Application of Metal Oxide Nanoparticles in Different Carcinomas

Abstract

Metal oxide nanoparticles (MONPs) have recently attracted much attention from researchers due to their use in cancer chemotherapy, targeted drug delivery, and diagnosis/MRI imaging. Various studies have demonstrated that different metal oxide NPs show cytotoxic effects by inducing apoptosis in cancerous cells and do not have any toxic impact on normal cells. The mechanism of cytotoxicity is shown through reactive oxygen species (ROS) generated by (MONPs) in the cancerous cell. In vitro and in vivo studies reveal that in some cases metal oxide NPs are used alone and somewhere these NPs are used in combination with other therapies such as photodynamic therapy and with anticancer nanomedicines as drug carriers or drug conjugates. The phenomenon of enhanced permeability and retention (EPR) effect has been the basis of targeted drug delivery to cancerous tumors. Finally, we also provide a simple and comparative analysis of the major apoptosis pathways proposed to increase beginner understanding of anti-cancer nanomaterials. Herein, we have reviewed the most important antitumor results obtained with different metal oxide nanoparticles such as ZnO, Fe₂O₃/Fe₃O₄, CuO/Cu₂O, TiO₂, CeO_2, and HfO₂, respectively. These NPs can be applied to treat cancer by either passive or active processes. A passive process uses the enhanced permeability and retention (EPR) effect. Superparamagnetic iron oxide nanoparticles (SPIONs), due to their unique magnetic and physiochemical properties have been used in magnetic fluid hyperthermia (MFH) and magnetic resonance imaging (MRI) in vitro as well as in vivo. Now, the research has reached the stage of clinical trials for the treatment of various types of cancer. ZnO NPs have been used very vastly in cytotoxic as well as in targeted drug delivery. These NPs are also used for loading anticancer drugs such as doxorubicin. Herein, in this review, we have examined current advances in utilizing MONPs and their analogs as cancer therapeutic, diagnostic, and drug-delivery agents.

1. Introduction

Cancer is a worldwide problem, responsible for an estimated 10 million deaths in 2020. Alarmingly, the World Cancer Report 2020 of the WHO suggests that approximately one in ten Indians will develop cancer, and one in fifteen will succumb to it [1]. Cancer is an uncontrolled growth of abnormal cells that causes a solid tumor in any organ or tissue of the body. The tumors are of two types benign non-cancerous and malignant cancerous. The benign tumors usually grow slowly and cannot be spread to other tissues. Malignant tumors are cancerous and can develop slowly or quickly depending on the metabolites and micro-environment of the tumor. Malignant tumors carry the risk of metastasis, or we can say the spreading to multiple tissues and organs. However, the actual reasons for tumor growth are still being investigated. In general, cancerous tumor growth is triggered by DNA mutations within the cells. As we know DNA contains genes that give information to the cells on how they have to operate, grow, and divide. When the DNA changes within the cells, these cells do not work properly. The most common types of cancer are melanoma (mainly skin cancer), lymphoma (cancer of lymphocytes), carcinoma, leukemia (cancer of bone marrow where blood cells generate), and sarcoma, respectively. Herein, sarcoma is a cancer of connective tissues like muscles, cartilage, blood vessels, and bones. As we know carcinoma occurs in body organs such as the breast, lungs, pancreas (pancreatic cancer), prostate (prostatic cancer), colon (colorectal cancer), and so on. The hallmarks of cancer consist of six biological distinct and complementary capabilities that are acquired by human tumors during their multistep development. These hallmarks are such as sustaining proliferative signalling, evading growth suppressors, enabling replicative immortality, inducing angiogenesis, resisting cell death, and activating invasion and metastasis, respectively. These hallmarks are schematically given in Figure 1. Sustaining proliferative signalling is the most fundamental characteristic of cancer cells that involves their capability to sustain chronic proliferation. The normal tissues control the production and release of growth-promoting signals. These growth-promoting signals lead the progression through the cell growth and division cycles. Thus, this process causes the homeostasis of cells.

The cytotoxic impact of different metal and metal oxide nanoparticles on varied cancer cell lines remains uncertain in terms of the precise molecular mechanism. Yet, apoptosis has been regarded as the main mechanism of cell death [2].

Chemotherapy is a common cancer treatment method relying on the use of drugs to mitigate or kill malignant cell division in cancerous tissues. These drugs rely on different mechanisms and can be grouped as DNA-interactive agents (e.g., cis-platin, doxorubicin, ifosfamide), antimetabolites (e.g., methotrexate, 5-fluorouracil), molecular targeting agents, anti-tubulin agents, etc. There are a lot of challenges in the use of these drugs in chemotherapy such as low solubility, high toxicity, multi-drug resistance, poor selectivity, and low bioavailability for many years. Nano-medicine can provide solutions to many of these challenges. Nanomaterials have dimensions of 1–100 nm and their large surface area-to-volume ratio provides a higher degree of functionality and diverse avenues for fine-tuning in comparison to bulk materials. It is not surprising that nanomaterials have found applications in fields from medicine to material science. Nano-biotechnology and nano-medicine explore the use of nanomaterials in enhancing medical outcomes in various diseases and conditions. Metal oxide nanoparticles (MONPs) have been extensively used in biomedical applications due to their size, high surface area, and functional tunability, so they can be used in anti-cancer imaging to therapy. The use of metal oxide nanoparticles in cancer treatment has received a lot of attention because of their unique physicochemical properties, which include a large surface area, customizable size, capacity for novel interactions with biological molecules, and functional tunability. Therefore, metal oxide nanoparticles have lately been studied as potential diagnostic and therapeutic tools.

