Nano zinc oxide in biomedicine has the ability to fight cancer, deliver drugs, heal wounds, treat diabetes…
Nano zinc oxide (ZnO NPs) are increasingly used in industrial products such as rubber, paints, coatings and cosmetics. Over the past two decades, ZnO NPs have become one of the most popular metal oxide nanoparticles in biological applications due to their excellent biocompatibility, economy and low toxicity. ZnO NPNs have emerged as a promising potential in biomedicine, especially in the areas of anticancer and antimicrobial resistance, which is related to their ability to trigger the production of various types of oxidative stress (ROS), release zinc ions and induce cell death. In addition, zinc is known for its role in maintaining the structural integrity of insulin. Thus, ZnO NPs have also been effectively developed for the treatment of diabetes. Moreover, the ZnO NPs exhibit excellent luminescence properties and have made them one of the main candidates for bioengineering. In the following, we summarize the synthesis and recent advances of ZnO NPs in biomedical fields, which will help advance their future research and focus on biomedical field.
Copyright by NanoCMM Technology
1. INTRODUCTION
Recently, biomedical nanomaterials have received more attention because of their outstanding biological characteristics and biomedical applications. With the development of nanomaterials, metal oxide nanoparticles show far and promising prospects for biomedical field, especially for bacteria, anticancer drug/gene delivery, imaging cells, biosensors, etc. [ first ].
Nano zinc oxide (ZnO NPs), as one of the most important metal oxide nanoparticles, are popularly used in various fields due to their exceptional physical and chemical properties [ 2 , 3 ]. ZnO NPs were first applied in the rubber industry because they can provide wear resistance to rubber composites, improve the performance of high polymers in terms of strength and strength as well as anti-aging, and other functions [ 4 , 5 ]. Due to ZnO’s strong UV-absorbing properties, they are increasingly used in personal care products, such as cosmetics and sunscreens [ 6]. In addition, ZnO NPs have excellent antibacterial, antimicrobial and UV blocking properties. Therefore, in the textile industry, the finished fabrics by adding ZnO NPs exhibit attractive functions of UV and visible light resistance, antibacterial and deodorizing [ 7 ]. In addition to the applications mentioned above, zinc oxide can also be used in other industries, including concrete production, photocatalysis, electronics, electrical engineering technology, and more. [ 4 , 8 ].
It is generally known that zinc as an essential trace element exists widely in all tissues of the body, including brain, muscles, bones, skin, etc. As a major component of various enzyme systems, zinc participates in the body’s metabolism and plays an important role in protein and nucleic acid synthesis, hematopoiesis, and neurogenesis [ 2 – 5 ]. Nano-ZnO, with its small particle size, makes it easier for the body to absorb zinc. Therefore, nano ZnO is often used as a food additive. Furthermore, ZnO is classified as a “GRAS” (generally recognized as safe) substance by the US Food and Drug Administration (FDA) [ 9]. With these properties, ZnO NPs have received more attention in biomedical applications. Compared with other metal oxide NPs, ZnO NPNs with their relatively inexpensive and relatively low toxicity properties exhibit excellent biomedical applications, such as anticancer, drug delivery, antimicrobial and therapeutic applications. treat diabetes; Anti-inflammatory; healing; and biological analysis [ 1 , 10 – 12 ].
Hereafter, in this review, we will summarize synthesis methods and recent exciting advances in the use of ZnO NPs in biomedical fields.
2. Synthesis of Nano zinc oxide – ZnO
The biological activity of nanoparticles depends on factors including surface chemistry, size distribution, particle morphology, and particle reactivity in solution. Therefore, the development of nanoparticles with controlled structures uniform in size, morphology and function is essential for various biomedical applications.
ZnO NPs appear in a variety of sizes and shapes that will provide a variety of properties. Methods for the preparation of stable ZnO NPs have been widely developed in recent years, mainly including chemical precipitation method, sol-gel method, solid-state pyrolysis method, and mechanical method. solution and biosynthetic method.
2.1. Chemical precipitation
The most common method for the preparation of ZnO NPs is chemical precipitation, which typically involves two reaction reagents: a high-purity zinc precursor such as zinc acetate (Zn(CH3COO)2 .2H 2 O), zinc nitrate (Zn(NO3)2 ), or zinc sulfate (ZnSO4) and a solution of a precipitant such as sodium hydroxide (NaOH) or ammonium hydroxide (NH3 .H2O) [ 13 ]. Usually, the precipitant is added dropwise to the dissolved zinc precursor until the pH reaches about 10. These solutions are then thoroughly mixed to obtain a white zinc hydroxide intermediate. Finally, the sample of zinc hydroxide (Zn(OH) 2) is converted to ZnO after high temperature sintering.
