 23 ], drug delivery [ 24 , 25 ], immunotherapy [ 26 , 27 ], pro-angiogenic properties [ 28 , 29 ], and wound healing [ 30 – 32 ]. There are many different methods of synthesis that can be used to synthesize ZnO NPs, such as chemical flooding, thermal discharge, thermoplastic solvent, mechanization, ultrasonic syntheses, and microwaves. Recently, biosynthesis techniques for synthesizing zinc oxide nanoparticles have been highlighted. Biosynthesis uses different sources of biological agents, such as plant extracts, microorganisms, fungi, etc., to synthesize nanoparticles from their corresponding precursors. In addition to the use of sustainable-friendly materials, the researchers expect that using these sources will generate unique ZnO NPs through the adhesion of the bioactive substances present in the bioresources to the surface of the nanoparticles. B. Naiel et al. [ 33 ] produced ZnO nanoparticles using an extract derived from Limonium pruinosum and evaluated their anti-cancer efficacy on A-431 skin cancer cells. The findings indicate that nanoparticles with an average size of approximately 41 nm, as determined by XRD and electron microscopy, had a noteworthy ability to impede cell growth. Furthermore, the extent of inhibition is directly correlated to the dosage of the nanoparticles. Additionally, the nanoparticles exhibit robust antibacterial and fungal resistance, as well as notable antioxidant capabilities. J. Iqbal and his colleagues [ 34 ] utilized the phytochemicals in the Elaeagnus angustifolia L. leaf extract that act as reducing and stabilizing agents to make ZnO NPs. The nanoparticles are spherical, 26 nm in size, highly crystallized, and have a characteristic UV-Vis absorption peak as high as 399 nm. In vitro tests show that the synthetic nanoparticles have pretty good biocompatibility. They don't destroy red and white blood cells at low doses. ZnO synthesized by this method also has the ability to inhibit the enzymes protein kinase and alpha-amylase at moderate levels, suggesting it has potential in the treatment of cancer and diabetes. In terms of cancer activity, the synthesized ZnO NPs can reduce the metabolic activity of liver cancer cells (HepG2 and HuH7) at low concentrations. Additional experiments have also shown that these nanoparticles were capable of resisting the tropical leishmania parasite and are antioxidants. In another study, G.K. Prashant et al. [ 35 ] conducted a work where they presented a unique green synthesis technique to produce ZnO NPs using extracts from Punica granatum L. and Tamarindus indica L. The combination, composed of zinc nitrate and the aforementioned extract, was thoroughly blended and subsequently placed in an oven at around 375 o C. This temperature causes the solution to to boil, resulting in the formation of a gel. Eventually, the gel decomposes, leading to the creation of zinc oxide nanoparticles (ZnO NPs). The size of nanoformed particles ranges from 4 to 20 nm. The nanoparticles were evaluated for their anti-cancer properties on MCF-7 breast cancer cells. It was observed that at a dosage of 100 µg/mL, the viability of the cancer cells decreased to approximately 58%. Regarding biocompatibility, at a concentration of 2.5 mg/mL, the cytotoxicity of ZnO NPs is minimal, with a cell-destruction potential of less than 5%. This suggests that these nanoparticles exhibit a high level of biocompatibility. Some of the research results, as mentioned, once again indicate that, although ZnO NPs are assessed as metal oxides, they have a higher biocompatibility among the metal oxides that can be applied in the biomedical field. However, ZnO NPs, like other inorganic nanoparticles, need to be further improved in terms of biocompatibility when they enter the human body. Finding the best way to synthesize ZnO NPs is almost impossible; instead, it is necessary to alter their surface properties. The method used is to attach highly biocompatible organic agents to the surface of ZnO NPs. Extensive studies have been conducted based on that idea. As an illustration, A. Abuelsamen et al. [ 36 ] coated the Pluronic F-127 on the ZnO NPs surface. The results showed that F-127 coatings did not alter the crystalline structure of ZnO NPs, and they significantly enhanced the nanoparticles' stability. The cell toxicity test of ZnO NPs coated with F-127 on normal healthy human AE.hy296 endocrine cells showed that the cell toxicitess of surface deformed nanoparticles has been significantly reduced, which demonstrates their improved biocompatibility. In another study, S. Mitral [ 24 ] manufactured a pH-sensitive targeting (ZnO-FA) material on a porous ZnO nanorod background that was attached to the surface with folic acid (FA). This material was designed to transport the anti-cancer medicine doxorubicin (DOX). The results showed that ZnO-FA has very high biocompatibility, a drug-carrying performance of up to 88%, and DOX release triggered by pH. G. Sundraraman and L. S. Jayakumari [ 37 ] synthesized PEG-coated ZnO nanoparticles for the purpose of transporting taxifolin loads. The results indicate that nanoparticles, when loaded with taxifolin, achieve a size of around 90 nm, demonstrating excellent dispersion. The pH level had a direct impact on the release of taxifoline. Specifically, when the pH is 5.5, which is the same as the pH level inside cancer cells, the process of drug release is considerably accelerated. Evaluations of the anti-cancer efficacy of breast cancer cells indicate that they lead to a decrease in reproductive capacity, death rate, and deterioration in breast cancer. In a prior investigation [ 38 ], we effectively produced ZnO nanoparticles by employing leaf extract as both reducing agents and stabilizing agents. Synthetic nanoparticles exhibit exceptional uniformity with a particle size ranging from 20 to 30 nm. The substances have undergone testing to determine their anti-cancer effectiveness on various cell lines, including A549, Hela, and MCF-7. While some of these findings demonstrate promise in the biomedical field, the efficacy of these nanoparticles requires additional enhancement. In this study, we conducted a surface modification of ZnO NPs that were generated from leaf extract using L-glutamic acid. The purpose was to enhance biocompatibility and enhance the anti-cancer properties of the zinc oxide nanoparticles synthesized from leaf extracts. 2. Material and Methods 2.1. Material The guava leaves were collected at a farm located at the following coordinates: 21.037461, 105.719186. Zinc acetate dihydrate (Zn(CH 3 COO) 2 .2H 2 O) from Merck KgaA (product code: 108802100) serves as the source material for zinc. Glutamic acid (L-glutamic acid) from Bio Basic (product: GB0221) is used as the surface coating for the nanoparticles. Additional chemicals, such as ethanol (EtOH, dehydrated ethanol, Macklin, China) and deionized water (DI, TDS ≤ 5), were used. 2.2. Preparation of ZnO NPs Guava leaf extract (GL-ext) was prepared according to the same procedure as our previous study [ 38 ]. The synthesis of ZnO NPs was carried out with the help of ultrasonic equipment (VCX500, Sonics & Materials, U.S.A.). It was performed as follows: A volume of 200 mL of GL-ext was added to a 1,000 mL beaker, along with an additional 200 mL of DI. A total of 10 grams of zinc acetate dihydrate were fully dissolved in 400 milliliters of deionized water. This solution was added gradually (10 mL/min) in combination with sonication (continuous, amplitude 35%). After the entire zinc acetate solution was added to the extract (about 40–45 minutes), the reaction mixture continued to be sonicated for another 15 minutes before being centrifuged (10,000 rpm, 5 minutes) to remove all liquid. The solid part is convectively dried in air at 50 o C for 8 hours or until the weight change is no more than 3%. The dried solid product was then calcined at 600 o C for 2 hours to obtain white powder ZnO NPs (Scheme 1 ). 