Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2025 Dec 12;10(51):62452–62463. doi: 10.1021/acsomega.5c02271

Influence of Yttrium (Y) Substitution in pH-Responsive 5‑Fluorouracil Delivery of Y–ZnO Nanoformulation

Somedutta Maity §, Sharanya Dattamandal §, Gauri Chavan §, Elayaraja Kolanthai †, Craig J Neal †, Yifei Fu †, Sudipta Seal †,‡,*, Dibakar Das §,*
PMCID: PMC12756809  PMID: 41487188

Abstract

The rise in cancer fatalities necessitates the development of advanced treatments employing nanomaterials with better biocompatibility and efficacy. 5-Fluorouracil (5-FU), a pyrimidine analogue with potent antitumor effects, inhibits diverse solid tumors by blocking thymidylate synthase and incorporating its metabolites into RNA and DNA, preventing cancer cell proliferation. However, poor oral absorption and bioavailability limit its therapeutic efficiency. Hence, the development of a pH-stable carrier is imperative to bolster the efficacy and mitigate side effects. In this study, the synthesis of 0 to 15 wt % yttrium (Y)-doped ZnO nanostructures via the sol–gel process and the distinct characteristics from their pure counterparts have been reported. Y doping modifies the energy bandgap of ZnO, fosters oxygen vacancy formation, hinders crystal growth by reducing the energy bandgap, facilitates Y3+ surface segregation, and augments Y3+ surface enhancement. The investigation demonstrates that 10% and 15% Y-doped materials exhibit enhanced inhibitory effects on MCF-7 cancer cells relative to pure ZnO and Y-doped ZnO with 5% and 15% concentrations. With an increase in the concentration of the structure-directing doping agent, the release rate also increases, reaching a maximum after a specific duration under pH 4 conditions. The synthesized Y-doped 5-FU ZnO demonstrates precise administration of the anticancer drug at the tumor site in a stimuli-responsive, pH-dependent manner, indicating controlled release over a defined time frame. In conclusion, the findings of the reported study highlight the anticancer potential of Y-doped ZnO nanoparticles, suggesting their importance for future medicinal applications.

graphic file with name ao5c02271_0011.jpg

graphic file with name ao5c02271_0009.jpg

1. Introduction

In the realm of cancer research, designing nanocarriers is emerging as a promising alternative pathway for the delivery of anticancer drugs. , Among various biocompatible materials, metal oxides have been extensively studied for their efficacy for this particular purpose. In this context, ZnO has the potential as a nanocarrier due to its versatile and unique properties, such as nontoxicity, varying morphology, nanometric size, strong catalytic efficiency, , cost-effectiveness, and excellent biocompatibility with human cells. Being recognized as “GRAS” (Generally Recognized as Safe) by the FDA (Food and Drug Administration), , inorganic metal oxide ZnO not only is preferred for anticancer and antibacterial treatments but also has been successfully employed in diverse biomedical applications, including biosensing, immunological response, and cellular imaging. One of the critical advantages of ZnO nanoparticles is their ability to generate reactive oxygen species (ROS) on their surfaces, which causes cytotoxicity toward highly proliferating cancerous cells. Owing to these characteristics, ZnO nanoparticles can be a suitable carrier for cancer therapy due to their enhanced potential to eliminate malignant cells.

Despite the promising results, the use of ZnO nanoparticles for biomedical purposes still holds some ambiguity due to its intrinsic properties with unavoidable consequences. ZnO nanoparticles possess a low stability in biological fluids making them difficult to control for biomedical purposes. Additionally, ZnO nanoparticles tend to induce cytotoxicity and mitochondrial dysfunction. The toxic effects of ZnO NPs arise due to the high solubility of the nanoparticles in cellular fluids and it can occur in three different ways primarily: dissolution in extracellular fluids, which causes uncontrollable release of Zn2+ in the intracellular region as well, direct entry into the cells and dissolution in the intracellular region, or direct dissolution in the lysosomes, which reduces the pH level of the cell. This phenomenon disrupts the cellular environment as enhancement of cytotoxicity reduces the ability of the nanoparticles to discriminate between healthy cells and malignant cells. To address these challenges, doping ZnO nanoparticles presents a suitable solution, as it can also contribute to the enhancement of physiochemical properties and efficacy in drug delivery. Rare earth (RE) elements and transition metals (TM) are two primary categories of materials used for the doping of ZnO for biomedical purposes due to their ability to modify the electronic band structure. Enhancement of bandgap energy induces optical absorption, facilitating photocatalytic properties of the material, which is an important activity to decompose organic and toxic materials in the presence of a light source. As a result, the generation of Reactive Oxygen Species (ROS) is increased, which makes the doped nanoparticles suitable for antibacterial and antitumoral applications. In this context, yttrium (Y) is one of the most suitable dopants for ZnO nanoparticles as it is considered both a rare earth element and a transition metal.

Doped ZnO NPs have been extensively used in various anticancer and antibacterial , activities. Rahini Rajendran et al. concluded that Ag-doped ZnO was less toxic to bacteria as well as induced apoptosis and destroyed UVB-induced cancer cells. Studies have shown that doped ZnO NPs decrease the cell viability of cancerous cells and induce apoptosis. , For example, Khawla et al. prepared Al–ZnO which demonstrated promising anticancer potential against MDA-MB231 cells, indicating its usefulness in developing therapies against cancer in general and breast cancer in particular. Ce-doped ZnO NPs have been regarded as interesting antibacterial and anticancer agents over pure ZnO due to their ability to form oxygen vacancies and to attain two oxidation states Ce3+/Ce4+, exhibiting different optical and electronic properties. Y. Zhihong et al. examined the electrical sensitivity and efficacy of Fe-, Mg-, Al-, and Ga-doped ZnO nanoclusters in interaction with the anticancer medication 5-FU, utilizing theoretical investigation through DFT. It was determined that the adsorption energy of 5-FU on the doped nanoclusters is comparatively higher than that of the pristine zinc oxide. Additionally, numerous investigators have reported that the characteristics of Y2O3 are suitable for application in biomedicine including fluorescence imaging, bioimaging, biosensing, drug delivery, and anticancer therapy, due to its antimicrobial and antioxidant nature. , Recent studies have reported synthesis of superior nanocrystalline Y–ZnO thin films at low growth temperatures, optimizing the Y concentration to enhance the structural characteristics of Y–ZnO. Wei-Chih Lai et al. examined the thermal stability of Y–ZnO films deposited on GaN substrates. Essia Hannachi et al. synthesized Y–Ce codoped ZnO NPs using a simple sol–gel autocombustion method. Their biocompatibility assessment showed a significant decrease in viable cells when HCT-116 cells were treated with Y–Ce codoped ZnO NP, suggesting that Y–Ce codoped ZnO has commercial potential for anticancer activity.