The controlled parameters in this method mainly include the concentration of the zinc precursor and the precipitate, the molar ratio of the two reagents, the reaction, and the calcination temperature.
Bisht et al. synthesized Nano zinc oxide by chemical precipitation method using Zn(CH3COO) 2 .2H 2 O and NaOH in a 1:5 molar ratio. The intermediate product was calcined at 200 °C for 2 h in a furnace. To obtain a fine white color, ZnO powder of size 18.67 ± 2.2 nm [ 14 ].
Bettini et al. introduced a simplified approach to precipitation in ZnO NPs using ZnSO4 and NaOH solution with a molar ratio of 1:2, which was performed under vigorous stirring conditions for 12 h at room temperature. The obtained white precipitate was washed several times and separated by centrifugation [15 – 17]. Finally, the precipitate (ZnO) was dried in an oven at 100 °C for 6 h. The prepared ZnO NPNs have a flake-like structure showing a size distribution of about 100 nm.
The acquisition of ZnO NPs by chemical precipitation is not only simple and controllable, but also easily industrialized. However, due to the surface effect of the nanoparticles, the precursors of nano oxides prepared by chemical precipitation method can easily form agglomerates.
2.2. Sol-Gel . method
Spanhel and Anderson [18] present for the first time a novel sol-gel synthesis of Nano zinc oxide, which mainly consists of three main steps:
(1)Preparation of zinc precursors
A sample of Zn(CH3COO) 2 .2H 2 O was dissolved in ethanol, introduced into the distillation apparatus, and then refluxed for several hours at atmospheric pressure. The solution was boiled nearly at 80 °C and stirred to obtain a condensation and hygroscopic reaction mixture.
(2) Modulation of ZnO . Clusters
The mixture after desiccation was diluted to an ethanol solution with the addition of LiOH.H2O powder. The suspension will become transparent with the help of an ultrasonic bath. This process can accelerate the release of OH ions, and the low temperature reaction under atmospheric conditions can prevent the rapid growth of particles and the receipt of ZnO sols.
(3)Crystal growth
Crystal growth is a self-inductive process that occurs at room temperature. But the amount of LiOH can strongly influence the growth rate, shape and size of the crystal which needs to be well controlled. The ZnO growth due to LiOH can be briefly summarized as follows:
Several other alkalis can also be used to grow ZnO; for example, Rani et al. synthesized ZnO NPs using NaOH instead of LiOH and successfully obtained ZnO NPs with the largest crystal size of 14 nm at pH 9 [ 19 ].
The sol-gel method is a topic of great interest, and considering its simplicity, low cost and relatively light synthesis conditions, can provide a simple route to quantum-sized ZnO particles. .
2.3. Solid state pyrolysis method
The solid-state pyrolysis method was first developed by Wang et al. with the advantage of low cost and easy operation to grow high quality ZnO nanoparticles [ 20 ].
The typical synthesis procedure is as follows: Zn(CH3COO)2 .2H2O and NaHCO3 are mixed at room temperature. The mixture is pyrolysis at the reaction temperature. Zn(CH3COO)2 .2H2O is converted to ZnO, while NaHCO3 is converted to CH3COONa and can finally be cleaned with deionized water. Then, white ZnO NPs can be obtained through thermal decomposition. The particle size can be adjusted by selecting different pyrolysis temperatures. Using this method, Wang et al. obtained ZnO NPs with different sizes in the range of 8–35 nm.
2.4. Mechanical method without solution
Solution-free mechanical preparation of ZnO NPs is a two-step synthesis method. The first step is to grind the powdered mixture of Zn(CH3COO)2 and H2C2O4 .2H2O for a certain time to form ZnC2O4 .2H2O [ 21 ] nanoparticles.
Zn(CH3COO)2 (solid, large particle) + H2C2O4 .2H2O (solid, large particle) = ZnC2O4 .2H2O (solid particle) + 2CH3COOH (liquid and gaseous) + H2C2O4 .2H2O (solid particle).
The second step is the thermal decomposition of ZnC2O 4 .2H2O nanoparticles at very high temperature to obtain zinc oxide nanoparticles:
The advantages of this method are low production cost and high homogeneity of crystal structure and morphology. But the morphology of ZnO NPs strongly depends on the grinding time of the reactant mixture, longer grinding time leads to smaller particle size. The obtained ZnO NPNs have average sizes ranging from 24 to 40 nm.
Pardeshi and Patil synthesized ZnO NPs with different crystal morphology and sizes using this method by varying the calcination temperature from 400 °C to 900 °C. It has been found that zinc oxide heated from 400 °C to 550 °C has the same crystal growth rate (38–50 nm) [ 22 ].