2.3. Surface coating of ZnO NPs with L-glutamic acid An amount of 2 g (0.0248 mol) of the synthesized ZnO NPs was ultrasonically dispersed in 400 mL of an EtOH/DI mixture (50:50, v/v). Add 0.9 g (6.12×10 − 3 mol) of glutamic acid (Glu). Stir vigorously for 30 minutes to completely dissolve the Glu. The reaction mixture was sonicated for 60 minutes (continuously, amplitude 35%). The reaction mixture was then centrifuged (10,000 rpm, 5 minutes), the white powder was recovered, washed twice with distilled water in an ultrasonic tank (5 minutes/turn), and then convection-dried at 50 o C for 12 hours to obtain Glu-coated ZnO. 2.4. Characterization of materials UV-Vis spectra were recorded on a UV-Vis device (Genesys 10S), scanning a range of 200–500 nm. The sample was ultrasonically dispersed in DI immediately before recording the spectrum. FTIR spectra were recorded on a Tensor II device (Bruker) using the KBr pelleting technique, scanning range from 400–4000 cm − 1 . The shape, size, and morphological characteristics of the materials were observed by scanning electron microscopy (SEM, JEOL-JMS 6490) and transmission electron microscopy (TEM, JEM 2100). The hydrodynamic size and zeta potential of the material were measured on a dynamic light scattering device (DLS, NanoPlus HD). The sample was ultrasonically dispersed in DI immediately before measurement. The crystal structure of the material is characterized by an XRD pattern measured on X'PERT PRO (PANalytical) equipment with CuKα radiation (λ = 0.154 nm) and a Bragg-diffraction angle from 20 o to 80 o . Thermal analysis was performed on the LABSYS evo device with a heating rate of 10 o C/min. 2.5. Anticancer activity assays The MTT assay method was utilized to evaluate the anticancer efficacy of the produced Glu-coated ZnO against cervical (HeLa), lung (A549), and breast (MCF7) cancer cells. The non-radioactive CellTiter 96® MTT test (Promega Corporation, Madison, WI, USA) was used to assess the vitality of the grown cells. Each well containing the cultivated samples was supplemented with a 15 µL amount of tetrazolium salt solution. The plates were then placed in an incubator at a temperature of 37°C for a duration of 3 hours. Following incubation, 100 µL of solubilization/stop solution was introduced into each well. Before utilizing a SpectraMax M5 plate reader (Molecular Devices, Sunnyvale, CA) to quantify the absorbance at 570 nm, the contents of each well were meticulously combined. The cell viability was assessed using Eq. ( 1 ): $$\text{Cell viability }\left(\text{\%}\right)\text{=}\frac{{\text{OD}}_{\text{5}\text{7}\text{0}}\left(\text{sample}\right)}{{\text{OD}}_{\text{5}\text{7}\text{0}}\left(\text{control}\right)}\text{×100\%}$$ 1 Where OD 570 (sample) represents the optical density of cells that have been exposed to different concentrations of Glu-coated ZnO. The variable OD 570 (control) represents the optical density of cells that have simply been incubated with the medium. 3. Results and Discussion 3.1. Synthesis of surface-modified ZnO NPs with glutamic acid (Glu-coated ZnO) The infrared spectrum is recorded based on the characteristic vibrations of the bonds, thereby indicating the presence of bonds and functional groups in the sample. In this study, bare ZnO, which was synthesized using guava leaf extract, L-glutamic acid, and surface-modified ZnO with glutamic acid (Glu-coated ZnO), was recorded (Fig. 1 a). Variation in the presence of functional groups was observed. In the FTIR spectrum of ZnO (below), there are characteristic absorption peaks at 3440 cm − 1 representing the O-H bond on the nanoparticle surface and a strong absorption peak at 455 cm − 1 which corresponds to the Zn-O bond. The FTIR spectrum of L-glutamic acid (top) has a broad absorption band that goes from 3180 cm − 1 to 2260 cm − 1 with a peak at 2915 cm − 1 cover peaks that characterize the O-H bonds in the carboxyl group, the N-H bonds in the amino group, and the C-H bonds in the main chain. The peak at 1685 cm − 1 corresponds to the C = O bond of the carboxyl group; 1530 cm − 1 shows the tensile vibration of the N-H bond in the amino group; and the peak at 1255 cm − 1 represents the bending vibration of COH. Lastly, the peak at 1120 cm − 1 signifies the presence of the C-O bond[ 39 ]. The FTIR spectrum of the Glu-coated ZnO (middle) shows the characteristic peaks of both ZnO and Glu. Notably, the most characteristic peaks are the 451 cm − 1 peak of the Zn-O bond and the 1620 cm − 1 peak of the C = O bond in the carbonyl group. A broad band from 3680 cm − 1 to 2850 cm − 1 indicative of the O-H bond in the carboxyl group. This summit encompasses the lower regions of the peaks. The N-H bond exhibits a frequency of 3330 cm − 1 , while the CH 2 group displays a frequency of 2920 cm − 1 . Figure 1 b displays the UV-Vis radiation absorption properties of the three compounds, which are similar to the FTIR spectra. The results indicate that the ZnO nanoparticles, in their original form, have a distinct absorption peak at a wavelength of 371 nm, corresponding to a band gap of 3.32 eV [ 40 ]. The UV-Vis spectra of L-glutamic acid (top) has an absorption band ranging from 200 to 230 nm. This absorption peak is also detected in the UV-Vis absorption spectrum of Glu-coated ZnO (middle). This absorption spectrum also exhibits a peak at 375 nm, which is ascribed to the distinctive absorption peak of ZnO. The UV-vis absorption property of Glu-coated ZnO NPs shows that the UV-Vis absorption properties of both Glu and ZnO NPs have been combined. Furthermore, there is a noticeable red shift observed in the UV-Vis spectra of ZnO and Glu-coated ZnO. More specifically, the absorption peak at 371 nm in ZnO nanoparticles is displaced to 375 nm in Glu-coated ZnO. The red shift is usually explained by functional groups that attract electrons [ 41 ], which fits with the fact that Glu was added to the surface of ZnO NPs. The FTIR and UV-Vis spectra demonstrated the bond between L-glutamic acid and ZnO NPs. The X-ray diffraction (XRD) spectrum results for Glu-coated ZnO are presented in Fig. 2 . The XRD diagram displays diffraction peaks at specific 2theta angles: 31.77 o , 34.44 o , 36.25 o , 47.53 o , 56.62 o , 62.86 o , 66.36 o , 67.93 o , and 69.09 o . These peaks correspond to the crystal planes (100), (002), (101), (102), (110), (103), (200), (112), and (201) of the ZnO crystal (PDF 01-071-6424). These findings demonstrate that the attachment of L-glutamic acid molecules to the surface of zinc oxide nanoparticles does not alter their crystal structure. Furthermore, the XRD pattern exhibits a distinct diffraction peak at the 2theta angle of 19.38 o , which can be attributed to the X-ray diffraction of the (111) plane of glutamic acid [ 42 ]. Ultimately, the XRD spectra confirmed the existence of Glu. Moreover, this existence did not alter the crystal structure of ZnO NPs. Figure 3 displays the Thermogravimetric Analysis (TGA) analysis diagram of Glu-coated ZnO material. The diagram illustrates the relationship between sample temperature and sample mass (Δm, black line) heat flow (HF, red line), and the first differential heat flow (dHF, blue line). In the dHF fluctuation, there are two prominent peaks observed at temperatures T = 102.98 o C and T = 296.84 o C. Prior to the first point, the HF curve exhibited minimal growth, indicating that the sample is effectively absorbing heat. The rationale behind this phenomenon is that the heat input is solely utilized to extract moisture. Therefore, the mass that has been lost so far may be attributed to the mass of water that has been absorbed by the Glu-coated ZnO material. This mass loss is measured to be 0.268 mg, which is comparable to 1.00% of the total mass. The dHF reaches its minimum when the temperature (T) is 102.98 o C. This might happen because heat was used to break up the bonds between L-glutamic acid molecules that were only loosely attached to the nanoparticle's surface. After that, the dHF went up significantly and quickly, showing that the combustion reaction involving the recently detached organic part from the nanoparticle surface had taken place. This sequence is almost repeated at the second notable time, at temperature T = 296.84 o C. It is reasonable to assume that this situation is the result of the thermal energy supplied separating the tightly bound organic molecules from the nanoparticle surface. This product then thermally decomposes, causing HF to rapidly increase. After about 450 o C, the sample mass seems stable; the change occurs with a very small amplitude. The change in sample mass during this period was caused by the reaction of metallic zinc or zinc oxide (Zn/ZnO) with gases like NO x and CO x that were made during the calcination process. From here, the mass loss period in the temperature ranges up to about 450 o C (Δm = 2.669 mg, equivalent to 9.998%) includes humidity mass (Δm = 0.268 mg, equivalent to 1.00%), and the remaining amount is equivalent to 8.998%. % is the mass of the organic fraction. The EDS spectrum of bare ZnO and Glu-coated ZnO is shown in Fig. 4 . This outcome demonstrates that ZnO consists solely of two constituent components, zinc, and oxygen. Meanwhile, with Glu-coated ZnO, in addition to the above two elements, there are also two elements: carbon (6.04% w) and nitrogen (3.36% w). This partly proves that glutamic acid was successfully attached to the surface of zinc oxide nanoparticles. In addition, it is also seen that, in addition to the characteristic dispersion peaks for the main elements