In addition, the doping of zinc oxide nanoparticles with specific metals has shown promising results in addressing the limitations associated with the use of ZnO NPs in nanomedicine. Doping increases the surface flaws of ZnO NPs, leading to the enhancement of photooxidation processes, making them effective in cancer treatment. Nanoscale doping of ZnO can also enhance its photoluminescence properties, adding to the detection of cancer cells. Numerous studies have reported improved optical characteristics of ZnO after doping. Yttrium (Y) is a particularly promising dopant due to its similar ionic radius to that of zinc. , While the potential of ZnO NPs in biomedicine has been acknowledged by researchers, limited attention has been given to the potential of Y-doped ZnO in biomedical therapy. , In a study by Nagajyothi et al., Y2O3 demonstrated anticancer effects when tested against kidney cancer cell lines, specifically Caki-2 cells. Yttrium plays a crucial role in enhancing the cytotoxic effect of the nanomaterial through multiple pathways: generation of Reactive Oxygen Species (ROS), mitochondrial dysfunction, and apoptosis induction. In fact, yttrium oxide nanoparticles have been shown to promote cytotoxicity, genotoxicity, apoptosis, and ferroptosis in human MDA-MB-231 cells, that have been diagnosed with triple-negative breast cancer.

The current study successfully utilized the sol–gel approach to synthesize yttrium-doped ZnO nanoparticles. These nanoparticles were produced with varying doping concentrations of Y (5, 10, and 15 wt. percentages). For the first time, the biocompatibility of 5-FU loaded Y-doped ZnO compositions and pH-dependent 5-FU release activities of these NPs were examined, and the sustainability of 5-FU release in a cancer cell medium was evaluated and reported in this manuscript.

2. Experimental Procedures

2.1. Reagents

All of the chemicals used in this investigation were of analytical grade. Zinc acetate (99.99%), yttrium­(III) nitrate hexahydrate (99.8%) precursors, and 5-fluorouracil (5-FU) were obtained from Sigma-Aldrich. Sodium hydroxide pellets (NaOH, 97%) used as a gelling agent were procured from SDFCL, India. Ethanol (99.98%) as the solvent was purchased from Pharmco-Aaper, India. Distilled water (DW) was used for all of the experiments.

2.2. Synthesis of Y–ZnO Nanoparticles

Y–ZnO nanoparticles were synthesized via a sol–gel method, employing zinc acetate and yttrium nitrate as the precursors. Initially, zinc acetate and NaOH were dissolved in ethanol solutions and stirred for 2 h. During this process, dropwise additions of NaOH solution were made to the zinc acetate solution to lower the pH to 5, resulting in the formation of a three-dimensional gel network. Subsequently, various samples containing yttrium nitrate solution in ethanol were prepared by stirring for two hours to incorporate yttrium into the ZnO lattice at concentrations of five, ten, and 15 wt % (Y5Z, Y10Z, and Y15Z). Following synthesis, the solutions were subjected to centrifugation, followed by rinsing with ethanol and DW to isolate the particles. The samples were then aged for 24 h at 120 °C and subsequently dried in an oven.

The same procedure was adopted to prepare pure ZnO NPs (Y0Z), with the only difference being the absence of the addition of yttrium in the process.

2.3. Characterizations

A powder X-ray diffractometer was used to determine the crystallinity and crystal structure of the nanoparticles (NPs). A Bruker D8 Advance diffractometer was used with Cu as the anode material. The samples were scanned in the 2θ range of 20°–80° with a 0.02° scan step. Transmission Electron Microscopy (TEM) studies were carried out to determine the size and morphology of the prepared NPs. A Philips Tecnai 300 kV HRTEM instrument was used for TEM imaging. Each sample was drop cast onto a TEM grid, dried, and then imaged. All of the TEM pictures were examined using ImageJ software. The elemental mapping of all of the samples was confirmed by a Carl Zeiss Ultra 55 FESEM with EDAX. X-ray Photoelectron Spectroscopy (XPS) analysis was done to determine the chemical composition of all of the samples. XPS studies were performed using a Thermo Scientific ESCALAB 250Xi spectrometer. Experiments were performed using an Al-Kα radiation source under high vacuum conditions (∼10–10 mbar pressure). Samples were prepared onto a gold substrate by the drop-casting technique. Avantage software was used to analyze the XPS data. The C 1s scan, specifically the C–C peak observed at 284.6 eV, was utilized as the reference point for peak shifting. UV–vis spectroscopic analysis was done to determine the optical bandgap energy and drug concentration and for the investigation of the release profiles studies of the loaded nanocarriers. A PerkinElmer spectrophotometer was used in the wavelength range of 200–800 nm and the drug concentration was estimated at a wavelength of 265 nm. The apoptotic cell death was studied by fluorescence microscopy. Using different filters, a Nikon fluorescence microscope was used to study and capture the images of live and dead cells.

2.4. 5-FU Loading on Y–ZnO and Its Release Study

Indirect methods were used to determine the Y–ZnO nanoparticle encapsulation efficiency.

A specific quantity of nanoparticles with the same concentration of the 5FU drug was utilized. After that, nanoparticles were spun for 30 min at 15,000 rpm, and the supernatants of 5-FU solutions were then quantified at 265 nm using a UV spectrophotometer (model: Lambda 750 spectrometer, PerkinElmer in λ = 180–900 nm range). The calibration curve was used to perform the calculations, and the encapsulation efficiencies were determined. The identical procedures were carried out for both doped and undoped samples.

The in vitro release profiles of different 5-FU nanoparticles were estimated as follows. Ten milligrams of powdered 5-FU nanoparticles were dissolved in 5.0 mL of phosphate buffer saline (PBS 4.6 and 7.4), and then the mixture was placed into a dialysis membrane bag with a molecular weight of 10 kDa, sealed, and submerged in 50.0 mL of PBS medium. The constant oscillation frequency was maintained at 37 °C throughout the whole system. At a certain time interval, 3 mL of release medium was withdrawn, and it was compensated with 3 mL of fresh PBS solution. 5-FU content in the release medium was assessed by UV–vis spectroscopic measurements. Every measurement was done three times. The following formulas were used to determine the 5-FU loading capacity (LC) and 5-FU encapsulation efficiency (EE) of nanoparticles

Entrapmentefficiency=(totalamountof5‐FU)−(free5‐FU)totalamountof5‐FUtakeninitially×100%
Loadingcapacity=(totalamountof5‐FU)−(free5‐FU)totalamountofnanoparticles×100%