2.5. Biological method
Physical and chemical methods for the fabrication of ZnO NPs have been widely developed. Nowadays, the development of green chemistry is of more and more interest because it is largely environmentally friendly [ 23 ]. Various plant extracts are used for biosynthesis of ZnO NPs such as leaves of Azadirachta indica (L.) [ 23 ], Cochlospermum religiosum (L.) [ 24 ], Plectranthus amboinicus [ 25 ], Andrographis paniculata [ 26 ] , Aloe barbadensis [ 27 , 28 ], rind of Rambutan (Nephelium lappaceum L) [ 29 ], root extract of Polygala tenuifolia [ 30 ], rhizome extract of Zingiber officinale [ 31 ], flower extract of Trifolium pratense [ 32 ], Jacaranda mimosifolia [ 33 ], seeds of Physalis alkekengi L.[ 34], and the like. Biosynthetic and eco-friendly technology for the synthesis of ZnO NPs is said to be more environmentally friendly, economical (cheap), non-toxic and biocompatible than chemical and physical methods. . The ZnO NPs prepared by this method have strong potential for biomedical applications such as its excellent antitumor and antibacterial activity.
3. Biomedical applications of Nano zinc oxide
ZnO nanoparticles, as a new type of low-cost and low-toxicity nanomaterials, have attracted great interest in various biomedical fields, including anti-cancer, antibacterial, and antioxidant activities. chemopreventive, antidiabetic and anti-inflammatory, as well as for drug delivery and applied bioimaging [9, 12]. Here, we have summarized recent advances in the use of zinc oxide nanoparticles in biomedicine. Zinc oxide nanoparticles smaller than 100 nm are considered to be relatively biocompatible, supporting their biomedical applications and exhibiting a powerful property in promoting biomedical research.
3.1. Anti-cancer activity
Cancer, a condition of uncontrolled malignant cell proliferation, has often been treated with chemotherapy, radiation, and surgery over the past few decades. Although all these therapies appear to be very effective in theory for killing cancer cells, these non-selective therapies also cause a lot of serious side effects [ 35 ]. Recently, nanomaterials-based research drugs, with high biocompatibility, easy surface functionalization, cancer targeting and drug delivery capabilities, have demonstrated potential to overcome these problems. this side effect. Zn 2+ is an essential nutrient for adults and zinc oxide nanomaterials are considered safe in vivo. Taking into account these advantages, ZnO NPs can be selected as biocompatible and biodegradable nanosheets and can also be explored for cancer therapy [36, 37]. The antitumor activity of ZnO NPs in different cancers is presented in Table 1.
3.1.1. Anti-cancer activity by inducing apoptosis of cancer cells
The mitochondrial electron transport chain is known to be involved in intracellular ROS generation, and antineoplastic agents entering cancer cells can disrupt the electron transport chain and release large amounts of ROS [ 58 , 59 ]. However, excessive ROS leads to mitochondrial damage and leads to an imbalance of protein activity that ultimately induces apoptosis [ 60 ]. ZnO NPNs exhibit certain cytotoxicity in cancer cells mainly based on higher intracellular release of soluble zinc ions, followed by increased ROS induction and induced cancer cell death through carcinogenesis. apoptosis signaling pathway.
Sharma et al. explored the effects of Nano zinc oxide on human liver cancer HepG2 cells and its possible pharmacological mechanism [42]. HepG2 cells exposed to ZnO NPs have higher cytotoxicity and genotoxicity, which is associated with ROS-mediated apoptosis that activates the mitochondrial pathway. Loss of the mitochondrial membrane potential can open the outer membrane pores, leading to the release of several relevant apoptotic proteins including cytochrome c into the cytosol and activation of caspase. Mechanistic studies have demonstrated that the loss of HepG2 cell apoptosis mediated by the mitochondrial membrane potential is mainly due to a decrease in the mitochondrial membrane potential and the Bcl-2/Bax ratio and is also associated with activation of caspase-9. Besides, ZnO NPs were able to significantly activate p38 and JNK, and induce and attract phosphorylation of p53 ser15 but independent of the JNK and p38 pathways (Figure 1). These results provided valuable insights into the mechanism of ZnO NPs-induced apoptosis in human liver HepG2 cells.
Moghaddam et al. biosynthesis of ZnO NPs using a novel yeast strain ( Pichia kudriavzevii GY1) and evaluated their antitumor activity in breast cancer MCF-7 cells [ 45 ]. ZnO NPs were observed to show potent cytotoxicity against MCF-7 cells, which is associated with the occurrence of apoptosis, rather than cell cycle arrest. ZnO NPs-induced apoptosis is mainly through both extrinsic and extrinsic apoptotic pathways, and several resistance genes Bcl-2, AKT1 and JERK/2 are downregulated, while the proapoptotic genes of p21, p53, JNK and Bax are conditioned.