Zn, O (for ZnO) and Zn, O, C, N (for Glu-coated ZnO), there is almost no difference. Dispersion peaks characteristic of other elements appear. This shows the purity of the as-prepared ZnO. The SEM and TEM images in Fig. 5 (a, b) depict the morphological characteristics of uncoated ZnO and ZnO coated with Glu, respectively. SEM picture of ZnO (Fig. 5 a) demonstrates that the nanoparticles have relatively great size homogeneity. Nanoparticles often have a spherical morphology. The borders between the particles were distinctly detected, suggesting that the nanoparticles produced using this technique exhibited reduced propensity for agglomeration. Furthermore, the spherical morphology of the nanoparticles has been revalidated by TEM images. The presence of nanoparticles with dimensions ranging from 20 to 30 nm is also more distinctly seen. Concurrently, SEM and TEM images of ZnO coated with Glu (Fig. 5 b) exhibit noticeable alterations. Based on the SEM image (top), the morphology of nanoparticles appears to have deviated from the spherical shape, with diminished visibility of the inter-particle boundaries. The transmission electron microscopy (TEM) pictures, depicted below, likewise exhibited comparable findings. The weak contrast in the photograph may be attributed to the existence of an organic covering on the surface. Nevertheless, TEM data provide enhanced visibility of the boundaries encompassing the particles, as well as a more distinct observation of their spherical shape. The particle size can be anticipated to exceed 20 nm. Results of particle size measurement by DLS (Fig. 6 a) show that ZnO NPs have an average particle size of about 25.32 nm, with particle size distributed in a narrow range from 18.17 nm to 37.84 nm. This result is consistent with the results observed under the electron microscope. Meanwhile, ZnO NPs after being coated with Glu on the surface have a size of about 43.82 nm (Fig. 6 b), significantly larger than that of ZnO, as well as the results obtained from electron microscope images. This is explicable by the fact that L-glutamic acid increases the interaction between the surface of nanoparticles and the water environment, increasing the hydrodynamic size of the particles. In addition, it is seen that the DLS graph of Glu-coated ZnO has a wide peak, showing a wide distribution of particle sizes, from 21.04 nm to 122.4 nm. The zeta potential of the nanoparticles before and after modification was also determined; accordingly, the zeta potential of ZnO without surface modification (Fig. 6 c) and after surface modification (Fig. 6 d) was − 9.05 mV and − 18.6 mV, respectively. This result shows that the zeta potential amplitude of the ZnO synthesized in this study is quite large, which means that the ZnO NPs have quite good stability and resistance to agglomeration. However, after surface modification of this nanoparticle with glutamic acid, the zeta potential amplitude increased more than two times, meaning they have much higher stability. 3.2. Evaluation of the cancer-killing effectiveness of Glu-coated ZnO The efficacy of Glu-Coated ZnO in inhibiting cancer growth is evaluated on three distinct cancer cell lines, namely Hela cervical cancer cells, A549 lung cancer cells, and MCF7 breast cancer cells. The graphs in Fig. 7 depict the test results regarding the impact of the dosage of Glu-Coated ZnO on the survival rate of these cancer cells after 72 hours of processing. The concentration of Glu-Coated ZnO ranges from 10 to 200 µg/ml. These findings indicate a negative correlation between the dose and the survival rate of cells after treatment time. When Hela cells are exposed to a dosage of 200 µg/ml of Glu-Coated ZnO, the survival rate of cells is 8.31%. However, when the dosage of Glu-Coated ZnO is reduced to 10 µg/ml, the survival rate jumps significantly to 92.23%. The percentage of the same trend was observed for A549 and MCF7 cells at survey levels of 200 µg/ml and 10 µg/ml, with values of 14.47% and 74.65%, and 9.31% and 70.15%, respectively. The results demonstrate that Glu-Coated ZnO exhibits a potent and dose-dependent effect on cancer cells. The impact of eliminating cancer cells is also observed as undergoing alterations within cancer cells. The survey results indicate that Glu-Coated ZnO exhibits the most significant treatment effect on MCF7 cells and the least significant effect on A549 cells. This is also demonstrated by the inhibitory value equivalent to half of the IC 50 , which is determined using mathematical models based on experimental data. The IC 50 values of Glu-Coated ZnO with Hela, A549, and MCF7 cells are 40.43 µg/ml, 44.23 µg/ml, and 37.20 µg/ml, respectively. When comparing the anti-cancer activity of zinc oxide nanoparticles (ZnO NPs) synthesized from leaf extract in a previous study [ 38 ] to their activity on these three types of cancer cells, it is evident that the surface functionalization of the nanoparticles has greatly improved their effectiveness in combating cancer. The precise mechanism by which glutamic acid interacts with cancer cells remains incompletely elucidated. However, it is also believed that glutamic acid serves crucial functions in cancer cells. Tumor cells require glutamine, which is a transformer form of glutamic acid, to provide nutrient sources of nitrogen and carbon for their anabolic processes [ 43 ]. Thus, it can be found that glutamic acid has its own attraction to tumor cells, so we suggest a hypothesis to explain the increase in the cancer-killing effectiveness of Glu-coated ZnO NPs. When the glutamine coating on the surface of ZnO NPs makes it easier for ZnO-NPs to have priority access to the tumor cells, it facilitates the intrusion and development of the cancerous cell-killing effect of ZnO's inherent capabilities. This is like the targeting capabilities of glutamine in the publication by J. Jonghwa and colleagues in their study [ 44 ]. Another perspective posits that Glu possesses inherent anti-cancer properties, as proposed in a study conducted by Luzzio et al. [ 45 ]. This idea gains further support from the observation of glutamine deficit in the muscles of cancer patients. It is thought to be due to abnormally high glutamine absorption by tumor cells and chronic protein metabolism. Additional research indicates that the activity of anti-cancer drugs can be enhanced by combining them with other substances known to combat cancer, such as All-Trans Retinoic (ATRA) [ 46 ], Cisplatin [ 47 ], Curcumin [ 48 ], 20 (S)-Camptothecin (CPT) [ 49 ], N-(4-Hydroxyphenyl) Retinamide (4HPR) [ 50 ], and Glutamic Acid. According to this idea, the mechanism behind the cancer cell-killing activity of Glu-Coated ZnO is attributed to the synergistic action of ZnO and Glutamic acid. Therefore, regardless of the circumstances, Glu-Coated ZnO in its original state has demonstrated a noteworthy impact in eradicating malignancy. 4. Conclusions The surface of zinc oxide nanoparticles produced with guava leaf extract was successfully coated with L-glutamic acid. The research findings have demonstrated that the FTIR spectra exhibits the amalgamation of Glu and ZnO. Additionally, the UV-Vis results display a red shift in the distinctive absorption peak of ZnO, which may be attributed to the existence of electron-attracting components. This observation is also in line with the presence of Glu. The EDS and TGA examination results reveal the presence of organic content in the nanoparticles synthesized. Based on calculations from the TGA data, this component constitutes approximately 8.998% of the total content. The electron microscope (SEM, TEM) analysis reveals that the nanoparticles exhibit a spherical shape with a diameter ranging from 20 to 30 nm. Furthermore, noticeable alterations in the morphology of the nanoparticles are detected before and after denaturation. Meanwhile, DLS analysis reveals that the mean diameter of the nanoparticles prior to modification is 25.4 nanometers; however, after the application of the Glu coating, it measures 43.82 nm. The zeta potential indicates that the nanoparticle will exhibit increased stability following modification. The test results for the anti-cancer activity of Glu-coated ZnO were satisfactory. The effectiveness of cancer-killing has improved significantly, with evidence that the half-inhibitory concentrations (IC 50 ) of Glu-coated ZnO for Hela, A549, and MCF7 cells are 40.43 µg/mL, 44.23 µg/mL, and 37.20 µg/mL, respectively, which has decreased 3–4 times compared to ZnO synthesized from leaf extract without surface treatment with glutamic acid. This demonstrates the considerable potential of Glu-coated ZnO for utilization in cancer therapy. Declarations Authors’ contributions Dr. Nguyen Thi Huong: Designed the experimental framework, analyzed and interpreted the results, provided critical insights and explanations, and contributed to securing research funding. MRes. Nguyen Ngoc Son: Designed the experimental framework, conducted the laboratory work, and drafted the manuscript. Prof. Dr. Vu Minh Thanh and Prof.Dr Ninh Duc Ha: Monitored the progress of the project, supervised the experimental procedures, and contributed to reviewing and editing the manuscript. Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments This research has received financial support from the Institute of Chemistry and Materials. Data Availability The datasets produced and examined in the present investigation can be obtained from the corresponding author upon a reasonable request. Ethical Approval (not applicable) References Segets D, Gradl J, Taylor RK, Vassilev V, Peukert W, ACS Nano. (2009) https://doi.org/10.1021/nn900223b Thakral F, Bhatia GK, Tuli HS, Sharma AK, Sood S, Curr Pharmacol Rep. (2021) https://doi.org/10.1007/s40495-021-00248-7 Chandrasekaran S, Anusuya S, Anbazhagan V, J Mol Struct. 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(2006) https://doi.org/10.1016/j.biomaterials.2006.08.016 Dubey SK, Sharma AK, Narain U, Misra K, Pati U, Eur J Med Chem. (2008) https://doi.org/10.1016/j.ejmech.2007.11.027 Singer JW, Bhatt R, Tulinsky J, Buhler KR, Heasley E, Klein P, de Vries P, J Control Release. (2001) https://doi.org/10.1016/S0168-3659(01)00323-6 Zou C, Brewer M, Cao X, Zang R, Lin J, Deng Y, Li C, Gynecol Oncol . (2007) https://doi.org/10.1016/j.ygyno.2007.07.077 Scheme Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Scheme1.tif Scheme 1. Synthesis process of Glu-coated ZnO NPs material Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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03:14:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3922581/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3922581/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51083217,"identity":"68fc90cf-06c6-4da8-b8b1-76744dd2dc17","added_by":"auto","created_at":"2024-02-13 19:39:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92529,"visible":true,"origin":"","legend":"\u003cp\u003eFTIR (a) and UV-vis (b) spectra of L-glutamic acid Glu, ZnO and Glu-coated ZnO\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/41f8cdaa7b4057721c9ac51f.png"},{"id":51084606,"identity":"11a132c4-e58d-4f58-a293-5a84ee6f4e76","added_by":"auto","created_at":"2024-02-13 19:47:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43078,"visible":true,"origin":"","legend":"\u003cp\u003eXRD pattern of Glu-coated ZnO\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/1ce8f011844cbc16e606e4ac.png"},{"id":51083216,"identity":"7e0ff11b-6078-404f-99be-b9d6f29a432a","added_by":"auto","created_at":"2024-02-13 19:39:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42213,"visible":true,"origin":"","legend":"\u003cp\u003eTGA diagram of Glu-coated ZnO\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/4c7bf498060df8c49a3d3662.png"},{"id":51083221,"identity":"8f78a5f0-4390-4c55-b881-320bc2c0a92c","added_by":"auto","created_at":"2024-02-13 19:39:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":452849,"visible":true,"origin":"","legend":"\u003cp\u003eEDS spectrum of ZnO NPs (a) and Glu-coated ZnO (b)\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/d2408bcf120cf32566da998f.png"},{"id":51083223,"identity":"dc8c679c-f7d3-4a7a-ad91-34a3cf4b22c8","added_by":"auto","created_at":"2024-02-13 19:39:28","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1113940,"visible":true,"origin":"","legend":"\u003cp\u003eSEM (top) and TEM (bottom) images of ZnO NPs (a) and Glu-coated ZnO (b)\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/667691a4d179873df871c351.png"},{"id":51083219,"identity":"c7fbc6bb-3229-42e4-9e6d-bc5e4ce7ddaa","added_by":"auto","created_at":"2024-02-13 19:39:26","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":71773,"visible":true,"origin":"","legend":"\u003cp\u003eHydrodynamic size distribution (top) and zeta potential (bottom) of ZnO NPs (a,c) and Glu-coated ZnO (b,d)\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/646d69ed55f5c182ebcad85f.png"},{"id":51083220,"identity":"79b7d66d-6dff-4fa4-9b4e-b9c6ff4d78d6","added_by":"auto","created_at":"2024-02-13 19:39:26","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1326204,"visible":true,"origin":"","legend":"\u003cp\u003eThe anti-cancer efficacy of ZnO coated with glucose was evaluated on Hela cervical cancer cells (a), A549 lung cancer cells (b), and MCF7 breast cancer cells (c) following a 72-hour treatment period.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/62faa7b6510eecf87f20f270.png"},{"id":51272065,"identity":"ff9c0729-6c4f-4a71-b399-bd10acbf261b","added_by":"auto","created_at":"2024-02-17 18:52:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3512714,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/c25fb5b8-2d0f-4a90-a1e1-57c45872922c.pdf"},{"id":51083224,"identity":"c823d800-cb08-4d0e-9a09-3218f42531aa","added_by":"auto","created_at":"2024-02-13 19:39:28","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":431824,"visible":true,"origin":"","legend":"\u003cp\u003eScheme 1. Synthesis process of Glu-coated ZnO NPs material\u003c/p\u003e","description":"","filename":"Scheme1.tif","url":"https://assets-eu.researchsquare.com/files/rs-3922581/v1/e44650a5ec6310db208d420d.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Glutamic Acid-Coated Zinc Oxide Nanoparticles: Synthesis, Characterization, and Anticancer Activity","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eZinc oxide is a semiconductor material with incredible application potential, used in many different fields, including agriculture, industry, electronics, chemicals, rubber, catalysis, and even biomedicine. ZnO is a wide-bandgap semiconductor with an energy gap of 3.37 eV at room temperature. They have the ability to absorb ultraviolet radiation with wavelengths around 366 nm [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, ZnO has been used as a UV inhibitor for fabric or skin protection products or applications in the photocatalyst field. Interestingly, although there have been many studies on the synthesis and applications of ZnO NPs, the properties and activities of these nanoparticles seem to be unstable. These depend greatly on the chemicals used and the procedure used to synthesize ZnO NPs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In the biomedical field, ZnO has been used since ancient times as a friendly antibacterial agent thanks to its antibacterial, antifungal, and skin-protecting activities [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Recently, ZnO NPs have found more applications in this field. They have been shown to have significant anti-cancer activity against some cancer cell lines, such as A549 cells [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], human colon cancer cells (LoVo cells) [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], human head and neck squamous carcinoma cells [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], myeloblastic leukemia cells (HL60) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], acute myeloid leukemia (AML) cells [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and MCF7 cells [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Their mechanism of killing cancer cells has been studied, and many researchers have agreed that the penetration of ZnO NPs into cancer cells triggers the mass production of reactive oxygen species (ROS), which leads to the apoptosis of cancer cells [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It is known that when a foreign body enters a cell, the cell's defense mechanism starts to make ROS. But with ZnO NPs, the unique properties of the nanoparticle surface act as oxidation-reduction reaction centers, causing a lot of ROS to be made, which leads to the apoptosis of cancer cells [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. ZnO NPs are also found to hold potential in various applications in the field of biomedicine, including diabetes treatment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], bioimaging [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], drug delivery [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], immunotherapy [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], pro-angiogenic properties [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and wound healing [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. There are many different methods of synthesis that can be used to synthesize ZnO NPs, such as chemical flooding, thermal discharge, thermoplastic