2.5. In Vitro Cell Studies

2.5.1. MTT Assay on Nanoparticles

The biocompatibility of synthesized Y–ZnO nanoparticles was investigated utilizing murine-derived macrophages cells, i.e., (RAW 264.7) and MCF-7, in triplicate. MCF-7 and RAW cells were purchased from ATCC, USA, and the cells were seeded in a T75 flask at a temperature of 37 °C in a CO2 incubator utilizing Dulbecco’s modified Eagle medium (DMEM). Cells were washed with PBS, and it was separated from the flask by adding 0.25% trypsin–EDTA solution flowed by scarping. Cells were collected using the centrifugation method, and it was quantified using an automatic cell counter (Thermo Fisher). Cells at passage number 10 for RAW 264.7 and MCF-7 (5 MCF-7) were used for all experiments. RAW 264.7 (30,000) and MCF-7 (10,000) cells per well were added to a 96-well plate and incubated at a temperature of 37 °C for a duration of 24 h under 5% CO2 conditions, to permit cell attachment to the plate. After 24 h, the cell culture medium was removed, and different concentrations of Y–ZnO nanoparticles (ranging from 0.39 to 100 μg/mL) mixed culture medium were added to the cells and incubated for 24 h. Then, 10 μL of 5 mg/mL solution of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was introduced into each well and subsequently incubated for a duration of 4 h inside a CO2 incubator. The MTT solution was subsequently removed following a four hour incubation period, and after that, 200 μL of DMSO was added to each well to solubilize the formazan crystals. The solution was agitated for 30 min using an orbital shaker to achieve homogeneity. The optical density of these solutions was ultimately assessed at 570 nm using a BMG Labtech multiplate reader. Cells cultivated without nanoparticle therapy were designated as the control group. Further, 5-FU drug activity from 5-FU-loaded Y–ZnO was investigated using MCF-7 cells. MCF-7 (10,000) cells per well were added to a 96-well plate and kept at 37 °C for 24 h in 5% CO2 conditions, to allow cell attachment to the plate. Further, the medium was removed and various concentrations of 5-FU Y–ZnO (25, 50, 100, and 200 μg/mL) mixed with cell culture medium were added to cells. After drug treatment, the cells were incubated for 24 h, and then MTT assay was conducted as described above. Non-nanoparticle treated cells were considered as the control.

2.5.2. Live/Dead Assay

A live/dead assay was conducted during the MTT test to assess the viability of cells after the incubation period. Cells treated with 5-FU Y–ZnO at concentrations of 25, 50, 100, and 200 μg/mL were cultured and incubated for 24 h. After incubation, the medium was aspirated and the cells were stained using the Molecular Probes Live/Dead assay kit. A staining solution containing 2 mM calcein AM and 4 mM ethidium homodimer-1 was added, and the well plates were incubated at 37 °C under CO2 atmospheric conditions for 30 min. The viable and nonviable cells were imaged using a Nikon fluorescence microscope.

2.6. Statistical Analyses

Cell studies and 5-FU loading and release studies experiment were performed in triplicate for each condition and average values were used for plotting the graph. To make the multiple comparison between drug and nanoparticles treated and non-treated cells, one-way ANOVA with Tukey’s test was used using GraphPad-8 software function, with statistical difference p < 0.05.

3. Results and Discussion

3.1. X-ray Diffraction (XRD) Study

Figure shows the crystallographic nature of the prepared Y-doped (5, 10, and 15 wt %) ZnO and pristine ZnO NPs. The obtained 2θ values were related to (100), (002), (101), (102), (110), (103), and (112) diffraction planes which correspond to the hexagonal wurtzite structure with P63 mc space group symmetry (reference code: 98-016-4690). The XRD pattern does not show any additional peak for the Y or secondary phase, which indicates the synthesized nanoformulation to be of high purity and the Y3+ ions are incorporated either at the interstitial sites or uniformly substituted in the ZnO lattice without altering its hexagonal structure. ,

1.

1

Open in a new tab

Powder X-ray diffraction pattern of x wt % Y2O3-doped ZnO (Y­(x)­Z, 0 ≤ x ≤ 15) nanopowders at room temperature.

Table presents the peak location (2θ), fwhm value, cell parameters “a” and “c”, c/a ratio, and the volume of the unit cell for various Y­(x)­Z nanoparticles (x = 0, 5, 10, 15). The obtained values of “a” and “c” for undoped ZnO are 3.2490 and 5.2050, respectively, which match well with the values reported in the literature. The lattice parameters “a” and “c” increase with increasing Y doping concentration in the ZnO lattice, confirming the replacement of Y (ionic radius = 0.89 Å) for Zn (ionic radius = 0.74 Å) sites. By comparing the XRD peaks of Y0Z to Y15Z, the diffraction peak (101) is seen to have slightly shifted toward a lower angle (Δθ ∼0.022°) with increasing Y concentration (from 36.262° to 36.240°).

1. Analysis of the Powder XRD Data of Y(x)Z (x = 0, 5, 10, 15 wt %) Nanopowders.

      lattice parameters
    
samples peak position (2θ) (deg) fwhm (β) (deg) a = b c c/a ratio cell volume
Y0Z 36.262 0.3614 3.2490 5.2050 1.6020 47.58
Y5Z 36.239 0.3728 3.2530 5.2110 1.6019 47.76
Y10Z 36.262 0.3786 3.2510 5.2100 1.6026 47.69
Y15Z 36.240 0.3861 3.2530 5.2110 1.6019 47.76
Open in a new tab

3.2. Transmission Electron Microscopy (TEM) Study

TEM and HRTEM images of undoped and Y–ZnO nanoparticles, as depicted in Figure , clearly show that the average size of all of the synthesized nanoparticles is within the nanometer scale. The image of undoped ZnO NPs, as shown in Figure a, indicates that the prepared NPs are well-dispersed, although some aggregation is observed, likely due to air-drying. The synthesized NPs are uniform in size with an average size of ∼12 nm and have spheroid-like morphology. Y–ZnO nanoparticles exhibit reduced dimensions relative to undoped ZnO nanoparticles. Figure b illustrates the spheroid-like morphology of Y5Z nanoparticles, measuring approximately 3–4 nm in size. Figure c illustrates a further reduction to 2–3 nm for Y10Z NPs. With a further increase in dopant concentration to 15%, for Y15Z, a slightly larger particle size of around 30–40 nm with distorted surface morphology has been observed (Figure d). Due to anisotropy, the calculation of particle size distribution was difficult.

2.

2

Open in a new tab

TEM images of x wt % Y2O3-doped ZnO (Y­(x)­Z, 0 ≤ x ≤ 15), (a) Y0Z, (b) Y5Z, (c) Y10Z, and (d) Y15Z; HRTEM images of (e) Y0Z, (f) Y5Z, (g) Y10Z, and (h) Y15Z.

The TEM images also indicate slight morphological changes in the nanocarrier upon doping, probably due to different growth velocities of different crystallographic planes of the host material. The HRTEM images presented in Figure e–g exhibit lattice spacings of 0.245, 0.256, and 0.258 Å, respectively, matching closely with the interplanar distance of the (101) plane in the standard Wurtzite-type ZnO structure. The lattice spacing for Y15Z is shown in Figure h. ZnO has a polar crystal characterized by the alternating arrangement of the atomic planes of Zn and O atoms with the basal plane (0001) featuring tetrahedral zinc accompanied by a terminal OH ligand. The comparative growth rate of the hexagonal crystal faces will influence the ultimate morphology and aspect ratio of the ZnO nanostructures.