Nano zinc oxide have been widely used in cancer therapy and are reported to exert a selective cytotoxic effect on cancer cell proliferation. Chandrasekaran and Pandurangan investigated the cytotoxicity of ZnO nanoparticles against C2C12 trophoblastic cancer cells and 3T3-L1 adipocytes, suggesting that ZnO NPNs can be cytotoxic to the cells. C2C12 myeloma cells than 3T3-L1 cells. Compared with 3T3-L1 cells, it seems that ZnO NPNs inhibited C2C12 cell proliferation and induced marked apoptosis through an intrinsic free-death pathway mediated by ROS and the ratio of p53, Bax/Bcl-2 and the caspase-3 pathway [61]. These results suggest that ZnO NPs can selectively induce cancer cell apoptosis, which could be used as a promising candidate for cancer therapy.
3.1.2. Fight cancer with Autophagy
Autophagy is a highly regulated catabolic process that is activated in response to various types of stress such as damaged organelles, ROS, antineoplastic agents, and protein incorporation. Excessive cell damage can lead to cell death by prolonging cell apoptosis and autolysis and leading to cancer cell apoptosis [ 62 , 63 ]. Thus, autophagy not only promotes cell survival but also activates apoptosis in cancer cells, thus being considered a key event in nanoparticle-induced cytotoxicity .
Bai et al. found that 20 nm zinc oxide nanocrystals reduced the viability of ovarian cancer SKOV3 cells in a concentration-dependent manner [51]. And further tested whether zinc oxide nanosheets could induce autophagy through fluorescence microscopy using LC3 antibody to detect LC3-II/I expression. showed remarkable fluorescence and was an essential component of autophagosomes after SKOV3 cells were exposed to higher concentrations of NPN ZnO. In addition, SKOV3 cells treated with ZnO NPs resulted in upregulation of LC3-I/II and p53 expression, which further induced autophagy cell death.
Arakha et al. fabricated zinc oxide nanosheets by chemical precipitation and further evaluated their antitumor activity [64], it was found that ZnO NPs with different sizes could clearly inhibit proliferation of HT1080 fibrosarcoma cells. The results demonstrated that the appearance of autophagy in cancer cells is associated with intracellular ROS generation. HT1080 cells stained with acridine orange dye markedly display orange and red fluorescence upon ZnO NP treatment, which indicates that autophagy cells have acidic vesicular organelles. Likewise, the relative levels of LC3 II in NPN ZnO-treated cells were relatively higher than in untreated cells, which also marks the degree of self-actualization. ZnO NPs interacting with the HT1080 cell had a relatively higher ROS generation capacity. Excessive ROS leads to biomolecular injuries including DNA damage and ultimately cell death.
Previous studies have shown that ROS and autophagy are involved in the cytotoxicity of ZnO NPs, but the regulatory mechanisms between autophagy and ROS have not been elucidated. Zhang et al. investigated the regulatory mechanism of autophagy and the link between autophagy and ROS in lung epithelial cells treated with ZnO NPs [ 65]. The results demonstrated that ZnO NPs could induce esophageal accumulation and autophagy flux depletion in A549 cells. This induction of autophagy is positively correlated with the dissolution of ZnO NPNs in lysosomes to release zinc ions, and zinc ions released from ZnO NPNs can damage lysosomes, leading to impaired autophagic flux and cells body. Depletion of self-executing flux leads to the accumulation of damaged mitochondria, which can induce excessive ROS to induce cell death. This study provided a new insight into the regulatory mechanism of the autophagy-lysosome-mitochondria-ROS axis, contributing to a better understanding of the toxicity of nanomaterials.
3.1.3. Distribution of anti-cancer drugs
Using nanoparticles in targeted drug delivery presents an exciting opportunity for a much safer and more effective cancer treatment. By targeting specific sites of cancer cells, nanoparticle-based drug delivery can reduce the total amount of drug administered and thus minimize unwanted side effects [ 9 , 66 ] . Compared with other nanomaterials, ZnO NP is very attractive due to its low toxicity and easy biodegradability properties. ZnO NPs have attracted great interest in cancer drug delivery. Various drugs such as doxorubicin, paclitaxel, curcumin, and baicalin or DNA fragments can be loaded onto ZnO NPNs to show better solubility, higher toxicity compared with the individual agents and effective on cancer cells [ 48 , 67- 69 ].