solvent, mechanization, ultrasonic syntheses, and microwaves. Recently, biosynthesis techniques for synthesizing zinc oxide nanoparticles have been highlighted. Biosynthesis uses different sources of biological agents, such as plant extracts, microorganisms, fungi, etc., to synthesize nanoparticles from their corresponding precursors. In addition to the use of sustainable-friendly materials, the researchers expect that using these sources will generate unique ZnO NPs through the adhesion of the bioactive substances present in the bioresources to the surface of the nanoparticles. B. Naiel et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] produced ZnO nanoparticles using an extract derived from Limonium pruinosum and evaluated their anti-cancer efficacy on A-431 skin cancer cells. The findings indicate that nanoparticles with an average size of approximately 41 nm, as determined by XRD and electron microscopy, had a noteworthy ability to impede cell growth. Furthermore, the extent of inhibition is directly correlated to the dosage of the nanoparticles. Additionally, the nanoparticles exhibit robust antibacterial and fungal resistance, as well as notable antioxidant capabilities. J. Iqbal and his colleagues [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] utilized the phytochemicals in the Elaeagnus angustifolia L. leaf extract that act as reducing and stabilizing agents to make ZnO NPs. The nanoparticles are spherical, 26 nm in size, highly crystallized, and have a characteristic UV-Vis absorption peak as high as 399 nm. In vitro tests show that the synthetic nanoparticles have pretty good biocompatibility. They don't destroy red and white blood cells at low doses. ZnO synthesized by this method also has the ability to inhibit the enzymes protein kinase and alpha-amylase at moderate levels, suggesting it has potential in the treatment of cancer and diabetes. In terms of cancer activity, the synthesized ZnO NPs can reduce the metabolic activity of liver cancer cells (HepG2 and HuH7) at low concentrations. Additional experiments have also shown that these nanoparticles were capable of resisting the tropical leishmania parasite and are antioxidants. In another study, G.K. Prashant et al. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] conducted a work where they presented a unique green synthesis technique to produce ZnO NPs using extracts from Punica granatum L. and Tamarindus indica L. The combination, composed of zinc nitrate and the aforementioned extract, was thoroughly blended and subsequently placed in an oven at around 375 \u003csup\u003eo\u003c/sup\u003eC. This temperature causes the solution to to boil, resulting in the formation of a gel. Eventually, the gel decomposes, leading to the creation of zinc oxide nanoparticles (ZnO NPs). The size of nanoformed particles ranges from 4 to 20 nm. The nanoparticles were evaluated for their anti-cancer properties on MCF-7 breast cancer cells. It was observed that at a dosage of 100 \u0026micro;g/mL, the viability of the cancer cells decreased to approximately 58%. Regarding biocompatibility, at a concentration of 2.5 mg/mL, the cytotoxicity of ZnO NPs is minimal, with a cell-destruction potential of less than 5%. This suggests that these nanoparticles exhibit a high level of biocompatibility. Some of the research results, as mentioned, once again indicate that, although ZnO NPs are assessed as metal oxides, they have a higher biocompatibility among the metal oxides that can be applied in the biomedical field. However, ZnO NPs, like other inorganic nanoparticles, need to be further improved in terms of biocompatibility when they enter the human body. Finding the best way to synthesize ZnO NPs is almost impossible; instead, it is necessary to alter their surface properties. The method used is to attach highly biocompatible organic agents to the surface of ZnO NPs. Extensive studies have been conducted based on that idea. As an illustration, A. Abuelsamen et al. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] coated the Pluronic F-127 on the ZnO NPs surface. The results showed that F-127 coatings did not alter the crystalline structure of ZnO NPs, and they significantly enhanced the nanoparticles' stability. The cell toxicity test of ZnO NPs coated with F-127 on normal healthy human AE.hy296 endocrine cells showed that the cell toxicitess of surface deformed nanoparticles has been significantly reduced, which demonstrates their improved biocompatibility. In another study, S. Mitral [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] manufactured a pH-sensitive targeting (ZnO-FA) material on a porous ZnO nanorod background that was attached to the surface with folic acid (FA). This material was designed to transport the anti-cancer medicine doxorubicin (DOX). The results showed that ZnO-FA has very high biocompatibility, a drug-carrying performance of up to 88%, and DOX release triggered by pH. G. Sundraraman and L. S. Jayakumari [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] synthesized PEG-coated ZnO nanoparticles for the purpose of transporting taxifolin loads. The results indicate that nanoparticles, when loaded with taxifolin, achieve a size of around 90 nm, demonstrating excellent dispersion. The pH level had a direct impact on the release of taxifoline. Specifically, when the pH is 5.5, which is the same as the pH level inside cancer cells, the process of drug release is considerably accelerated. Evaluations of the anti-cancer efficacy of breast cancer cells indicate that they lead to a decrease in reproductive capacity, death rate, and deterioration in breast cancer.\u003c/p\u003e \u003cp\u003eIn a prior investigation [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], we effectively produced ZnO nanoparticles by employing leaf extract as both reducing agents and stabilizing agents. Synthetic nanoparticles exhibit exceptional uniformity with a particle size ranging from 20 to 30 nm. The substances have undergone testing to determine their anti-cancer effectiveness on various cell lines, including A549, Hela, and MCF-7. While some of these findings demonstrate promise in the biomedical field, the efficacy of these nanoparticles requires additional enhancement. In this study, we conducted a surface modification of ZnO NPs that were generated from leaf extract using L-glutamic acid. The purpose was to enhance biocompatibility and enhance the anti-cancer properties of the zinc oxide nanoparticles synthesized from leaf extracts.\u003c/p\u003e"},{"header":"2. Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Material\u003c/h2\u003e \u003cp\u003eThe guava leaves were collected at a farm located at the following coordinates: 21.037461, 105.719186. Zinc acetate dihydrate (Zn(CH\u003csub\u003e3\u003c/sub\u003eCOO)\u003csub\u003e2\u003c/sub\u003e.2H\u003csub\u003e2\u003c/sub\u003eO) from Merck KgaA (product code: 108802100) serves as the source material for zinc. Glutamic acid (L-glutamic acid) from Bio Basic (product: GB0221) is used as the surface coating for the nanoparticles. Additional chemicals, such as ethanol (EtOH, dehydrated ethanol, Macklin, China) and deionized water (DI, TDS\u0026thinsp;\u0026le;\u0026thinsp;5), were used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Preparation of ZnO NPs\u003c/h2\u003e \u003cp\u003eGuava leaf extract (GL-ext) was prepared according to the same procedure as our previous study [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The synthesis of ZnO NPs was carried out with the help of ultrasonic equipment (VCX500, Sonics \u0026amp; Materials, U.S.A.). It was performed as follows: A volume of 200 mL of GL-ext was added to a 1,000 mL beaker, along with an additional 200 mL of DI. A total of 10 grams of zinc acetate dihydrate were fully dissolved in 400 milliliters of deionized water. This solution was added gradually (10 mL/min) in combination with sonication (continuous, amplitude 35%). After the entire zinc acetate solution was added to the extract (about 40\u0026ndash;45 minutes), the reaction mixture continued to be sonicated for another 15 minutes before being centrifuged (10,000 rpm, 5 minutes) to remove all liquid. The solid part is convectively dried in air at 50 \u003csup\u003eo\u003c/sup\u003eC for 8 hours or until the weight change is no more than 3%. The dried solid product was then calcined at 600 \u003csup\u003eo\u003c/sup\u003eC for 2 hours to obtain white powder ZnO NPs (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Surface coating of ZnO NPs with L-glutamic acid\u003c/h2\u003e \u003cp\u003eAn amount of 2 g (0.0248 mol) of the synthesized ZnO NPs was ultrasonically dispersed in 400 mL of an EtOH/DI mixture (50:50, v/v). Add 0.9 g (6.12\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e mol) of glutamic acid (Glu). Stir vigorously for 30 minutes to completely dissolve the Glu. The reaction mixture was sonicated for 60 minutes (continuously, amplitude 35%). The reaction mixture was then centrifuged (10,000 rpm, 5 minutes), the white powder was recovered, washed twice with distilled water in an ultrasonic tank (5 minutes/turn), and then convection-dried at 50 \u003csup\u003eo\u003c/sup\u003eC for 12 hours to obtain Glu-coated ZnO.