Due to the faster growth rate of the ZnO lattice along the [0 0 0 1] plane direction, undoped ZnO has hexagonal prism or pyramid-like structures. Increasing the Y-doping concentration from Y0Z to Y10Z, the sample morphology changed into a quasi-spherical structure. Yttrium doping does not significantly affect the directional growth rate of ZnO, since the lattice spacing values for undoped and Y–ZnO nanoparticles are almost identical and do not substantially modify the Wurtzite-type structure. However, the presence of Y doping in all the growth planes equalizes the growth velocity in every direction, and thus, Y–ZnO appears quasi-spherical in shape.

3.3. Energy-Dispersive X-ray Spectroscopy (EDS) Study

Figure shows the EDS spectra analysis of Y–ZnO samples to confirm the Y3+ ion doping in ZnO NPs. The majority of the elements seen in EDS spectra are Zn, O, Y, and Au. Gold sputtering is responsible for the occurrence of the Au signal. Figure a–d presents the typical EDS spectra for Y0Z, Y5Z, Y10Z, and Y15Z, respectively.

3.

3

Open in a new tab

Energy-dispersive X-ray (EDS) spectra of x wt % Y2O3-doped ZnO (Y­(x)­Z, 0 ≤ x ≤ 15), (a) Y0Z, (b) Y5Z, (c) Y10Z, and (d) Y15Z nanopowders at room temperature. The inset of corresponding figures shows the quantitative weight of the component elements, Zn, O, and Y.

The inset of the corresponding figures shows the quantitative weight of the component elements Zn, O, and Y. Y is present in ZnO NPs, according to the EDS analysis. Figures demonstrate that the intensity of Y and its weight % increases from 0 to 0.7, 1.2, and 4.5 for Y0Z, Y5Z, Y10Z, and Y15Z, respectively.

The difference in actual and theoretical weight % might originate from an improper sampling volume. If the signal is collected from a very limited sampling volume, then the elements with smaller quantities might disappear from the spectra. The observed difference in weight % can also be due to experimental errors.

3.4. X-ray Photoelectron Spectroscopy (XPS) Study

X-ray photoelectron spectroscopy (XPS) was performed for all material formulations to assess material (surface) compositions and chemical state distributions, especially with respect to the doping fraction. Elemental binding energy scans were performed over energy ranges associated with Zn 2p, O 1s, and Y 3d (Figure ). Spectra for all samples over the Zn 2p region (Figure a) have a common character, with prominent peaks related to 2p3/2 and 2p1/2, separated by a splitting energy of 23 eV. Additionally, a loss feature (broad, centered approximately at 1040 eV) is visible in all formulations and can be ascribed to a predominant zinc oxide chemical state. Yttrium (Figure b) doping is highlighted as a trend in increasing peak signal intensity with increasing yttrium concentrations during the synthesis (over the range of 5 to 15 wt %). Yttrium peaks are largely similar in character across formulations, with a splitting energy of 2 eV. O 1s spectra (Figure c) were satisfactorily fit with two peaks which may be ascribed to metal oxide lattice oxygen (peak center: ∼531 eV) and metal hydroxide/hydrate (peak center: ∼532 eV). − Interestingly, the relative intensities (O–OH/Olattice) between these two peaks were observed to change with increasing yttrium content. This observation suggests that yttrium doping has a significant effect on material surface chemistry with hydroxides/hydrates at the material surface potentially contributing to the adsorption of solution-dispersed chemical species.

4.

4

Open in a new tab

High-resolution XPS spectra of Y­(x)­Z (x: 0, 5, 10, 15 wt %) nanopowders for (a) Zn 2p, (b) Y 3d, and (c) O 1s peaks.

3.5. Drug Loading Study

Drugs can be released from nanoparticles in two different ways: “burst release” and “sustained release”. The term “Burst release” refers to describe a drug’s quick release from a metal matrix or the surface of nanoparticles. The drug may rapidly enter the bloodstream and achieve an effective concentration. Sustained release denotes the gradual release of the drug from nanoparticles as they undergo degradation. The drug can sustain an effective concentration in the bloodstream for an extended duration. Figure a,b presents the in vitro absorption spectra of 5-FU and the linear fitting of concentration-dependent absorbance spectra for the standard solutions of 5-FU.

5.

5

Open in a new tab

(a) UV–vis absorption spectra and (b) linear fitting of concentration-dependent absorbance spectra of the standard solutions of 5-FU.

The absorbance of the supernatant was assessed at λmax to determine the concentration of the free drug present. The results are listed in Table .

2. Drug Loading Capacities of 5-FU@Y–ZnO Nanoparticles.

      absorbance of supernatant
    
S. no. nanocarrier drug abs mg total amount of drug taken (mg) encapsulation capacity (%)
1 Y0Z 5-FU 3.4 0.489 10 95.11
2 Y5Z 5-FU 4.8 0.633 10 93.67
3 Y10Z 5-FU 5.4 0.783 10 92.17
4 Y15Z 5-FU 6.8 0.934 10 90.46
Open in a new tab

3.6. In Vitro Release Study

The in vitro release studies of 5-FU from undoped and Y–ZnO nanoparticles were performed in two different pH (4.6 and 7.4) for 68 h. Nanoparticles were employed to achieve controlled drug release and improve the bioavailability of drug molecules. 5-FU@Y0Z demonstrated an initial rapid release of 5-FU (up to 4 h) at pH 4.6 and pH 7.4, with drug release rates of approximately 6.4% and 0.6%, respectively, as illustrated in Figure a. In Y0Z with 5-FU, the total release observed was about 19.2% and 7.8% at pH 4.6 and 7.4, respectively (Figure a). The first rapid release resulted from the desorption of drug molecules from the pores on the nanoparticle surface. The release studies data for 5-FU@Y0Z and 5-FU@Y5Z nanoparticles demonstrated an initial burst release of 5-FU at pH 4.6 (8.9%) and pH 7.4 (2.6%) throughout the first four hours, with a total drug release of approximately 23.5% and 8.8%, respectively, as seen in Figure b. 5-FU@Y10Z nanoparticles exhibited an initial burst release of 5-FU, reaching 31.5% at pH 4.6 and 22.9% at pH 7.4 during the first four hours, with a total drug release of about 52.1% and 39%, respectively, as seen in Figure c. 5-FU@Y15Z NPs showed less % drug release compared to others. 5-FU@Y15Z showed an overall drug release of 7.9% and 5.4% at pH 4.6 and pH 7.4, respectively, as shown in Figure d.

6.

6

Open in a new tab

Drug release profiles of (a) 5-FU@Y0Z, (b) 5-FU@Y5Z, (c) 5-FU@Y10Z, and (d) 5-FU@Y15Z at pH 4.6 and 7.4.

The drug release is known to be carrier size-dependent. As the smaller particles have a larger surface-to-volume ratio, most of the drug will be at or near the particle surface, leading to faster drug release. − In the case of drug release, surface area is directly related to the dissolution rate of the drug. Moreover, a decrease in particle size causes the thickness of the diffusion layer surrounding the drug particles to decrease, increasing the concentration gradient. In the current study, the TEM results suggest that the size of the Y–ZnO particles varies from 3–4 nm to 30–40 nm, which significantly influences the drug release behavior of these particles.