Hariharan et al. used co-precipitation technique to obtain modified ZnO nanoparticles in PEG 600 solution (ZnO/PEG NPs), after loading doxorubicin (DOX) to form DOX-ZnO/PEG nanomaterials [ 52 ] . DOX-ZnO/PEG nanomaterials not only enhance the accumulation of DOX in cells, but also have a concentration-dependent inhibitory effect on HeLa cell proliferation of cervical cancer. Deng and Zhang also used chemical precipitation to prepare ZnO nanorods, which were applied to carry Dox to produce Dox-ZnO nanorods [ 44]. After co-culture with SMMC-7721 hepatocellular carcinoma cells, Dox-ZnO nanounits act as an efficient drug delivery system to enter Dox into SMMC-7721 cells and enhance uptake Dox in cells significantly. Furthermore, together with ultraviolet (UV) illumination, Dox-ZnO nanounits induce more cell death through photocatalytic properties and simultaneously activate caspase-dependent death.
Puvvada et al. established a novel ZnO (HZnO) hollow nanocarrier designed with biocompatible substrates by surface after incorporation with a folic acid (FA)-targeting agent and loaded with paclitaxel (PAC). to be designated as FCP-ZnO nanocomplex [ 48 ]. FCP-ZnO nanounits show preferential bioaccumulation and cancer cell uptake in MDA-MB-231 breast cancer cells overexpressing the folate receptor. Due to FA-mediated intracellular lysis and intracellular clearance in acidic endolysosomes, FCP-ZnO nanosheets not only exhibit significantly higher cytotoxicity in MDA-MB-231 cells in vitro but also reduced MDA-MB-231 xenograft tumors in nude mice.
To improve the solubility and bioavailability of curcumin, Dhivya et al. fabricated two novel copolymer coated Nano zinc oxide to carry curcumin, Cur/PMMA-PEG/ZnO NPs and Cur/PMMA-AA/ZnO nanocomposites [54, 55]. By experimental study, PMMA-PEG/ZnO nanomaterials with average size less than 80 nm can release curcumin faster under acidic conditions at pH ∼5.8. Compared with the constituent nanomaterials (nanocurcumin, PMMA-PEG, ZnO NP and PMMA-PEG/ZnO), the Cur/PMMA-PEG/ZnO nanocomposite performed the largest observable inhibition on the ability survival of human gastric cancer AGS cells (IC 50 ∼0.01 μ g/mL −1) and induced cell cycle initiation in S phase. For another nanocomposite, PMMA NPs -AA/ZnO with size 42 ± 5 nm can carry a large amount of curcumin and also has obvious anti-proliferative effect on AGS cancer cells.
3.1.4. Targeting Function
Targeted nanoparticles (NPs) also offer more therapeutic benefits besides specificity and specific localization such as high loading, multi-drug conjugation, easy modulation of release kinetics, selective localization filter and bypass multidrug resistance [70]. To increase the targeting effect and selectivity against cancer cells, many functionalization techniques have been reported to modify nanoparticles. Surface-modified ZnO NPs further improved their stability and promoted their selectivity towards specific cancer cells. Focused attention is on surface functionalization of zinc oxide nanoparticles with different types of biomolecules including proteins, peptides, nucleic acids, folic acid, hyaluronan, etc. [ 47 , 57 , 71 – 73 ]. The biocompatibility coating of these substances did not affect the antitumor activity of ZnO NPs but augmented the targeted effect against cancer cells and improved the safety of the cells. normal.
For example, Chakraborti et al. synthesized PEG-transformed ZnO NPs and tested it against different breast cancer cell lines [ 74 ]. It has been found that PEG-ZnO NPs are active against most breast cancer cell lines. The main mechanism by which PEG-ZnO kills cancer cells is by inducing ROS and activating p53-dependent apoptosis leading to cell death.
Namvar et al. production of hyaluronan/ZnO (HA/ZnO) nanocomposites through green synthesis for the first time for cancer therapy [ 57 ]. HA/ZnO nanocompounds induce morphological changes and inhibit the proliferation of cancer cells (pancreatic carcinoma PANC-1 cells, ovarian carcinoma CaOV-3 cells , COLO205-cell adenocarcinoma and HL-60-cell acute lymphoblastic leukemia) were dose- and time-dependent. Encouragingly, treatment with the HA/ZnO nanocomplex for 72 h was not toxic to the human normal lung fibroblast cell line (MRC-5). Compared with bare ZnO NPs, RGD peptide transformation also increased the targeting effect of ZnO NPs on integrase receptors α v β 3 overexpressing MDA-MB-231 cells [ 47]. It seems to increase the toxicity of ZnO NPs towards MCF-7 and MDA-MB-231 breast cancer cells at lower doses.
Collectively, the antitumor activity of nanoscale ZnO materials with outstanding functionality may offer new opportunities for the exploitation of ZnO NPs in cancer therapy. Theoretical analysis and experimental studies have demonstrated that ZnO NPs with fewer side effects have higher selectivity between normal cells and cancer cells. It is reported that ZnO NPs induce cell death, mainly associated with intracellular ROS generation, which further induces cancer cell death through apoptosis or autophagy signaling pathway . But so far, research into the advanced anticancer mechanism of ZnO NPs is still lacking, especially in enhancing molecular and cellular mechanisms. Therefore, in further research work, we should give more importance to their molecular mechanism in vitro and in vivo and overcome its limitations in cancer therapy.