Nanoparticles are smaller than human cells and have higher penetration power which makes them ideal for therapeutic and diagnostic tasks. Similarly, magnetic MONPs such as those of Fe₃O₄ have been used for MRI-based imaging or targeted delivery. The ZnO NPs are also widely used because of their inherent cytotoxicity due to ROS production within the cell. Metal oxide nanoparticles are prepared from metal precursors. These nanoparticles can be synthesized by various methods such as chemical wet, electrochemical, sol-gel, co-precipitation, hydrothermal, solvothermal, micro-emulsion technique, laser ablation technique, thermal decomposition, high-energy ball milling technique, and green method. In chemical methods, the metal nanoparticles are obtained by reducing the metal-ion precursors in solution with chemical reducing agents. These MONPs can adsorb small molecules and have high surface energy. Several researchers have reviewed the MONPs for oncological applications. These MONPs are used in chemotherapy, photodynamic therapy, MRI imaging, drug delivery, etc. El-Boubbou et al. have used iron oxide mesoporous magnetic nanostructures (IO-MMN) in selective drug delivery for breast and colon cancerous cells [3]. These mesoporous nano-vehicles have been synthesized with the nano replication wet-etching technique. This strategy is required for reducing cytotoxicity in normal cells. Folic acid-coated SPIONPs have been conjugated with poloxamer 407. These NPs have been used in vivo for active targeting of the folic acid receptor and in MR imaging of cancerous tissues. The anticancer activity of metal oxide nanoparticles might be either due to intrinsic effects or external stimuli such as hyperthermia. The intrinsic antitumor effect such as the antioxidant nature of nanoparticles is due to specific physicochemical properties. Surface-modified SPIONs (Fe₃O₄) show a very good heating efficiency for hyperthermia tumor therapy. Herein, reactive oxygen species are generated in the presence of an externally applied magnetic field or infrared radiation and due to oxidative stress, the tumor cell is killed. Anzai et al. have used SPIONs coated with dextran (BMS 180549; Squibb Diagnostics, Princeton, NJ, USA) in MR imaging of lymph nodes in the neck and head of healthy male volunteers [4]. Herein, these NPs have been investigated as a contrast agent in phase-1 clinical trials. Zinc oxide nanoparticles (ZnO NP) and iron oxide NPs show selective cytotoxicity against tumor cells through the generation of reactive oxygen species (ROS). These nanoparticles are promising therapeutic nano-medicine because these NPs are non-toxic, low-cost, biocompatible, and safe. The cytotoxicity can be delayed with a silica shell which can help in the future for safe transport in the bloodstream. The cellular damage can be an induced apoptotic cell death when treated with ZnO NPs at incubation for 48 h. Metal oxide NPs are formulated with various types of molecules such as micelles, protein molecules, anticancer medicine, antibodies, and conjugated ligands for selective cytotoxicity and targeted drug delivery to reduce the side effects on normal tissues. However, in some research papers, it is reported that the targeted drug delivery also shows a toxic effect if inflamed tissues have vasculature spaces. In that condition targeted drug leaks through vasculature space in the inflamed tissue and creates side effects. Since 2007, iron oxide nanoparticles have been utilized in biomedical applications such as cancer treatment and diagnosis like targeted drug delivery, thermo-ablation, magnetic fluid hyperthermia, and contrast agents in MRI. These demonstrated the abovementioned oncological applications due to their unique magnetic and semiconductor properties. TiO₂ NPs synthesized with the ball milling method are used in vitro models of colon cancer cell lines (HCT116) [5]. Spherical-shaped copper oxide NPs are used in an in vitro study of A549 cell lines for cytotoxicity [6]. Due to its substantially fewer side effects, cancer immunotherapy is regarded as one of the most effective and promising treatment approaches.

Cancer immunotherapy uses immune system activation to target and kill/destroy cancer cells, potentially producing long-lasting antitumor effects and preventing relapse and metastasis. Cancer immunotherapy using nanoparticles has a lot of potential. Several copper-doped TiO₂ nanoparticles have been developed by Hesemans et al. for improved immunotherapy [7]. In another study, Bai et al. reported the multifunctional ultra-small iron-doped titanium oxide nanodots sonosensitizer for chemodynamic therapy [8]. Furthermore, the treated animals (mice) show no discernible long-term toxicity since most of these ultra-small Fe-TiO₂ nanodots were efficiently eliminated in a month.

In the last few decades, nano-immunotherapy-which combines immunotherapy and nanotechnology to fight tumors- has emerged as a very potential chemotherapy approach. Hu et al. reported polyacrylic acid-coated ultrasmall superparamagnetic iron-oxide nanoparticles with doxorubicin liposomes as chemo–-immunotherapeutic agent for chemo-resistance and metastasis of triple-negative breast cancer (TNBC) [9]. The authors observed that these nanoparticles have the potential to target tumors, bone, liver, lungs, and tumor-draining lymph nodes (TDLNs). In another investigation, after receiving local treatment, iron nanoparticles hold substantial potential for combining magnetic hyperthermia with immunotherapy to produce a long-lasting systemic therapeutic effect [10]. Similarly, Chen et al. reported a pH-activated promodulator of iron oxide nanoparticles that respond to tumor acidic microenvironment for photothermal-enhanced chemodynamic immunotherapy of cancer. These nanoparticles induce immunogenic cell death and directly destroy the cancer cells [11].

In this review, we explore recent developments in the utilization of MONPs and their derivatives as diagnostic, therapeutic, and drug-delivery agents to combat cancer. The study of metal oxide nanoparticles (MONPs) in various carcinomas is significant in multiple fields of cancer research, diagnosis, and therapy. This study has the potential to revolutionize cancer management by increasing the accuracy, effectiveness, and safety of cancer treatments. It helps create a more individualized, less harmful, and more successful cancer treatment in the future, which will ultimately increase patient survival and quality of life around the globe. Even if issues like toxicity and regulatory constraints still need to be resolved, ongoing research is addressing these issues and clearing the way for more personalized and effective cancer treatments in the future. Promising prospects to improve patient outcomes in the fight against carcinoma are presented by the continuous developments in nanotechnology and cancer treatment. The schematic representation of oncological applications of metal-oxide nanoparticles has been given in Figure 2.