The release of 5-FU from Y-doped NPs is significantly dependent on pH, with 5-FU being released much faster in acidic conditions compared with that in a neutral medium. This indicates that Y–ZnO nanoparticles are effective in releasing drugs in an acidic environment, making them well-suited for pH-responsive drug delivery. The reason for this behavior is likely due to the pK a value of fluorouracil (7.935), indicating that it is a weak acid and thus released more efficiently in acidic conditions than in neutral ones. The result shows that bare ZnO NPs release less drug (±19%) compared to doped NPs (±23.5%, ±68.57%, and ±7.49%). These findings strongly suggest that the nanoparticle size plays a crucial role in drug release. The particle size of bare ZnO is approximately 12 nm, while Y5Z is approximately 3.2 nm, Y10Z is approximately 2.2 nm, and Y15Z is approximately 30 nm with a distorted surface morphology.

The pH-sensitive drug release is considered a smart strategy for drug delivery and targeting in cancer therapy and bacterial infection. In solid tumors, the cells produce lactic acids by metabolizing glucose exceptionally. These acids are transferred to the extracellular fluid which results in a change in pH, which is very important for pH-dependent drug delivery by the nanocarriers. Due to the engagement of the main therapeutic groups of 5-FU, the functionality of the delivery system particles might change. Thus, it is crucial to assess the anticancer activity of drug-loaded nanoformulation. To check the anticancer effects of 5-FU-loaded undoped and Y-doped ZnO nanoparticles, an MTT assay was carried out to determine the cell cytotoxicity against MCF-7 breast cancer cells.

3.7. MTT Assay

Biocompatibility is one of the most crucial factors in assessing drug carrier nanoparticles. In this study, the biocompatibility of synthesized pure and Y-doped ZnO nanoparticles was examined using normal macrophage (RAW 264.7) Figure a,b and breast cancer (MCF-7) Figure c,d cells through the MTT assay. The relationship between nanoparticles concentration and cell viability is presented in Figure a,c. The results indicate that the percentage of cell viability increased at low concentrations (0.39 to 12.5 μg/mL) but decreased at higher concentrations (50 and 100 μg/mL) of pure and Y-doped ZnO nanoparticles. Cells treated with 25 μg/mL displayed no significant change in the percentage of cell viability (Figure a). Overall, cells treated with the nanoparticles exhibited over 80% of cell viability, indicating that 100 μg/mL pure and various Y-doped ZnO nanoparticles are biocompatible with macrophage cells. Also, varying levels of yttrium doping in ZnO nanoparticles did not significantly affect the cell viability. To further validate these results, a live/dead assay was performed. Fluorescence images of cells treated with 100 μg/mL of Y0Z, Y5Z, Y10Z, and Y15Z nanoparticles are shown in Figure b.

7.

7

Open in a new tab

Biocompatibility studies of the synthesized Y–ZnO nanoparticles were conducted using two different cells such as macrophage and breast cancer cells. Both macrophage (RAW 264.7) (a,b) and MCF-7 (c,d) cells were cultured with varying concentrations (0.49, 0.78, 1.56, 1.25, 6.25, 12.5, 25, 50, and 100 μg/mL) of pure (Y0Z) and Y-doped ZnO (Y5Z, Y10Z, and Y15Z) nanoparticles for 24 h, Untreated cells were considered as the control group. After 24 h of incubation, the cell viability of both macrophage and MCF-7 cells was quantified using the MTT assay at 570 nm (a,b). The results are presented and expressed as the mean standard deviation from three independent experiments. Statistically significant difference was indicated by an asterisk (*), with differences calculated using GraphPad software at a significance level of p < 0.05, comparing control cells to nanoparticle treated cells. Bright-field microscopy images revealed the morphological changes in macrophage and MCF-7 cells after 24 h of nanoparticle treatment (b,d). Further, a live/dead assay was performed on both control and nanoparticle treated cells (b,d). Fluorescent imaging showed live cells stained green, dead cells red, and merged images representing the live/dead cells population at specific image spots. These results demonstrated the biocompatibility of the nanoparticles based on the live-to-dead cells ratio observed in the treated cell populations. The scale bar is equal to 200 μm.

Control cells and those treated with a low concentration of pure and Y-doped ZnO nanoparticles showed predominantly viable cells (green fluorescence). But cells exposed to higher concentrations of pure and Y-doped ZnO nanoparticles showed reduced green fluorescence, confirming a decrease in cell viability at higher concentration. Similarly, the cell viability of MCF-7 cells cultured with these nanoparticles is shown in Figure c. The percentage of cell viability significantly decreased for cells treated with nanoparticles, except at concentrations of 0.39 μg/mL of both pure and Y-doped ZnO nanoparticles. For all other nanoparticle treated cells, cell viability remained unaffected up to a concentration of 12.5 μg/mL, apart from the Y15Z sample. Furthermore, at concentrations of 50 and 100 μg/mL, both pure and Y-doped ZnO nanoparticles demonstrated a significant reduction in cell viability. These results further confirmed that higher concentration (100 μg/mL) of nanoparticle treated cells led to decreased viability compared to control cells, as corroborated by live/dead staining images presented in Figure d.

5-FU an anticancer drug was loaded into pure Y–ZnO nanoparticles to study their anticancer activity against MCF-7 cancer cells. The percentage of cell death was calculated from the MTT assay, as shown in Figure a. The study assessed the cancer cell killing efficacy of 5-FU-loaded pure and Y-doped ZnO NPs at varying concentrations from 25 to 200 μg/mL.

8.

8

Open in a new tab

Cytotoxic effect of 5-FU-loaded Y-doped ZnO (Y–ZnO) nanoparticles on MCF-7 cells was analyzed using the MTT assay. MCF-7 cells were cultured with varying concentrations (25, 50, 100, and 200 μg/mL) of 5-FU-loaded Y-doped ZnO (Y5Z, Y10Z, and Y15Z) nanoparticles for 24 h with untreated cells considered as the control. After 24 h of incubation, MCF-7 cell death was quantified using the MTT assay at 570 nm (a). Results are presented as the mean standard deviation from three independent experiments. Statistically significant difference was indicated by an asterisk (*), with differences calculated using GraphPad software at a significance level of p < 0.05, comparing control cells to nanoparticle treated cells. Bright-field microscopy images revealed morphological changes in MCF-7 cells after 24 h of nanoparticle treatment (b). Further, a live/dead assay was performed on 100 μg/mL of both control and nanoparticle treated cells (b). Fluorescent imaging showed live cells stained green, dead cells red, and merged images representing the live/dead cells population at specific image spots. These results displayed the cancer cells killing efficiency of 5-FU-Y-doped ZnO nanoparticles, as evidenced by the observed live-to dead cell ratios in the nanoparticle treated sample. The scale bar is equal to 100 μm.