3.2. Antibacterial activity
ZnO NP can be selected as an antibacterial material because of its superior properties, such as large specific surface area and high activity to block a wide range of pathogens. But recently, the antibacterial activity of ZnO NPs is still very little known. As shown in Figure 2 , previous reports have suggested the main antibacterial toxicity mechanism of ZnO NPs based on their ability to generate excess ROS, such as superoxide anion, hydroxyl radicals, and production hydrogen peroxide [ 10 ]. The antibacterial activity may be related to the accumulation of ZnO NPs in the outer membrane or cytoplasm of the bacterial cell and the activation of Zn 2+ release, which would induce the breakdown of the bacterial cell membrane, membrane protein damage, and genomic instability, leading to bacterial cell death [ 75 – 77 ].
Jiang et al. reported the potential antibacterial mechanisms of zinc oxide nanoparticles against E. coli [ 76 ]. It was shown that ZnO NPNs with an average size of about 30 nm induced cell death by direct contact with the phospholipid bilayer of the membrane, destroying the integrity of the membrane. The addition of root scavengers such as mannitol, vitamin E and glutathione could block the bactericidal activity of ZnO NPs, potentially revealing that ROS production plays a necessary function in the antimicrobial properties of ZnO NPs. ZnO NPs. But the Zn 2+ released from the suspension of ZnO NPs is not clearly exerting an antibacterial effect. Reddy prepared ZnO NPs with size ∼13 nm and examined their antibacterial ( E. coli and S. aureus) activities [ 78 ]. The results were summarized that ZnO NPNs completely resisted the growth of E. coli at a concentration of about 3.4 mM but inhibited the growth of S. aureus at much lower concentration (≥1 mM). Furthermore, Ohira and Yamamoto also found that the antibacterial activity ( E. coli and S. aureus ) of small-crystal ZnO NPNs was stronger than that of large-crystal particles [ 97 ]. From the ICP-AES measurement, the amount of Zn 2+ released from the small ZnO NPNs is much higher than that of the large ZnO powder and E. coli is more sensitive to Zn 2+ than S. aureus. Therefore, we can believe that Zn 2+ eluted from ZnO NPs also plays an important role in antibacterial activity.
Iswarya et al. immunomolecular extraction of crustacean binding protein β-1,3-glucan (Ph β -GBP) from the heamolymph of Paratelphusa hydrodromus and then successfully fabricated Ph β -GBP-coated ZnO NPs. The Ph β -GBP-ZnO NPs are spherical in shape with a particle size of 20–50 nm and inhibit the growth of S. aureus and P. vulgaris . It should be noted that S. aureus is more sensitive to Ph β -GBP-ZnO NPs than P. vulgaris . In addition, Ph β -GBP-ZnO NPs can alter membrane permeability and trigger ROS formation to a high degree both in S. aureus and P. vulgaris [ 87 ]. Therefore, it highlights that Ph β -GBP-ZnO NPs can be considered as excellent antibacterial nanomaterials.
Cholera epidemic, a severe diarrheal disease caused by infection with Gram-negative bacteria V. cholera , mainly affects populations in developing countries [ 81 , 94 ]. In order to develop nanomedicine against cholera , Sarwar et al. performed a detailed study of ZnO NPs against Vibrio cholerae (two organisms of cholera (classical and El Tor)). Zinc oxide nanoparticles were observed to be more effective in inhibiting the growth of the El Tor organism (N16961) of V. cholera, which is closely related to ROS production. These results would damage bacterial membranes, increase osmotic stability, and significantly alter their morphology [ 85 ]. They also detected the antibacterial activity of Nano zinc oxide ZnO NPs in cholera toxin (CT) mouse models. It was found that ZnO NPs can cause the secondary structure of CT to gradually collapse and interact with CT by disrupting CT binding to the GM1 anglioside receptor [ 98 ].
Although ZnO in nanoparticle form is a promising antibacterial agent due to its broad activity against both Gram-positive and Gram-negative bacteria, the exact antibacterial mechanism of ZnO NPs has not been clearly established. Therefore, studying it deeply has many important theoretical and practical values. In the future, we believe that ZnO NPs can be explored as antibacterial agents, such as ointments, lotions, and mouthwashes. In addition, it can be coated on a variety of substrates to prevent bacteria from adhering, spreading and multiplying in medical devices.