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Characterization of materials\u003c/h2\u003e \u003cp\u003eUV-Vis spectra were recorded on a UV-Vis device (Genesys 10S), scanning a range of 200\u0026ndash;500 nm. The sample was ultrasonically dispersed in DI immediately before recording the spectrum. FTIR spectra were recorded on a Tensor II device (Bruker) using the KBr pelleting technique, scanning range from 400\u0026ndash;4000 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The shape, size, and morphological characteristics of the materials were observed by scanning electron microscopy (SEM, JEOL-JMS 6490) and transmission electron microscopy (TEM, JEM 2100). The hydrodynamic size and zeta potential of the material were measured on a dynamic light scattering device (DLS, NanoPlus HD). The sample was ultrasonically dispersed in DI immediately before measurement. The crystal structure of the material is characterized by an XRD pattern measured on X'PERT PRO (PANalytical) equipment with CuKα radiation (λ\u0026thinsp;=\u0026thinsp;0.154 nm) and a Bragg-diffraction angle from 20\u003csup\u003eo\u003c/sup\u003e to 80\u003csup\u003eo\u003c/sup\u003e. Thermal analysis was performed on the LABSYS evo device with a heating rate of 10 \u003csup\u003eo\u003c/sup\u003eC/min.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Anticancer activity assays\u003c/h2\u003e \u003cp\u003eThe MTT assay method was utilized to evaluate the anticancer efficacy of the produced Glu-coated ZnO against cervical (HeLa), lung (A549), and breast (MCF7) cancer cells. The non-radioactive CellTiter 96\u0026reg; MTT test (Promega Corporation, Madison, WI, USA) was used to assess the vitality of the grown cells. Each well containing the cultivated samples was supplemented with a 15 \u0026micro;L amount of tetrazolium salt solution. The plates were then placed in an incubator at a temperature of 37\u0026deg;C for a duration of 3 hours. Following incubation, 100 \u0026micro;L of solubilization/stop solution was introduced into each well. Before utilizing a SpectraMax M5 plate reader (Molecular Devices, Sunnyvale, CA) to quantify the absorbance at 570 nm, the contents of each well were meticulously combined. The cell viability was assessed using Eq.\u0026nbsp;(\u003cspan refid=\"Equ1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003cdiv id=\"Equ1\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equ1\" name=\"EquationSource\"\u003e\n$$\\text{Cell viability }\\left(\\text{\\%}\\right)\\text{=}\\frac{{\\text{OD}}_{\\text{5}\\text{7}\\text{0}}\\left(\\text{sample}\\right)}{{\\text{OD}}_{\\text{5}\\text{7}\\text{0}}\\left(\\text{control}\\right)}\\text{\u0026times;100\\%}$$\u003c/div\u003e\u003cdiv class=\"EquationNumber\"\u003e1\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eWhere OD\u003csub\u003e570\u003c/sub\u003e(sample) represents the optical density of cells that have been exposed to different concentrations of Glu-coated ZnO. The variable OD\u003csub\u003e570\u003c/sub\u003e(control) represents the optical density of cells that have simply been incubated with the medium.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and Discussion","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Synthesis of surface-modified ZnO NPs with glutamic acid (Glu-coated ZnO)\u003c/h2\u003e \u003cp\u003eThe infrared spectrum is recorded based on the characteristic vibrations of the bonds, thereby indicating the presence of bonds and functional groups in the sample. In this study, bare ZnO, which was synthesized using guava leaf extract, L-glutamic acid, and surface-modified ZnO with glutamic acid (Glu-coated ZnO), was recorded (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Variation in the presence of functional groups was observed. In the FTIR spectrum of ZnO (below), there are characteristic absorption peaks at 3440 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e representing the O-H bond on the nanoparticle surface and a strong absorption peak at 455 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e which corresponds to the Zn-O bond. The FTIR spectrum of L-glutamic acid (top) has a broad absorption band that goes from 3180 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e to 2260 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e with a peak at 2915 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e cover peaks that characterize the O-H bonds in the carboxyl group, the N-H bonds in the amino group, and the C-H bonds in the main chain. The peak at 1685 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e corresponds to the C\u0026thinsp;=\u0026thinsp;O bond of the carboxyl group; 1530 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e shows the tensile vibration of the N-H bond in the amino group; and the peak at 1255 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e represents the bending vibration of COH. Lastly, the peak at 1120 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e signifies the presence of the C-O bond[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The FTIR spectrum of the Glu-coated ZnO (middle) shows the characteristic peaks of both ZnO and Glu. Notably, the most characteristic peaks are the 451 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e peak of the Zn-O bond and the 1620 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e peak of the C\u0026thinsp;=\u0026thinsp;O bond in the carbonyl group. A broad band from 3680 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e to 2850 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e indicative of the O-H bond in the carboxyl group. This summit encompasses the lower regions of the peaks. The N-H bond exhibits a frequency of 3330 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, while the CH\u003csub\u003e2\u003c/sub\u003e group displays a frequency of 2920 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb displays the UV-Vis radiation absorption properties of the three compounds, which are similar to the FTIR spectra. The results indicate that the ZnO nanoparticles, in their original form, have a distinct absorption peak at a wavelength of 371 nm, corresponding to a band gap of 3.32 eV [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The UV-Vis spectra of L-glutamic acid (top) has an absorption band ranging from 200 to 230 nm. This absorption peak is also detected in the UV-Vis absorption spectrum of Glu-coated ZnO (middle). This absorption spectrum also exhibits a peak at 375 nm, which is ascribed to the distinctive absorption peak of ZnO. The UV-vis absorption property of Glu-coated ZnO NPs shows that the UV-Vis absorption properties of both Glu and ZnO NPs have been combined. Furthermore, there is a noticeable red shift observed in the UV-Vis spectra of ZnO and Glu-coated ZnO. More specifically, the absorption peak at 371 nm in ZnO nanoparticles is displaced to 375 nm in Glu-coated ZnO. The red shift is usually explained by functional groups that attract electrons [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], which fits with the fact that Glu was added to the surface of ZnO NPs. The FTIR and UV-Vis spectra demonstrated the bond between L-glutamic acid and ZnO NPs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe X-ray diffraction (XRD) spectrum results for Glu-coated ZnO are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The XRD diagram displays diffraction peaks at specific 2theta angles: 31.77\u003csup\u003eo\u003c/sup\u003e, 34.44\u003csup\u003eo\u003c/sup\u003e, 36.25\u003csup\u003eo\u003c/sup\u003e, 47.53\u003csup\u003eo\u003c/sup\u003e, 56.62\u003csup\u003eo\u003c/sup\u003e, 62.86\u003csup\u003eo\u003c/sup\u003e, 66.36\u003csup\u003eo\u003c/sup\u003e, 67.93\u003csup\u003eo\u003c/sup\u003e, and 69.09\u003csup\u003eo\u003c/sup\u003e. These peaks correspond to the crystal planes (100), (002), (101), (102), (110), (103), (200), (112), and (201) of the ZnO crystal (PDF 01-071-6424). These findings demonstrate that the attachment of L-glutamic acid molecules to the surface of zinc oxide nanoparticles does not alter their crystal structure. Furthermore, the XRD pattern exhibits a distinct diffraction peak at the 2theta angle of 19.38\u003csup\u003eo\u003c/sup\u003e, which can be attributed to the X-ray diffraction of the (111) plane of glutamic acid [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Ultimately, the XRD spectra confirmed the existence of Glu. Moreover, this existence did not alter the crystal structure of ZnO NPs. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e displays the Thermogravimetric Analysis (TGA) analysis diagram of Glu-coated ZnO material. The diagram illustrates the relationship between sample temperature and sample mass (Δm, black line) heat flow (HF, red line), and the first differential heat flow (dHF, blue line). In the dHF fluctuation, there are two prominent peaks observed at temperatures T\u0026thinsp;=\u0026thinsp;102.98 \u003csup\u003eo\u003c/sup\u003eC and T\u0026thinsp;=\u0026thinsp;296.84 \u003csup\u003eo\u003c/sup\u003eC. Prior to the first point, the HF curve exhibited minimal growth, indicating that the sample is effectively absorbing heat. The rationale behind this phenomenon is that the heat input is solely utilized to extract moisture. Therefore, the mass that has been lost so far may be attributed to the mass of water that has been absorbed by the Glu-coated ZnO material. This mass loss is measured to be 0.268 mg, which is comparable to 1.00% of the total mass. The dHF reaches its minimum when the temperature (T) is 102.98 \u003csup\u003eo\u003c/sup\u003eC. This might happen because heat was used to break up the bonds between L-glutamic acid molecules that were only loosely attached to the nanoparticle's surface. After that, the dHF went up significantly and quickly, showing that the combustion reaction involving the recently detached organic part from the nanoparticle surface had taken place. This sequence is almost repeated at the second notable time, at temperature T\u0026thinsp;=\u0026thinsp;296.84 \u003csup\u003eo\u003c/sup\u003eC. It is reasonable to assume that this situation is the result of the thermal energy supplied separating the tightly bound organic molecules from the nanoparticle surface. This product then thermally decomposes, causing HF to rapidly increase. After about 450 \u003csup\u003eo\u003c/sup\u003eC, the sample mass seems stable; the change occurs with a very small amplitude. The change in sample mass during this period was caused by the reaction of metallic zinc or zinc oxide (Zn/ZnO) with gases like NO\u003csub\u003ex\u003c/sub\u003e and CO\u003csub\u003ex\u003c/sub\u003e that were made during the calcination process. From here, the mass loss period in the temperature ranges up to about 450 \u003csup\u003eo\u003c/sup\u003eC (Δm\u0026thinsp;=\u0026thinsp;2.669 mg, equivalent to 9.998%) includes humidity mass (Δm\u0026thinsp;=\u0026thinsp;0.268 mg, equivalent to 1.00%), and the remaining amount is equivalent to 8.998%. % is the mass of the organic fraction.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe EDS spectrum of bare ZnO and Glu-coated ZnO is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. This outcome demonstrates that ZnO consists solely of two constituent components, zinc, and oxygen. Meanwhile, with Glu-coated ZnO, in addition to the above two elements, there are also two elements: carbon (6.04% w) and nitrogen (3.36% w). This partly proves that glutamic acid was successfully attached to the surface of zinc oxide nanoparticles. In addition, it is also seen that, in addition to the characteristic dispersion peaks for the main elements Zn, O (for ZnO) and Zn, O, C, N (for Glu-coated ZnO), there is almost no difference. Dispersion peaks characteristic of other elements appear. This shows the purity of the as-prepared ZnO. The SEM and TEM images in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e (a, b) depict the morphological characteristics of uncoated ZnO and ZnO coated with Glu, respectively. SEM picture of ZnO (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea) demonstrates that the nanoparticles have relatively great size homogeneity. Nanoparticles often have a spherical morphology. The borders between the particles were distinctly detected, suggesting that the nanoparticles produced using this technique exhibited reduced propensity for agglomeration. Furthermore, the spherical morphology of the nanoparticles has been revalidated by TEM images. The presence of nanoparticles with dimensions ranging from 20 to 30 nm is also more distinctly seen. Concurrently, SEM and TEM images of ZnO coated with Glu (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb) exhibit noticeable alterations. Based on the SEM image (top), the morphology of nanoparticles appears to have deviated from the spherical shape, with diminished visibility of the inter-particle boundaries. The transmission electron microscopy (TEM) pictures, depicted below, likewise exhibited comparable findings. The weak contrast in the photograph may be attributed to the existence of an organic covering on the surface. Nevertheless, TEM data provide enhanced visibility of the boundaries encompassing the particles, as well as a more distinct observation of their spherical shape. The particle size can be anticipated to exceed 20 nm.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eResults of particle size measurement by DLS (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea) show that ZnO NPs have an average particle size of about 25.32 nm, with particle size distributed in a narrow range from 18.17 nm to 37.84 nm. This result is consistent with the results observed under the electron microscope. Meanwhile, ZnO NPs after being coated with Glu on the surface have a size of about 43.82 nm (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb), significantly larger than that of ZnO, as well as the results obtained from electron microscope images. This is explicable by the fact that L-glutamic acid increases the interaction between the surface of nanoparticles and the water environment, increasing the hydrodynamic size of the particles. In addition, it is seen that the DLS graph of Glu-coated ZnO has a wide peak, showing a wide distribution of particle sizes, from 21.04 nm to 122.4 nm. The zeta potential of the nanoparticles before and after modification was also determined; accordingly, the zeta potential of ZnO without surface modification (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec) and after surface modification (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ed) was \u0026minus;\u0026thinsp;9.05 mV and \u0026minus;\u0026thinsp;18.6 mV, respectively. This result shows that the zeta potential amplitude of the ZnO synthesized in this study is quite large, which means that the ZnO NPs have quite good stability and resistance to agglomeration. However, after surface modification of this nanoparticle with glutamic acid, the zeta potential amplitude increased more than two times, meaning they have much higher stability.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Evaluation of the cancer-killing effectiveness of Glu-coated ZnO\u003c/h2\u003e \u003cp\u003eThe efficacy of Glu-Coated ZnO in inhibiting cancer growth is evaluated on three distinct cancer cell lines, namely Hela cervical cancer cells, A549 lung cancer cells, and MCF7 breast cancer cells. The graphs in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e depict the test results regarding the impact of the dosage of Glu-Coated ZnO on the survival rate of these cancer cells after 72 hours of processing. The concentration of Glu-Coated ZnO ranges from 10 to 200 \u0026micro;g/ml. These findings indicate a negative correlation between the dose and the survival rate of cells after treatment time. When Hela cells are exposed to a dosage of 200 \u0026micro;g/ml of Glu-Coated ZnO, the survival rate of cells is 8.31%. However, when the dosage of Glu-Coated ZnO is reduced to 10 \u0026micro;g/ml, the survival rate jumps significantly to 92.23%. The percentage of the same trend was observed for A549 and MCF7 cells at survey levels of 200 \u0026micro;g/ml and 10 \u0026micro;g/ml, with values of 14.47% and 74.65%, and 9.31% and 70.15%, respectively. The results demonstrate that Glu-Coated ZnO exhibits a potent and dose-dependent effect on cancer cells. The impact of eliminating cancer cells is also observed as undergoing alterations within cancer cells. The survey results indicate that Glu-Coated ZnO exhibits the most significant treatment effect on MCF7 cells and the least significant effect on A549 cells. This is also demonstrated by the inhibitory value equivalent to half of the IC\u003csub\u003e50\u003c/sub\u003e, which is determined using mathematical models based on experimental data. The IC\u003csub\u003e50\u003c/sub\u003e values of Glu-Coated ZnO with Hela, A549, and MCF7 cells are 40.43 \u0026micro;g/ml, 44.23 \u0026micro;g/ml, and 37.20 \u0026micro;g/ml, respectively. When comparing the anti-cancer activity of zinc oxide nanoparticles (ZnO NPs) synthesized from leaf extract in a previous study [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] to their activity on these three types of cancer cells, it is evident that the surface functionalization of the nanoparticles has greatly improved their effectiveness in combating cancer. The precise mechanism by which glutamic acid interacts with cancer cells remains incompletely elucidated. However, it is also believed that glutamic acid serves crucial functions in cancer cells. Tumor cells require glutamine, which is a transformer form of glutamic acid, to provide nutrient sources of nitrogen and carbon for their anabolic processes [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Thus, it can be found that glutamic acid has its own attraction to tumor cells, so we suggest a hypothesis to explain the increase in the cancer-killing effectiveness of Glu-coated ZnO NPs. When the glutamine coating on the surface of ZnO NPs makes it easier for ZnO-NPs to have priority access to the tumor cells, it facilitates the intrusion and development of the cancerous cell-killing effect of ZnO's inherent capabilities. This is like the targeting capabilities of glutamine in the publication by J. Jonghwa and colleagues in their study [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Another perspective posits that Glu possesses inherent anti-cancer properties, as proposed in a study conducted by Luzzio et al. [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. This idea gains further support from the observation of glutamine deficit in the muscles of cancer patients. It is thought to be due to abnormally high glutamine absorption by tumor cells and chronic protein metabolism. Additional research indicates that the activity of anti-cancer drugs can be enhanced by combining them with other substances known to combat cancer, such as All-Trans Retinoic (ATRA) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], Cisplatin [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], Curcumin [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], 20 (S)-Camptothecin (CPT) [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], N-(4-Hydroxyphenyl) Retinamide (4HPR) [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], and Glutamic Acid. According to this idea, the mechanism behind the cancer cell-killing activity of Glu-Coated ZnO is attributed to the synergistic action of ZnO and Glutamic acid. Therefore, regardless of the circumstances, Glu-Coated ZnO in its original state has demonstrated a noteworthy impact in eradicating malignancy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Conclusions","content":"\u003cp\u003eThe surface of zinc oxide nanoparticles produced with guava leaf extract was successfully coated with L-glutamic acid. The research findings have demonstrated that the FTIR spectra exhibits the amalgamation of Glu and ZnO. Additionally, the UV-Vis results display a red shift in the distinctive absorption peak of ZnO, which may be attributed to the existence of electron-attracting components. This observation is also in line with the presence of Glu. The EDS and TGA examination results reveal the presence of organic content in the nanoparticles synthesized. Based on calculations from the TGA data, this component constitutes approximately 8.998% of the total content. The electron microscope (SEM, TEM) analysis reveals that the nanoparticles exhibit a spherical shape with a diameter ranging from 20 to 30 nm. Furthermore, noticeable alterations in the morphology of the nanoparticles are detected before and after denaturation. Meanwhile, DLS analysis reveals that the mean diameter of the nanoparticles prior to modification is 25.4 nanometers; however, after the application of the Glu coating, it measures 43.82 nm. The zeta potential indicates that the nanoparticle will exhibit increased stability following modification. The test results for the anti-cancer activity of Glu-coated ZnO were satisfactory. The effectiveness of cancer-killing has improved significantly, with evidence that the half-inhibitory concentrations (IC\u003csub\u003e50\u003c/sub\u003e) of Glu-coated ZnO for Hela, A549, and MCF7 cells are 40.43 \u0026micro;g/mL, 44.23 \u0026micro;g/mL, and 37.20 \u0026micro;g/mL, respectively, which has decreased 3\u0026ndash;4 times compared to ZnO synthesized from leaf extract without surface treatment with glutamic acid. This demonstrates the considerable potential of Glu-coated ZnO for utilization in cancer therapy.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Nguyen Thi Huong: Designed the experimental framework, analyzed and interpreted the results, provided critical insights and explanations, and contributed to securing research funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRes.\u0026nbsp;Nguyen Ngoc Son: Designed the experimental framework, conducted the laboratory work, and drafted the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eProf. Dr. Vu Minh Thanh\u0026nbsp;and Prof.Dr Ninh Duc Ha: Monitored the progress of the project, supervised the experimental procedures, and contributed to reviewing and editing the manuscript.\u003c/p\u003e\n\u003cp\u003eConflict of interest\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eThis research has received financial support from the Institute of\u0026nbsp;Chemistry\u0026nbsp;and Materials.\u003c/p\u003e\n\u003cp\u003eData Availability\u003c/p\u003e\n\u003cp\u003eThe datasets produced and examined in the present investigation can be obtained from the corresponding author upon a reasonable request.\u003c/p\u003e\n\u003cp\u003eEthical Approval (not applicable)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSegets D, Gradl J, Taylor RK, Vassilev V, Peukert W, ACS Nano. 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(2007) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ygyno.2007.07.077\u003c/span\u003e\u003cspan address=\"10.1016/j.ygyno.2007.07.077\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Scheme ","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"L-Glutamic acid, Zinc oxide nanoparticles, Ancticancer, Guave leaf","lastPublishedDoi":"10.21203/rs.3.rs-3922581/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3922581/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis paper presents a method to enhance the compatibility of zinc oxide nanoparticles (ZnO NPs) produced from guava leaf extract by modifying the nanoparticle surface with L-glutamic acid. The Glu-coated ZnO material was subjected to characterization using Fourier transform infrared spectroscopy (FTIR), X-ray scattering spectroscopy (XRD), UV-Vis spectroscopy, and electron energy scattering spectroscopy (EDS). The results corroborated the attachment of glutamic acid to the surface of the nanoparticle. The thermal density analysis (TGA) results indicate that the Glu-coated ZnO material contains around 8.998% organic content. The morphology and size of nanoparticles were assessed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering spectroscopy (DLS) both before and after modification. The findings demonstrate that the bare ZnO nanoparticles had an average size of around 25.32 nm, but the Glu-coated ZnO nanoparticles measure 41.88 nm. Their zeta values are \u0026minus;\u0026thinsp;9.05 mVs and \u0026minus;\u0026thinsp;18.6 mV, respectively. The anti-cancer effect of ZnO nanoparticles coated with glutamic acid was evaluated on various cell lines including HeLa (cervical cancer), A549 (lung cancer), and MCF7 (breast cancer). The findings demonstrated a significant enhancement in the anti-cancer efficacy of ZnO NPs with the application of Glu coating on their surface. The IC50 values of Glu-coated ZnO for the Hela, A549, and MCF7 cancer cell lines are 40.43 \u0026micro;g/mL, 37.20 \u0026micro;g/L, and 44.23 \u0026micro;g/mL, respectively. The findings indicate that the utilization of Glu-coated ZnO material holds significant promise in the field of cancer treatment.\u003c/p\u003e","manuscriptTitle":"Glutamic Acid-Coated Zinc Oxide Nanoparticles: Synthesis, Characterization, and Anticancer Activity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-13 19:39:21","doi":"10.21203/rs.3.rs-3922581/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9de81ffc-8462-4cae-9ea1-fb555f222f98","owner":[],"postedDate":"February 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-02-17T18:44:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-13 19:39:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3922581","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3922581","identity":"rs-3922581","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}