As expected, no cell death was observed in the control. However, 5-FU-loaded pure and Y-doped ZnO NPs significantly decreased cancer cell viability, as shown in Figure a. The results indicate that increasing the 5-FU-NPs concentration from 25 to 100 μg/mL correspondingly increased cell death from 50% to 80%. Interestingly, at a higher concentration of 200 μg/mL, the cell death rate was like that observed at 100 μg/mL. These findings suggest that 100 μg/mL of 5-FU-loaded NPs is sufficient to achieve maximum cell death. Furthermore, the percentage of cell death was considerably higher for 5-FU@Y–ZnO nanoparticles than for unloaded Y–ZnO nanoparticles. The MTT assay results confirmed that the developed 5-FU@Y–ZnO nanoparticles could be considered as an alternative anticancer agent. Pure and Y-doped ZnO NPs alone did not exhibit significant cytotoxicity toward MCF-7 cells, as evidenced in Figure b,d. However, 5-FU@Y–ZnO nanoparticles showed a pronounced cytotoxic effect on MCF-7 cells after 24 h treatment. Fluorescence microscopy images (Figure b) further corroborated these findings, showing greater cancer cell death for 5-FU Y–ZnO nanoparticles compared with 5-FU-ZnO NPs and the control. Moreover, increasing the dopant concentration from 5 to 15 wt % resulted in enhanced cell death.

Notably, cancer cells were killed more effectively when the dopant concentration was increased from 10 to 15 wt %, which could be attributed to the increase in particle size, potentially slower drug release from 5-FU@Y15Z. Among the formulations tested, 5-FU@Y10Z showed the largest number of dead cancer cells, indicating that the synthesized nanoformulation can effectively induce apoptosis in cancer cells.

4. Conclusions

A sol–gel technique was used to synthesize ZnO NPs doped with different amounts of Y3+ ions. XRD analysis of the crystal structure verified that all samples had a hexagonal wurtzite structure. The size of the 5-FU@Y–ZnO nanoparticles shrank from 12 nm at Y = 0 to 2.2 nm at Y = 10 wt % when the concentration of Y3+ increased up to 10 wt %. The size of the Y–ZnO nanoparticles increases to 30–40 nm when the Y3+ concentration is increased to 15% wt %. The prepared Y–ZnO nanoparticles with a sustained release profile showed around 95% of the 5-FU loading capacity. As the amount of Y-doped ZnO NP loaded with 5-FU increased, the MTT experiment showed a significant decrease in the proliferation of cancer cells. The results showed that 5-FU-ZnO NPs doped with 10% and 15% Y3+ ions significantly reduced the viability of cancer cells, indicating that they might be used in future cancer treatments. The innovative nanoformulation of Y2O3-doped ZnO provides an effective drug delivery system that can be regulated by pH and responds to stimuli; it dramatically decreases the lifespan of MCF-7 cancer cells. The findings point to 5-FU@Y–ZnO nanoparticles as a viable option for breast cancer treatment due to their biocompatibility, pH specificity, and improved drug loading and release profile. This innovative nanoformulation provides an improved alternative to traditional chemotherapy, which not only kills cancer cells but also threatens the survival of other healthy cells. Additionally, anticancer medications may be readily functionalized onto Y–ZnO nanoparticles for targeted administration, which protects healthy cells from harm. Furthermore, the 5-FU@Y–ZnO nanoparticles have the potential to be used for imaging and other diagnostic purposes all at once, which is an advantage over prior hyperthermia treatments.

Acknowledgments

This work is supported by the IoE Directorate through grant no. UoH/IoE/RC1/RC1-20-017 dated 07-12-2020, University of Hyderabad, and ANRF-PAIR project with sanction no. ANRF/PAIR/2025/000012/EPAIR Dt, 20-09-2025. The technical support obtained from the Advanced Materials Processing Analysis Center (AMPAC), University of Central Florida, Orlando, USA, and the School of Physics, University of Hyderabad, Hyderabad, India is gratefully acknowledged.

∥.

Somdutta Maity and Sharanya Dattamandal contributed equally. Dibakar Das and Sudipta Seal were responsible for conceptualization, methodology, reviewing, editing of the manuscript, and funding acquisition. Material preparation, data collection, and analysis of the data were performed by Somdutta Maity, Sharanya Dattamandal, Gauri Chavan, Elayaraja Kolanthai, and Craig J. Neal. Manuscript preparation, reviewing, and editing were done by Somdutta Maity, Sharanya Dattamandal, Gauri Chavan, Elayaraja Kolanthai, Craig J Neal, and Yifei Fu. All authors have read and approved the final manuscript.

The authors declare no competing financial interest.