3.3. Nano zinc oxide ZnO NPs for the treatment of diabetes
Diabetes is a serious public health problem and WHO has estimated that, in 2014, more than 400 million adults had diabetes worldwide [ 99 ]. Diabetes mellitus is a metabolic disease caused by the body’s inability to produce insulin or inefficient use of the insulin produced [ 100 , 101 ]. Zinc is a trace element and mineral found abundantly in all human tissues and fluids. Zinc is known to preserve the structural integrity of insulin and has an active role in insulin secretion from pancreatic cells. It is also involved in insulin synthesis, storage, and secretion [ 102]. Therefore, NPs of ZnO as a novel agent for zinc delivery were developed and evaluated for their antidiabetic potential.
Kitty and associates. used natural extract of red sandalwood (RSW) as an effective antidiabetic agent upon conjugation with ZnO NPs. The antidiabetic activity was evaluated with the help of α -amylase and α -glucosidase inhibition assays with extracts from the pancreas and small intestine of dogs [ 103 ]. The results showed that the ZnO-RSW conjugate possessed a moderately higher rate of inhibition (20%) for porcine pancreatic α -amylase and was more effective for porcine crude pancreatic glucosidase than any other inhibitor. which of the two elements (RSW and ZnO NP). Conjugated ZnO-RSW showed 61.93% inhibition in glucosidase while bare ZnO and RSW NPNs showed 21.48% and 5.90%, respectively.
In 2015, Nazarizadeh and Asri-Rezaie performed a study to compare the antidiabetic activity and oxidative stress of ZnO and ZnSO 4 NPs in diabetic rats. It was found that small-sized ZnO NPs at higher dosages (3 and 10 mg/kg) had a much greater antidiabetic effect than ZnSO 4 (30 mg/kg). It has been shown to significantly reduce blood sugar and increase insulin levels as well as improve serum zinc status in a dose- and time-dependent manner. However, severe induced oxidative stress, particularly at higher doses, was also observed by altered erythrocyte antioxidant enzyme activities, increased malondialdehyde (MDA) production, and markedly reduced capacity serum total antioxidant [ 100 ].
Hyperglycemia may directly increase inflammation by regulating C-reactive protein (CRP) and cytokines, such as interleukin, which are involved in the development of cardiovascular diseases. Hussein et al. fabricated ZnO NPs using hydroxyl ethyl cellulose as a stabilizer to alleviate diabetes complications [104]. It reported that zinc oxide nanoparticles were able to significantly reduce malondialdehyde (MDA) and rapid blood sugar and asymmetric dimethylarginine (ADMA) levels. Inflammatory markers, interleukin-1 (IL-1 α ) and CRP, were also significantly reduced after treatment with ZnO NPs, concomitant with an increase in serum nitric oxide (NO) and antioxidant enzyme levels. PON-1) in diabetic rats.
All reports on nano zinc oxide in the treatment of diabetes are summarized in Table 3 , and the present data imply that ZnO NPs can be used as a promising agent in the treatment of diabetes. and reduce its complications.
3.4. Anti-inflammatory activity
Inflammation is part of a complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants [ 111 ]. Since the advent of nanoparticles and considering these biological activities of zinc ions, the anti-inflammatory effects of ZnO NPs have also attracted much attention.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by impaired skin barrier functions, which is associated with a complex interaction between genetic and environmental factors [ 112]. , 113 ]. Textiles have the longest and strongest contact with human skin. Wiegand explored the role of ZnO-functionalized textile fibers in controlling oxidative stress in AD in vitro and in vivo [ 114 ]. The study showed that AD pruritus and subjective sleep quality was a clear improvement when AD patients wore ZnO woven clothing overnight for 3 consecutive days. This may be due to the high antioxidant and strong antibacterial ability of ZnO textiles.
Ilves et al. investigated whether ZnO particles of different sizes could penetrate injured skin and injured atopic skin in a mouse AD model [ 115 ]. Their experiments clearly gave evidence that only nano-sized ZnO (nZnO) could reach the deep layers of atopic skin, but large ZnO (bZnO) remained in the upper layers. of both damaged and allergic skin. Compared with bZnO, nZnO has higher anti-inflammatory properties by strongly reducing proinflammatory cytokines (IL-10, IL-13, IFN- γ , and Th2 cytokines) in a mouse model of AD. These results demonstrated that ZnO NPs with small size have excellent effect on reducing skin inflammation in AD models.