2. Metal Oxide Nanoparticles for Therapeutic Effect

A vast amount of work has been done on the cytotoxic effect of MONPs against cancerous cells. They have been used against the most common types of carcinomas such as prostatic cancer, colorectal cancer, pancreatic cancer, and so on. Zinc oxide nanoparticles (ZnO NPs) are non-toxic, chemically stable, have a high drug-loading capacity, and are highly biocompatible. In recent years, the ZnO NPs have been used in anticancer activities such as drug carriers/targeting drug delivery, biosensors, imaging agents, and cytotoxic toward various cancer cell lines. The ZnO has been an attractive candidate for anti-cancer therapeutics due to its ability to induce cell death with/without drug loading. This is because of its ability to increase reactive oxygen species (ROS) production within the cell causing oxidative stress which leads to apoptosis. Mahanta et al. have synthesized ZnO NPs with a chemical route and further, it is functionalized with Bovine α-lactalbumin (BLA) via crosslinking [12]. These functionalized ZnO NPs are more cytocompatible and show improved hemocompatibility. These ZnO NPs demonstrate an enhanced antiproliferative activity in breast cancer cells. Thus, surface functionalization of ZnO with BLA leads us to develop excellent therapeutic strategies for the treatment of cancer. Surface-functionalized superparamagnetic iron oxide nanoparticles (SPIOs) have been synthesized and used as nanomedicines to treat liver cancer via magnetic fluid hyperthermia (MFH)-based thermotherapy. Herein, an in vitro study has been done on liver cancer cells (HepG2) via trypan blue assay at two different times (24 h and 48 h). The HepG2 cancer cells (3.5 × 10⁴) are seeded in 24-well plates and incubated for 24 h. After that, these SPIOs at specific concentrations (5, 10, 15, 20, and 25 μg Fe) per well are incubated in triplicates at 37 °C under a 5% CO₂ atmosphere. Park et al. reported the formation of doxorubicin (DOX)-loaded liposomal IONP (Lipo-IONP/DOX) and their efficacy for combined chemo-photothermal cancer treatment was assessed in both in vitro and in vivo conditions. Figure 3 represents the scheme for Lipo-IONP/DOX for combined chemo-photothermal cancer therapy [13] (open access).

In one study, Liang et al. reported core-shell NPs of hollow Au nanocages with MnO₂ layer for activating the H₂O₂ reaction, which released O₂ in the tumor environment (Figure 4) [14]. In the presence of NIR, this system generates ROS that triggers PDT for metastatic triple-negative breast cancer (mTNBC). Furthermore, the impact of PDT not only efficiently eliminates the primary tumor but also triggers immunogenic cell death (ICD).

Altering the noxious tumor microenvironment (TME) rather than directly eliminating/killing cancer cells may enhance the therapeutic advantages of cancer treatment. To modify the TME and improve tumor radiation and immunotherapy, Gong et al. designed the FeWO_X bimetallic nanosheets as cascade bioreactors [15]. The synthesized bimetallic nanosheet system could generate ROS, which ultimately enhances the oxidative stress in the tumor microenvironment and is applied for chemodynamic therapy. Similarly, to attain better tumor therapeutic efficacy, Koo et al. synthesized a heterogeneous copper–iron peroxide nanoparticles-based chemodynamic therapy (CDT) system [16]. Radiation therapy is widely used in tumor treatment. However, severe adverse effects are observed in the nearby normal tissues during radiation-induced treatment. Ma et al. have developed gadolinium-intercalated carbon dots (Gd@C-dots) as radiation sensitizers for non-small cell lung cancer treatment [17].

Zinc oxide nanoparticles (ZnO NP) and iron oxide NPs show selective cytotoxicity against tumor cells through the generation of reactive oxygen species (ROS). Various studies have reported that the green synthesized ZnO NPs, made via fungi, algae, and plant-mediated platforms are highly selective towards cancer cell lines and exhibit high cytotoxicity. ZnO NPs synthesized with the waste of Rheum rhaponticum (MCF-7; breast), R. radix extract (MG63; bone cancer), A. lebbeck stem bark (MCF-7, MDAMB231; breast), M. indica leaves (A549; lung), T. castanifolia flower (A549; lung) G. sylvestre leaves (A498; kidney), S. muticum algae extract (HepG2; liver), G. edulis algae extract (SiHa; cervical), etc. are some recent designs in this area [18]. The IC₅₀ values of NPs are enormously large for healthy cells as compared to cancer cell lines, which indicate their selective cytotoxicity. These NPs produce ROS like O²⁻, ^•OH, and H₂O₂, consequently the oxidative stress increases in the cell which induces cell death.

Although, very few in vivo studies of ZnO NPs have been reported in the literature. The NPs synthesized with the leaves of H. officinalis are also tested in a mouse model to control tumor growth in liver and spleen cancers and also in vitro study on HUH7 and HepG2 human liver cancer cell lines. Herein, these green synthesized ZnO NPs demonstrate the synergistic effect on cytotoxicity. Further, apart from increased ROS concentration, the NPs also activate the expression of pro-apoptotic genes p53 and Bax [19].

Similarly, several groups have also exploited other metal oxide nanoparticles. MgO NPs showed appreciable cytotoxicity with a low IC₅₀ of 37.5 µg/mL against A549 lung cancer cell lines. They also indicate poor hemolytic activity, which allows IV-based treatments [20]. CuO NPs synthesized from Cordia myxa L. extract showed the effective killing of breast cancer lines MCF-7 and AMJ13, as Cu (II), bind to the mitochondrial DNA by disrupting the mitochondrial membrane. However, these NPs show relatively little damage to healthy cell lines (HBL-100) [21]. Even though bulk Cu is toxic to humans, this study is an example of how nanomedicine can overcome the challenges faced in traditional chemotherapy.