References

  1. Vandebriel R. J., De Jong W. H.. A Review of Mammalian Toxicity of ZnO Nanoparticles. Nanotechnol. Sci. Appl. 2012;5(1):61–71. doi: 10.2147/NSA.S23932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Maity B., Moorthy H., Govindaraju T.. Tumor Microenvironment pH-Sensitive Peptidomimetics for Targeted Anticancer Drug Delivery. Drug Delivery Biochemistry. 2025;64(6):1266–1275. doi: 10.1021/acs.biochem.4c00657. [DOI] [PubMed] [Google Scholar]
  3. Colon G., Ward B. C., Webster T. J.. Increased Osteoblast and Decreased Staphylococcus Epidermidis Functions on Nanophase ZnO and TiO2. J. Biomed. Mater. Res. Part A. 2006;78A(3):595–604. doi: 10.1002/jbm.a.30789. [DOI] [PubMed] [Google Scholar]
  4. Krishna S. B. N., Jakmunee J., Mishra Y. K., Prakash J.. ZnO based 0–3D diverse nano-architectures, films and coatings for biomedical applications. J. Mater. Chem. B. 2024;12:2950–2984. doi: 10.1039/D4TB00184B. [DOI] [PubMed] [Google Scholar]
  5. Brust M., Kiely C. J.. Some Recent Advances in Nanostructure Preparation from Gold and Silver Particles: A Short Topical Review. Colloids Surfaces A Physicochem. Eng. Asp. 2002;202(2):175–186. doi: 10.1016/S0927-7757(01)01087-1. [DOI] [Google Scholar]
  6. Arya S. K., Saha S., Ramirez-Vick J. E., Gupta V., Bhansali S., Singh S. P.. Recent Advances in ZnO Nanostructures and Thin Films for Biosensor Applications: Review. Anal. Chim. Acta. 2012;737:1–21. doi: 10.1016/j.aca.2012.05.048. [DOI] [PubMed] [Google Scholar]
  7. Afroz S., Medhi H., Maity S., Minhas G., Battu S., Giddaluru J., Kumar K., Paik P., Khan N.. Mesoporous ZnO nanocapsules for the induction of enhanced antigen-specific immunological responses. Nanoscale. 2017;9:14641–14653. doi: 10.1039/C7NR03697C. [DOI] [PubMed] [Google Scholar]
  8. Kleinekathöfer U., Tang K. T., Toennies J. P., Yiu C. L.. Van Der Waals Potentials of He2, Ne2, and Ar2 with the Exchange Energy Calculated by the Surface Integral Method. J. Chem. Phys. 1997;107(22):9502–9513. doi: 10.1063/1.475246. [DOI] [Google Scholar]
  9. Rajendran R., Mani A.. Photocatalytic, Antibacterial and Anticancer Activity of Silver-Doped Zinc Oxide Nanoparticles. J. Saudi Chem. Soc. 2020;24(12):1010–1024. doi: 10.1016/j.jscs.2020.10.008. [DOI] [Google Scholar]
  10. Premanathan M., Karthikeyan K., Jeyasubramanian K., Manivannan G.. Selective Toxicity of ZnO Nanoparticles toward Gram-Positive Bacteria and Cancer Cells by Apoptosis through Lipid Peroxidation. Nanomedicine. 2011;7(2):184–192. doi: 10.1016/j.nano.2010.10.001. [DOI] [PubMed] [Google Scholar]
  11. Carofiglio M., Barui S., Cauda V., Laurenti M.. Doped Zinc Oxide Nanoparticles: Synthesis, Characterization and Potential Use in Nanomedicine. Appl. Sci. 2020;10(15):5194. doi: 10.3390/app10155194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Pandurangan M., Kim D. H.. In Vitro Toxicity of Zinc Oxide Nanoparticles: A Review. J. Nanoparticle Res. 2015;17(3):158. doi: 10.1007/s11051-015-2958-9. [DOI] [Google Scholar]
  13. Hamdi S., Smaoui H., Guermazi S., Leroy G., Duponchel B.. Enhancing the Structural, Optical and Electrical Conductivity Properties of ZnO Nanopowders through Dy Doping. Inorg. Chem. Commun. 2022;144(July):109819. doi: 10.1016/j.inoche.2022.109819. [DOI] [Google Scholar]
  14. Baruah S., Dutta J.. Hydrothermal Growth of ZnO Nanostructures. Sci. Technol. Adv. Mater. 2009;10(1):013001. doi: 10.1088/1468-6996/10/1/013001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lai W.-C., Lin C.-N., Lai Y.-C., Yu P., Chi G. C., Chang S.-J.. GaN-Based Light-Emitting Diodes with Graphene/Indium Tin Oxide Transparent Layer. Opt. Express. 2014;22(S2):A396–A401. doi: 10.1364/OE.22.00A396. [DOI] [PubMed] [Google Scholar]
  16. Hannachi E., Khan F. A., Slimani Y., Rehman S., Trabelsi Z., Akhtar S., Al-Suhaimi E.. Fabrication, Characterization, Anticancer and Antibacterial Activities of ZnO Nanoparticles Doped with Y and Ce Elements. J. Clust. Sci. 2022;34:1777–1788. doi: 10.1007/s10876-022-02348-w. [DOI] [Google Scholar]
  17. Khashan K. S., Sulaiman G. M., Hussain S. A., Marzoog T. R., Jabir M. S.. Synthesis, Characterization and Evaluation of Anti-Bacterial, Anti-Parasitic and Anti-Cancer Activities of Aluminum-Doped Zinc Oxide Nanoparticles. J. Inorg. Organomet. Polym. Mater. 2020;30(9):3677–3693. doi: 10.1007/s10904-020-01522-9. [DOI] [Google Scholar]
  18. Yousefi M., Amiri M., Azimirad R., Moshfegh A. Z.. Enhanced Photoelectrochemical Activity of Ce Doped ZnO Nanocomposite Thin Films under Visible Light. J. Electroanal. Chem. 2011;661(1):106–112. doi: 10.1016/j.jelechem.2011.07.022. [DOI] [Google Scholar]
  19. Zhihong Y., Ye Y., Pejhan A., Nasr A. H., Nourbakhsh N., Tayebee R.. A Theoretical Study on the Pure and Doped ZnO Nanoclusters as Effective Nanobiosensors for 5-Fluorouracil Anticancer Drug Adsorption. Appl. Organomet. Chem. 2020;34(4):e5534. doi: 10.1002/aoc.5534. [DOI] [Google Scholar]
  20. Srivastava M., Sahu S. K., Singh A. R., Agrawal R., Kumar S., Ningthoujam R. S.. Codoping of Yttria (Y2O3): Ho–Yb Nanoparticles with Li Increase Emitted Green Light Intensity for Security Ink and Bioimaging. ACS Appl. Nano Mater. 2023;6:20887–20898. doi: 10.1021/acsanm.3c03903. [DOI] [Google Scholar]
  21. Rajakumar G., Mao L., Bao T., Wen W., Wang S., Gomathi T., Gnanasundaram N., Rebezov M., Shariati M. A., Chung I.-M., Thiruvengadam M., Zhang X.. Yttrium Oxide Nanoparticle Synthesis: An Overview of Methods of Preparation and Biomedical Applications. Appl. Sci. 2021;11:2172. doi: 10.3390/app11052172. [DOI] [Google Scholar]
  22. Keerthana S., Kumar A.. Potential Risks and Benefits of Zinc Oxide Nanoparticles: A Systematic Review. Crit. Rev. Toxicol. 2020;50(1):47–71. doi: 10.1080/10408444.2020.1726282. [DOI] [PubMed] [Google Scholar]
  23. Zeidan M. M., Abedrabbo S.. Enhancing Photoluminescence Spectra for Doped ZnO Using Neutron Irradiation. ACS Omega. 2023;8:16722–16728. doi: 10.1021/acsomega.3c00218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hassan S. M. u., Akram W., Saifullah A., Khurshid A., Ali Z., Shahzad F., Iqbal Z., Ahmad J.. Novel PEGylated ZnO Nanoparticles with Optimized Y Dopant Exhibiting PL Imaging, PDT and CT Contrast Properties. Mater. Lett. 2022;315:131986. doi: 10.1016/j.matlet.2022.131986. [DOI] [Google Scholar]