The anti-inflammatory activity of nano zinc oxide is not only limited to atopic dermatitis, but has also been shown to be very effective against other inflammatory diseases. Nagajyothi et al. described a simple, inexpensive and environmentally friendly ZnO NPN using the root extract of P. tenuifolia , and the anti-inflammatory activities were investigated in LPS-stimulated RAW 264.7 macrophages. [ 30 ]. ZnO NPs showed remarkable anti-inflammatory activity by inhibiting dose-dependent NO production as well as related protein expressions of iNOS, COX-2, IL-1 β , IL-6 and TNF -α . Thatoi et al. prepared ZnO NPNs under optical conditions using aqueous extracts of two mangrove plants, Heritiera fomes and Sonneratia apetala , and found that ZnO particles had a higher anti-inflammatory potential (79%) ) compared with silver nanoparticles (69.1%) [ 116 ].
Reports of ZnO NPs with anti-inflammatory activity are summarized in Table 4. Therefore, zinc oxide nanoparticles also have the potential to be used for anti-inflammatory treatment.
3.5. Nano zinc oxide ZnO NPs for bioforming
ZnO NPs exhibit effective blue emission and near-UV emission, having green or yellow luminescence associated with oxygen vacancies, thus further expanding the application its in the field of biological imaging [ 12 , 36 , 120 ].
Using a simple sol-gel method, Xiong et al. For the first time, ZnO @ polymer core-shell nanoparticles were prepared in stable water (ZnO @ poly(MAA-co-PEGMEMA)). ZnO@polymer core-shell nanoparticles exhibit high quantum yield and very stable broad luminescence in aqueous solution. As shown in Figure 3, in human hepatoma cells, ZnO-1 (derived from LiOH) with an average size of 3 nm gave green fluorescence, while ZnO-2 (derived from NaOH) with an average size of 3 nm. The average size 4 nm is yellow. It is worth noting that these nanoparticles did not show any significant toxicity to human hepatoma cells when their concentration was less than 0.2 mg/mL. Furthermore, the luminescence was very stable during cell culture and the cells were still alive after 45 min of exposure. Thus, as a safe and inexpensive type of luminescent label, ZnO@polymer core-shell nanoparticles can be used as fluorescence probes for in vitro cell imaging [ 121 ].
Jiang et al. fabricated ZnO nanopanels for imaging cultured cells. They treated drug-sensitive K562 lineage leukemia cells with ZnO nanosheets, and orange-yellow light emission was clearly observed around or inside the cells under UV radiation (365 nm) at room temperature [ 122 ]. ZnO nanostructures were successfully attached to or penetrated into cells, which suggests that ZnO nanosheets with visible yellow-orange emission could act as a viable label for imaging biological.
Tang et al. Preparation of zinc oxide nanoparticles by chemical precipitation method. It exhibits blue, green, yellow and orange emission colors [123]. The emission color can be changed through adjusting the pH of the precipitated solution. To stabilize the ZnO NPs in water, they coated the ZnO NPs with silica to form a ZnO@silica core-shell nanostructure. The obtained ZnO@silica core-shell nanoparticles exhibit excellent water stability, and the visible emission of ZnO is retained. It can be successfully attached to NIH/3T3 cell surface and displays different fluorescence colors with different emission wavelengths.
The bioimaging case studies of ZnO NPs are summarized in Table 5. Based on its advanced intrinsic fluorescence, Nano zinc oxide can also be used as a promising candidate for cytological and pathological imaging studies.
4. Conclusion and future outlook
Nano zinc oxide have shown promising biomedical applications based on their anticancer, antibacterial, antidiabetic, anti-inflammatory, drug delivery, as well as bioimaging activities. Due to the inherent toxicity of zinc oxide nanoparticles they exert potent inhibitory effects against cancer cells and bacteria, by inducing intracellular ROS and activating the apoptotic signaling pathway, making ZnO NPs a potential candidates as anticancer and antibacterial agents. In addition, ZnO NPs are also known to promote bioavailability of therapeutic drugs or biomolecules when acting as drug carriers to achieve enhanced therapeutic effects. Furthermore, with its ability to lower blood sugar and increase insulin levels, ZnO NP has shown promising potential in treating diabetes and reducing its complications,
Nano zinc oxide are listed by the FDA as a safe substance. However, several important problems of Nano zinc oxide need to be further explored, including the following: (1) lack of comparative analysis of its biological advantages over other metal nanoparticles , (2) the limitations of NPN ZnO toxicity to biological systems remain controversial in recent studies, (3) lack of evidence-based randomized studies specifically exploring therapeutic role in improving anticancer, antibacterial, anti-inflammatory and antidiabetic activities, and (4) lack of insight into the respective animal studies for anticancer potential, Its antibacterial, anti-inflammatory, and antidiabetic activities. Further studies focusing on the above-mentioned issues may shed light on and better understand the potential uses of ZnO nanoparticles in the fields of biomedical diagnosis and treatment. We believe that nanomaterials will significantly promote the development of medicine, and ZnO nanoparticles are expected to make more interesting contributions in these fields.
Reference source:
The Advancing of Zinc Oxide Nanoparticles for Biomedical Applications