Manimaran et al. reported the cytotoxic effect of FeONPs synthesized using an aqueous extract of P. citrinopileatus on the MG-63 cell lines [22]. The study’s findings demonstrated that an inhibition range with an IC₅₀ value of 59.11 was observed at 55.63 µg/mL extract concentration. Mohsin et al. synthesized core/shell nanocomposite of hexagonal boron nitride (h-BN) and doped with gadolinium oxide (Gd₂O₃) [23]. The authors studied the anticancer activity of the synthesized nanocomposites on various cell lines namely human colon adenocarcinoma cells (HT-29), human breast cancer cells (MCF-7), and normal breast cell line (MCF-10A). The proliferation of HT-29 and MCF-7 was reduced whereas no effect was observed on the proliferation of MCF-10A. In another report, TiO₂ nanoparticles were utilized by Hadi et al. to study their antiproliferative efficacy against prostate cancer cell lines [24]. The laser ablation technique was used for the synthesis of TiO₂ nanoparticles. Phalake et al. investigated the effectiveness of chitosan-coated manganese-iron oxide nanoparticles functionalized with doxorubicin and an aptamer (AS1411) in a 3-D breast cancer model [25]. The synthesized nanoparticles have a crystallite size of 16.88 nm. The anticancer viability was decreased to about 92.2% in the 3-D model. This study investigated sophisticated 3D in vitro tumor models as a viable substitute to imitate the entire range of tumor features.

In another investigation, four different surface formulations of Fe₃O₄ nanoparticles using different polysaccharide polymers (Gum Arabic, beta-cyclodextrin (β-CD), Alginate, and Chitosan) were reported for their application in cancer therapy [26]. The doxorubicin drug was loaded on these modified Fe₃O₄ nanoparticles. The quantum mechanics and molecular dynamics simulation studies were performed to identify the interaction mechanism between the polymer and the drug doxorubicin. The loading efficiency and capacity were found to be maximum for β-CD-Fe₂O₃ formulation. Furthermore, compared to MCF-10A normal cells, DOX-loaded β-CD-Fe₂O₃ NPs showed greater toxicity in MDA-MB468 malignant cells.

Surface-functionalized TiO₂ NPs have been studied for targeted cancer therapy. Herein, these functionalized TiO₂ NPs have been used to show the cytotoxic effect on cancerous cell lines of T-24, HeLa, and U937 cells, respectively [27]. These NPs combine with the cell membrane and enter the cytoplasm. TiO₂ has been used in the photodynamic therapy of cancer. Herein, photodynamic therapy has been found to be less effective in the presence of UV-visible light as compared to near-infrared (NIR) light. Because UV-visible light has a limited penetration power in cancerous tissue compared to near-infrared (NIR) light. The maximum penetration into cancerous tissue has been reported in the range of near-infrared (NIR) from 700 nm to 1000 nm. So, for the treatment of deep cancerous tumors, TiO₂ can be used in the presence of the NIR light in photodynamic therapy. Lu et al. studied the efficacy of Salmonella (Sal) in microbial immunotherapy against tumors [28]. This precise remodelling indicates a fundamental change in the tumor immune microenvironment. In addition to introducing a treatment approach that combines Sal with MnO₂ NPs to boost efficacy synergistically, the study sheds light on the crucial but little-studied role of neutrophils in bacteria-mediated tumor therapy. The authors also reported that the neutrophil population increased within the tumor microenvironment due to the colonization of Sal. Du et al. reported the synthesis of metal-organic framework nanoparticles loaded with D-arginine [29]. These nanoparticles were extremely effective at enabling osteosarcoma to be highly sensitive to radiation therapy while being comparatively safe. They also stopped mice from developing lung metastasis after receiving radiation treatment.

Metal oxide nanoparticles have significant benefits over metal- and carbon-based nanomaterials in anti-tumor applications, since they have unique characteristics and functions targeted to cancer treatment. Metal oxide nanoparticles have advantages such as biocompatibility and stability, intrinsic antitumor properties, versatility in functionalization, optical and photothermal properties, magnetic and imaging capabilities, cost and scalability, etc. For instance, iron oxide nanoparticles are employed in contrast-enhanced magnetic resonance imaging (MRI) as a diagnostic tool [30,31,32].

The comparison of metal oxide nanoparticles, metal nanoparticles, and carbon-based nanomaterials is shown in Table 1 [33,34,35,36,37,38,39,40,41,42].

3. Major Apoptosis Mechanisms

Throughout our literature survey, we came across suggested pathways and mechanisms that induce cell death in cancer cells and how NPs are designed to take advantage of and manipulate them. Major apoptosis mechanisms triggered by nanoparticles have been shown in Figure 5.

3.1. Oxidative Stress Caused by Enhanced ROS Production

Metal oxide NPs and their derivatives have band gaps that can produce reactive oxygen species (ROS) within the cell. Although ROS levels are required for healthy functioning of the cell, excessive ROS levels can lead to lipid peroxidation and end up in cell death. ZnO, Au, Ag NPs, and many more function on this basis. Many studies reported here measure ROS levels during cytotoxicity assays to verify this mechanism. A recent study also explained the cytotoxicity of iron oxide NPs due to increased ROS expression. They synthesized ultra-small PEG-modified polydopamine NPs and chelated Fe(II) and Fe(III) ions to them. This led to ferroptosis in the cell, which is a phenomenon described by Dixon et al. in 2012 [43]. Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Lipophilic antioxidants and iron chelators can prevent ferroptosis cell death. The iron ions are also able to convert the H₂O₂ produced by band gap catalysis into the most harmful ^•OH via the Fenton reaction. Photoexcited nanostructured TiO₂ has been used as a nano-medicine for cancer diseases [44]. Herein, photo activated TiO₂ induces the production of pairs of holes and electrons, respectively. These pairs of electrons and holes react with water and oxygen molecules and give reactive oxygen species (ROS) which destroy the cancerous cells and initiate the controlled growth of cells.

3.2. Caspase Cascade

ZnO NPs were known to cause cell death in gingival squamous cell carcinoma (GSCC) lines but the mechanism was not fully understood. A study by Wang et al. reported the role of caspases in inducing apoptosis [45]. When Ca9-22 and OECM-1 oral cancer cells are treated with ZnO NPs, superoxide production increases along with increased expression of caspases 8 and 9 which are initiator caspases. Caspases are cysteine acid proteases that regulate apoptosis. The cleavage of caspase-9 due to ZnO NP treatment leads to cleavage of caspase-3 (effect of caspase) as a result of the expression of cytochrome C. This in turn leads to the expression of poly-(ADP-ribose) polymerase (PARP) which causes cell death. Due to the expression and cleavage of downstream substrates, this process has been termed a cascade.

3.3. Disrupting Cell-Signalling Pathways

Cell signalling genes are important in cell functioning as well as proliferation. Some well-known targets in this regard are p53 signalling pathways, Bcl-2 genes, p70S6K signalling pathway, histone expression, etc. For instance, in bladder cancer, methylation of histone leads to epigenetic changes which lead to tumor and T24 cell proliferation and migration. Histone methyltransferase is responsible for promoting the methylation of histone. In a study, ZnO NPs have been used to treat bladder cancer cells and it is seen that EZH2 expression is greatly reduced and minimum amounts of ROS increase. This points to the fact that the suppression of EZH2 levels is responsible for controlling tumor growth [46]. Maspin expression increases when MCF-7 (breast) cell lines are treated with ZnO NPs. Maspin is a mammary serine protease inhibitor that is toxic to T-cancer cells [47].

Another aspect worth mentioning is the interplay of BCL-2 and BAX gene levels. BCL-2 is pro-survival while BAX is pro-apoptosis. ZnO NPs produced with R. rhaponticum waste caused cytotoxicity in MCF-7 cancer cells [48]. Herein, a comparative study has been done with MCF7 breast cancer and normal Human HFF and HDF cells. Herein, the apoptotic activities of ZnO NPs have been tested via the determination of the cell morphology, BCL2- BAX genes expression profile, and AO/PI-fluorescent cell staining. All cell lines were incubated for 24, 48 and 72 h, respectively. This study reveals that the ZnO NP dose (7.5 μg/mL, 15 μg/mL, 30 μg/mL) decreased gene expression of BCL-2 whereas gene expression of BAX increased, which is the cause of cell death. Thus, this effect works in synergy with ROS induction. Many of the NPs reported here show a similar increase in the BAX/BCL-2 ratio, which ultimately explains their cytotoxic properties.

4. Metal Oxide Nanoparticles for Drug Delivery

Employing nanoparticles for the delivery of cancer drugs is a fertile area of research. Low solubility, high toxicity, multi-drug resistance, poor selectivity, and low bioavailability often restrict the use of drugs in treatment or cause detrimental effects. Apart from cancer drug delivery, they are also used in the targeted delivery of anti-microbial and bactericidal compounds.

Drug targeting conventionally has been based on passive targeting. Uncontrolled multiplication of cancerous cells causes nanometre-range lesions leading to a ‘leaky’ tumor. This gives rise to the enhanced permeability and retention (EPR) effect, where either cancer drugs such as doxorubicin and cisplatin, or cytotoxic nanoparticles, accumulate at the ‘leak’ and cause damage. The enhanced permeability and retention (EPR) effect works as the foundation of anticancer nano-medicine and its design by using various drug formulations. Drug delivery based on the EPR effect is an effective strategy for most solid tumors [49]. The vascular mediators including prostaglandins, bradykinin, and nitric oxide play a vital role in facilitating and maintaining EPR effect dynamics. The advanced stage of cancers may induce activated blood coagulation cascades, which cause thrombus formation in tumor vasculature. The drug delivery, as well as the EPR effect, will be enhanced by restoring obstructed tumor blood flow and improving tumor vascular permeability through vascular mediators. Moreover, the efficiency of the EPR effect depends on the pathophysiological conditions of tumors, drug formulations, and other factors such as the tumor microenvironment. In the physiological location, research on magnetite nanoparticles coupled with lipids reveals a low selectivity for the targeted organ/tissue. However, accumulation in tumor tissues would result from passive targeting, which is facilitated by the ERP effect in tumors via fenestrated arteries (Figure 6) [50].

The microenvironment of tumors is mainly affected by blood flow in cancerous tissue which also plays a critical role in the effective EPR effect. However, this approach has many drawbacks principally that of damage to other cells as the drug/nanoparticles need to be in circulation for increased periods to allow sufficient concentration in the tumor, and also there is a lack of specificity. These significant failures and potential side effects call the effectiveness of EPR into question. Therefore, the renewed focus has been on targeted delivery. Ligands or antigens are used to bind to receptors that are typically present or over-expressed in a tumor environment. Biotin, folic acid, aptamers, antibodies, and peptides are common binding agents that are incorporated into the design for active targeting [51]. Physical phenomena such as electromagnetic radiation, pH changes, and magnetic fields are also used to induce active targeting.

Magnetic nanoparticles, such as oxides of iron, cobalt, and nickel have been exploited to enhance biomedical applications for decades as they can be controlled via a magnetic field and directed to the cancer site. Fe₃O₄ has been widely studied in this regard often associated with polymer or biomaterials to enhance its bioavailability and safety. Recently, Fe₃O₄ NPs were modified with chitosan (CS) and loaded with Imatinib as a kinase inhibitor. The system showed a pH-responsive drug release at pH 5.4 which is ideal as the tumor micro-environment is slightly acidic. As compared to pure Imatinib, the Fe₃O₄@CS/Imatinib had a 49% reduction in IC₅₀ dose [52].

Curcumin is another proposed anti-cancer drug performing poorly on ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters and pharmacokinetics/pharmacodynamics (PK/PD) standards, which determine the suitability of a drug and thus having a short half-life. As a result, improving the bioavailability of curcumin is a challenging task. A group used musk melon seeds to produce ZnO NPs which were then conjugated with dialdehyde cellulose to create a chitosan-based nanocomposite hydrogel for curcumin delivery. At pH 4.0, the hydrogel swelled and was loaded with a high loading efficiency of 89.68%. At pH 7.0, a slow sustained first-order release was seen. When tested on A431 skin carcinoma cells, the highest cytotoxicity was seen with the curcumin-loaded nanocomposite, which was greater than pure curcumin and demonstrated the vital function of targeted delivery. The IC₅₀ for pure curcumin was 23 µg/mL whereas 16 µg/mL for the curcumin-loaded nanocomposite. Moreover, the biocompatibility of the nanocomposite was also better [53].

Alternatively, another study used casein, a protein found in milk as a capping agent during the synthesis of ZnO NPs, and loaded it with curcumin. The casein-ZnO-curcumin composite was also conjugated with folic acid to target folic receptors in cancer cell lines. In HeLa (cervical) cell lines, there was a 10% higher cytotoxicity when folic acid was incorporated. Further, drug release studies showed a pH-controlled release of curcumin at pH 5.0 in addition to a 15% increase in cytotoxicity. The increased cytotoxicity in comparison to naked ZnO NPs was attributed to the additive killing effects of both ZnO NPs and curcumin. The nanocomposite showed no hemolysis. Similar cytotoxic effects were seen in MCF-7 (breast), MDA-MB-231 (breast), and MG63 (bone) cancer cells. Ginsenoside Rh2, the active component of ginseng was loaded on hyaluronic acid (HA)-functionalized ZnO NPs. Ginsenosides in general suffer from poor solubility, poor bioavailability due to hydrophobic groups, and non-targeted cytotoxicity. However, the functionalized ZnO NPs showed impressive cytotoxicity against A549 (lung), HT29 (colon), and MCF-7 (breast) cancer cells [54].

Another way to improve the targeted action of nanoparticles is by incorporating them into composites. These nanocomposites often contain compounds such as folic acids which can bind to the tumor site and thus prevent collateral damage to healthy cells. Other metals such as Ag and Au, popularly used in traditional medicine, have shown remarkable therapeutic action via increasing intracellular oxidative stress against a variety of mutated cell lines and have been extensively studied.

Mesoporous silica NPs (SiO₂) have been used in targeted drug delivery. Herein, various stimuli such as pH-sensitive, thermo-sensitive, light-sensitive, enzyme-sensitive, redox-sensitive, magnetic field-sensitive, and ultrasound-responsive drug delivery systems have been discussed [55]. Various targeted drug delivery systems based on different metal oxide nanoparticles are given in Table 2 [56,57,58,59,60,61,62,63,64,65,66].

5. Metal Oxide Nanoparticles for Cancer Diagnosis/Imaging

5.1. Magnetic Resonance Imaging (MRI)

The imaging of tumors and cancer cell proliferation is dynamic in tracking the growth of cancer and helps in changing the strategy of treatment in the early stage. In both cases, differentiating between healthy and cancerous cells is a challenge and thus both these applications are closely connected. Magnetic nanomaterials and composites are especially favored in this field due to their high sensitivity, high signal-to-noise ratio, low limit of detection, and reusability. Iron-based NPs are already widely studied and reviewed as MRI contrast agents. For synergistic therapy and multimodal imaging, He et al. offered a novel approach using silver core/AIE (aggregation-induced emission) shell nanoparticles [67]. Wang et al. reported using superparamagnetic Fe₂O₃ NPs coupled with anti-CD133 monoclonal antibodies which can bind to cell-marker antigen CD133 in vitro model of human brain glioblastoma cancer stem cells and be used for fluorescence and MRI imaging. This is especially significant as the blood-brain barrier is notoriously difficult to cross. Tiny and previously undetected lymph node metastases in prostate cancer patients can now be identified through a macrophage-specific magnetic resonance (MR) contrast agent. This has a significant clinical effect since it will result in a better accurate diagnosis that requires less intrusive testing. Thus, this will consequently lower morbidity and medical expenses. Ultra-small superparamagnetic iron oxide (USPIO) particles have been used in getting high-resolution MRI images. Herein, these USPIO have been used as a lymph node-specific contrast agent for nodal stages in prostate cancer. This study has been performed on 24 healthy volunteer men. When these USPIO particles are injected intravenously into the patients, they are transported by macrophages to only normal lymph node tissue as macrophage activity, but these particles are not transported in metastatic tissue. These particles change the magnetic properties and consequently signal intensity alters, which is detected by MRI. Therefore, normal functioning lymph nodes look black in MRI after 24–36 h administration of USPIO. However, in the metastatic node, the signal intensity does not change due to the absence of iron particles. Ferumoxytol (Fe₃O₄, Feraheme) is commonly used in contrast-enhanced magnetic resonance imaging (MRI) as a diagnostic tool. Ferumoxytol is a non-stoichiometric magnetite (superparamagnetic iron oxide) that is coated with polyglucose sorbitol carboxy-methyl ether. Ferumoxytol is the better alternative material as compared to the standard gadolinium-based contrast agents because it is more feasible in patients with impaired renal function. Ferumoxytol is available in the market of USA as the only intravascular MRI contrast agent.

Early diagnosis of cancer can vastly improve patient outcomes due to interventions in the primary stages. Peptide-targeted gadolinium oxide-based multifunctional NPs have been used for the diagnosis of prostate cancer using magnetic resonance imaging as well as fluorescent molecular imaging [68]. Herein, synthesized Gd₂O₃-FI-PEG-BBN NPs have uniformity in size and are spherically shaped with a 53.2 nm diameter. The longitudinal relaxivity (r₁) of Gd₂O₃-FIPEG-BBN (r₁ = 4.23 mM⁻¹ s⁻¹) matches with the clinically used gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) which is known as Magnevist in the market. Herein, in vitro cellular, MRI is found receptor-specific for gastrin-releasing-peptide (GRP). Also, enhanced cellular uptake of the Gd₂O₃-FI-PEG-BBN is found to be in PC-3 tumor cells. Cellular MRI has been performed with composites of amino dextran-coated Fe₃O₄ NPs with graphene oxide (GO) by Chen et al. [69]. Herein, this nanocomposite of Fe₃O₄ has been used as a T2-weighted contrast agent. These nanocomposites of Fe₃O₄ show very low cytotoxicity and very good physiological stability in MRI diagnosis. Herein, HeLa cells are treated with this composite of Fe₃O₄ and their staining has been done with Prussian blue. The staining analysis demonstrates that the Fe₃O₄-GO nanocomposites are internalized in the HeLa cells very efficiently. Thangudu et al. effectively designed biocompatible FeCO₃ nanoparticles as an MRI agent for in vivo lung tumors [70]. Guan et al. reported the synthesis of glycol-quantum dots (glycol-QDs) as an efficient tumor bio imaging agent [71]. These glycol-QDs can deeply penetrate tumors. Table 3 summarizes several metal oxide nanoparticles employed as a contrast agent in Magnetic Resonance Imaging (MRI) [72,73,74,75,76,77,78].

5.2. Computed Tomography (CT) Scan Imaging

Formerly a CT scan was known as computed axial tomography (CAT scan), an imaging technique in which X-rays are used as a source. It is a diagnostic tool for finding images of the body non-invasively. Hafnium oxide-PEG (HfO₂-PEG) based nanocrystals have been designed and tested in vivo in a mouse model. The nanocrystals have been administered intravenously and accumulated in the 4T1 breast cancer tumor which has been imaged using a CT scan. The nanocrystals, therefore, provided targeted imaging preventing radiation damage to surrounding normal cells. Moreover, the nanocrystals have been excreted quickly and do not show unhealthy deposits in the heart, liver, and other vital organs without any side effects over a 90-day window [79]. Similarly, nanostructured cerium oxide with polyethylene glycol-α-maleimide-ω-n-hydroxide succinimide (NHS-PEG-Mal CeO₂) bioconjugated with anti-HER2 has been used to detect abnormal concentrations of HER2 which are over-expressed in breast cancer patients. Blood serum samples have been tested and the electrochemical study has also been used to ascertain HER2 concentrations using the bioconjugate which is more selective and sensitive than most other HER2 nano-immunosensors [80].

6. Conclusions

We have given a brief outlook on the contemporary research exploiting metal oxide nanoparticles for anti-cancer applications. The area and the work of researchers therein, prove the diverse potential of the field. We have documented recent work whereby therapeutic metal oxide nanoparticles have shown promising cytotoxic activity toward various cell lines. The incorporation of green methods, phytochemical-mediated and bio-functionalized nanoparticle synthesis also opens avenues for reducing present challenges posed by the medical use of nanoparticles in terms of toxicity and excessive retention. Combined with other issues such as environmental impact, it becomes clear that toxicity must be an essential focus area during the design of new nanoparticle candidates.

The field of imaging already employs MONPs such as superparamagnetic iron oxide nanoparticles (SPIONs) for MRI-based imaging. Clinical trials have been done on younger patients and children having brain tumors for viewing the vessels of the brain. Herein, a comparative study has been done for getting MRI images using paramagnetic iron oxides as well as gadolinium as contrast agents. Initially, ferumoxytol has been used as an MRI contrast agent because of its efficacy in shortening T1 and T2 relaxation times. Preclinical and clinical studies on ferumoxytol have reported the overall safety and effectiveness of this novel contrast agent, which is used in MRI imaging. There is no evidence of allergic reactions after injection in the patients. A combinatorial approach whereby imaging and drug delivery or imaging or therapy are amalgamated and made more efficient will enrich real-time monitoring of the prognosis of the cancer. Immunosensors, such as those mentioned earlier, can be path-breaking in early identification and intervention and thus enhance patient outcomes. Small-molecule drug delivery is a well-established application for nanoparticles in cancer treatment research.

Finally, our summary of the prevalent apoptosis mechanisms gives a brief overview to help picture the various processes. We hope that it will prove beneficial to researchers and students beginning their exploration into this immensely vital and diverse area, contributing to treatments and strategies against cancer which was responsible for potentially one in six deaths worldwide.

Author Contributions

N.R.: writing—original draft; Y.K.: conceptualization, writing—original draft. S.Y.: reference editing; K.S.: supervision, review, and editing; D.M.: review and editing. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

The authors would like to thank Principal, Miranda House, University of Delhi for providing a lab facility to carry out the research work. Yousuf Khan would like to thank his dearest friends for their constant encouragement, time, and support.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

ADMET, absorption, distribution, metabolism, excretion and toxicity; CA125, cancer antigen 125; CS, chitosan; CT, computed tomography; Dox, doxorubicin; Endo-G, endonuclease-G, mitochondrial; EPR, enhanced permeability and retention; EZH2, enhancer of zeste homolog 2; GPX4, glutathione peroxidase 4; HA, hyaluronic acid; HER2, Human epidermal growth factor receptor 2; MONPs, metal oxide nanoparticles; MRI, magnetic resonance imaging; NPs, nanoparticles; PARP, poly-(ADP-ribose) polymerase; PEG, poly(ethylene) glycol; PK/PD, pharmacokinetics/pharmacodynamics; ROS, reactive oxygen species; SPIONs, superparamagnetic iron oxide nanoparticles.

Footnotes

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Figures and Tables

Figure 1. Six pathological hallmarks of cancer.

Figure 2. Oncological applications of metal-oxide nanoparticles.

Figure 3. Schematic representation of Lipo-IONP/DOX for combined chemo-photothermal cancer therapy [13] (open access).

Figure 4. Represented the working principle of AuNCs@MnO2 (AM) nanomaterial for ICD (immunogenic cell death) (a) synthesis procedure for AM and generation of O2 (b) Therapeutic approach of AM for inducing ICD by stimulating more dead tumor cells (c–e) Identification of different ICD signal molecules during AM and laser treatments (c) fluorescence microscopy images showing CRT expression in 4T1 cells (d,e) liberated ATP and HMGB1 in the supernatant (f) diagrammatic illustration of ICD-induced DC activation (g) CD83 and CD86 expression after DC maturation (h) liberated IL-12 in the culture supernatant. Asterisks (*) denote statistically significant differences between PBS and other treatments. ** p [less than] 0.01, *** p [less than] 0.001. # p [less than] 0.05 (n = 5) indicates that the differences between the two groups are statistically significant. Reproduced with permission from [14], Copyright 2018, Elsevier.

Figure 5. Major apoptosis mechanisms triggered by nanoparticles.

Figure 6. SPIONs are administered intravenously (IV) for multimodal diagnostic and/or therapeutic uses [50] (open access).

Table 1

The comparison of metal oxide nanoparticles, metal nanoparticles, and carbon-based nanomaterials.

Nanoparticles	Cells	Size of Nps	Concentration of Nps	Exposure Duration	Results	Reference
ZnO	N417, H82, H187 Human small-cell Lung cancer	20 nm	10 μg/mL	120 min	Low viability, even in cells orthotopically grafted onto mouse models	[33]
ZnO-Loaded Syringic Acid	A549 cells	120 nm	12.5 μM	24 h	The ZnO-Loaded Syringic Acid indued ROS have induced the cell death in A549 cancer cells	[34]
Annona muricata-ZnO	A549 and MOLT4 Cells	80 nm	0–500 μg/mL	24 h	Am-ZnO treated cancer cells underwent programmed cell death with depolarization in their MMP.	[35]
TiO2	MDAMB231 cells	140 nm	100 μg/mL	72 h	TiO2 nanostructures inhibited the migration and colony formation of breast cancer MDAMB231 cells.	[36]
Fe3O4 nanoparticles coloaded with homoharringtonine	K562, HL-60, SHI-1, and NB4 cells	-	1.875 μg/mL	24 h	Fe3O4 nanoparticles coloaded with homoharringtonine had cooperative effect in suppression of tumor cell growth	[37]
TiO2	4T1 cells (Mice)	21 nm	1 μg/mL	21 days	Peritoneal macrophage exposed to P-25 TiO2 NPs displayed activated M1 macrophage response	[38]
AgPt	Detroit 551-CCL-110, #A375 and U 87 cells	~42 nm	10–250 μg/mL	1–3 days	AgPt nanoparticles demonstrated a remarkable and statistically significant ability to reduce the viability of cancer cells	[39]
Au	HCT-116 cells	50 nm	200 μg/mL	1 h	target the abnormal growth of HCT-116 colon cancer cells	[40]
Ag	HCT-116 cells	24–80 nm	100 μg/mL	1 h	target the abnormal growth of HCT-116 colon cancer cells	[40]
Graphene	U251 human glioma cells	50 nm,	2.5–10 mg/mL	24 h	graphene nanoparticles performed significantly better than CNT in inducing photothermal death of U251 cells	[41]
Carbon nanotubes	U251 human glioma cells	60 nm,	2.5–10 mg/mL	24 h	graphene nanoparticles performed significantly better than CNT in inducing photothermal death of U251 cells	[41]
Carbon nanotube	MCF-7 breast cancer cells	1.5 nm in diameter and 200 nm in length	10 mg/ml	48 h	SWNT-drug showed target specificity in vitro	[42]

Table 2

Various targeted drug delivery system based on different metal oxide nanoparticles.

Nanoparticles	Synthesis Method	Cancer Cells	Drug Delivered	Reference
Fe2O3	Biosynthesis method	MCF7 cancer cells	Doxorubicin	[56]
Fe2O3-Au	-	A549 Human lung cancer cells	Doxorubicin	[57]
ZnO	Organic precursor method	MCF7 cancer cells	5-Fluorouracil	[58]
ZnO	-	CD44 cancer cells	Doxorubicin	[59]
Fe3O4	Laser pyrolysis	MCF7 cancer cells	Violamycine B1	[60]
Poly(acrylic acid)-calcium phosphate passivated TiO2	Hydrothermal synthesis	MCF7 cancer cells	Doxorubicin	[61]
TiO2	Green synthesis	HSF and MCF-7 cancer cells	Doxorubicin	[62]
CuO-NiO	Co-precipitation method	MCF-7 cancer cells	Paclitaxel	[63]
NiO	Hydrothermal synthesis	MDA-MB-231 breast cancer cells	Quercetin	[64]
MgO	Sol-gel method	MCF-7 cancer cells	Curcumin/β-cyclodextrin	[65]
MgO	Co-precipitation method	MDA-MB-231 cancer cells	5-fluorouracil	[66]

Table 3

Several metal oxide nanoparticles employed as a contrast agent in Magnetic Resonance Imaging (MRI).

Nanoparticles	Size	MRI Contrast Agent Type	Advantages	Reference
Carboxyl decorated-Fe3O4	~10 nm	T2 contrast agent	Good colloidal stability, high r2 value, and high-efficiency	[72]
dextran-coated Fe3O4	~13 nm	T2 contrast agent	Improved MRI images of liver, marrow and lymph	[73]
MnO	~28 nm	T1 contrast agent	High r1 relaxivity, favored infarcted myocardium retention characteristic, and good biocompatibility	[74]
Gd2O3	18–66 nm	Both T1 and T2 contrast agent	T1- and T2-shortening MRI contrast agents, especially with their large T1 relaxation rate.	[75]
Co3O4	-	T2 contrast agent	High photothermal conversion efficiency, excellent colloidal stability, biocompatibility and multifunctional groups	[76]
ZnO	~20 nm	T2 contrast agent	Directly and dynamically	[77]
ZnO/Gd2O3	~50 nm	T2 contrast agent	High adsorption and water stability, and high-efficiency	[78]

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