  25. Xu J.-J., Lu Yi-N., Tao F.-F., Liang P.-F., Zhang P.-A.. ZnO Nanoparticles Modified by Carbon Quantum Dots for the Photocatalytic Removal of Synthetic Pigment Pollutants. ACS Omega. 2023;8:7845–7857. doi: 10.1021/acsomega.2c07591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Faisal S., Jan H., Shah S. A., Shah S., Khan A., Akbar M. T., Rizwan M., Jan F., Wajidullah, Akhtar N., Khattak A., Syed S.. Green Synthesis of Zinc Oxide (ZnO) Nanoparticles Using AqueousFruit Extracts of Myristica fragrans: Their Characterizations and Biological and Environmental Applications. ACS Omega. 2021;6:9709–9722. doi: 10.1021/acsomega.1c00310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hassan S.M., Akram W., Saifullah A., Khurshid A., Ali Z., Shahzad F., Iqbal Z., Ahmad J.. Novel PEGylated ZnO nanoparticles with optimized Y dopant exhibiting PL imaging, PDT and CT contrast properties. Mater. Lett. 2022;315:131986. doi: 10.1016/j.matlet.2022.131986. [DOI] [Google Scholar]
  28. Nagajyothi P. C., Pandurangan M., Veerappan M., Kim D. H., Sreekanth T. V. M., Shim J.. Green synthesis, characterization and anticancer activity of yttrium oxide nanoparticles. Mater. Lett. 2018;216:58–62. doi: 10.1016/j.matlet.2017.12.081. [DOI] [Google Scholar]
  29. Emad B., WalyEldeen A. A., Hassan H., Sharaky M., Abdelhamid I. A., Ibrahim S. A., Mohamed H. R.. Yttrium Oxide nanoparticles induce cytotoxicity, genotoxicity, apoptosis, and ferroptosis in the human triple-negative breast cancer MDA-MB-231 cells. BMC Cancer. 2023;23:1151. doi: 10.1186/s12885-023-11649-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ahn S. E., Lee J. S., Kim H., Kim S., Kang B. H., Kim K. H., Kim G. T.. Photoresponse of Sol-Gel-Synthesized ZnO Nanorods. Appl. Phys. Lett. 2004;84(24):5022–5024. doi: 10.1063/1.1763633. [DOI] [Google Scholar]
  31. Tsolou A., Angelou E., Didaskalou S., Bikiaris D., Avgoustakis K., Agianian B., Koffa M. D.. Folate and Pegylated Aliphatic Polyester Nanoparticles for Targeted Anticancer. Drug Delivery. Int. J. Nanomed. 2020;15:4899–4918. doi: 10.2147/IJN.S244712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Maity S., Tomar M. S., Wasnik K., Patra S., Modak M. D., Gupta P. S., Pareek D., Singh M., Paik P.. Azadirachta Indica Seed Derived Carbon Nanocapsules: Cell Imaging, Depolarization of Mitochondrial Membrane Potential, and Dose-Dependent Control Death of Breast Cancer. ACS Biomater. Sci. Eng. 2022;8(8):3608–3622. doi: 10.1021/acsbiomaterials.2c00463. [DOI] [PubMed] [Google Scholar]
  33. Munawar T., Yasmeen S., Mukhtar F., Nadeem M. S., Mahmood K., Saqib Saif M., Hasan M., Ali A., Hussain F., Iqbal F.. Zn0.9Ce0.05M0.05O (M = Er, Y, V) Nanocrystals: Structural and Energy Bandgap Engineering of ZnO for Enhancing Photocatalytic and Antibacterial Activity. Ceram. Int. 2020;46(10):14369–14383. doi: 10.1016/j.ceramint.2020.02.232. [DOI] [Google Scholar]
  34. Anandan S., Muthukumaran S.. Influence of Yttrium on Optical, Structural and Photoluminescence Properties of ZnO Nanopowders by Sol–Gel Method. Opt. Mater. (Amst). 2013;35(12):2241–2249. doi: 10.1016/j.optmat.2013.06.009. [DOI] [Google Scholar]
  35. Zheng J. H., Song J. L., Jiang Q., Lian J. S.. Enhanced UV Emission of Y-Doped ZnO Nanoparticles. Appl. Surf. Sci. 2012;258(18):6735–6738. doi: 10.1016/j.apsusc.2012.03.010. [DOI] [Google Scholar]
  36. Yang J., Wang R., Yang L., Lang J., Wei M., Gao M., Liu X., Cao J., Li X., Yang N.. Tunable Deep-Level Emission in ZnO Nanoparticles via Yttrium Doping. J. Alloys Compd. 2011;509(8):3606–3612. doi: 10.1016/j.jallcom.2010.12.102. [DOI] [Google Scholar]
  37. Sharma S. K., Sudheer Pamidimarri D. V. N., Kim D. Y., Na J.-G.. Y-Doped Zinc Oxide (YZO) Nanoflowers, Microstructural Analysis and Test Their Antibacterial Activity. Mater. Sci. Eng. C. Mater. Biol. Appl. 2015;53:104–110. doi: 10.1016/j.msec.2015.04.007. [DOI] [PubMed] [Google Scholar]
  38. Lu Y. F., Ni H. Q., Mai Z. H., Ren Z. M.. The Effects of Thermal Annealing on ZnO Thin Films Grown by Pulsed Laser Deposition. J. Appl. Phys. 2000;88(1):498–502. doi: 10.1063/1.373685. [DOI] [Google Scholar]
  39. Kumar V., Singh F., Ntwaeaborwa O. M., Swart H. C.. Effect of Br+6 Ions on the Structural, Morphological and Luminescent Properties of ZnO/Si Thin Films. Appl. Surf. Sci. 2013;279:472–478. doi: 10.1016/j.apsusc.2013.04.145. [DOI] [Google Scholar]
  40. Ingo G. M., Paparazzo E., Bagnarelli O., Zacchetti N.. XPS Studies on Cerium, Zirconium and Yttrium Valence States in Plasma-Sprayed Coatings. Surf. Interface Anal. 1990;16(1–12):515–519. doi: 10.1002/sia.7401601107. [DOI] [Google Scholar]
  41. Wang H., Xie C.. The Effects of Oxygen Partial Pressure on the Microstructures and Photocatalytic Property of ZnO Nanoparticles. Phys. E Low-dimensional Syst. Nanostructures. 2008;40(8):2724–2729. doi: 10.1016/j.physe.2007.12.012. [DOI] [Google Scholar]
  42. Maity S., Modak M. D., Tomar M. S., Wasnik K., Gupta P. S., Patra S., Pareek D., Singh M., Pandey M., Paik P.. Facile Cost-Effective Green Synthesis of Carbon Dots: Selective Detection of Biologically Relevant Metal Ions and Synergetic Efficiency for Treatment of Cancer. Biomed. Mater. 2024;19(2):025043. doi: 10.1088/1748-605X/ad2a3c. [DOI] [PubMed] [Google Scholar]
  43. Gonçalves C., Pereira P., Gama M.. Self-Assembled Hydrogel Nanoparticles for Drug Delivery Applications. Materials (Basel) 2010;3(2):1420–1460. doi: 10.3390/ma3021420. [DOI] [Google Scholar]
  44. Chavan G., Das D.. Design and Characterizations of PH-Responsive Drug Delivery Vehicles Using Molecular Docking. Mater. Technol. 2023;38(1):2196490. doi: 10.1080/10667857.2023.2196490. [DOI] [Google Scholar]
  45. Xiao X., Liang S., Zhao Y., Huang D., Xing B., Cheng Z., Lin J.. Core-Shell Structured 5-FU@ZIF-90@ZnO as a Biodegradable Nanoplatform for Synergistic Cancer Therapy. Nanoscale. 2020;12(6):3846–3854. doi: 10.1039/C9NR09869K. [DOI] [PubMed] [Google Scholar]
  46. Singh R., Lillard J. W.. Nanoparticle-based targeted drug delivery. Exp. Mol. Pathol. 2009;86(3):215–223. doi: 10.1016/j.yexmp.2008.12.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES