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. 2025 Sep 14;15(10):346. doi: 10.1007/s13205-025-04502-3

Antitumor potential of silver nanoparticles against lung cancer: current trends, scope and relevance

Anshika Kamboj 1, Mayank Raj 1, Vikas Kumar 2, Sushil Kumar Upadhyay 1, Manoj Singh 1,✉, Ajay Sharma 3,4, Anil Kumar Sharma 5,✉
PMCID: PMC12433929  PMID: 40959144

Abstract

Lung cancer continues to be a disease that is feared on a global scale due to its high mortality rates. The annual incidence of lung cancer is estimated to be 1.8 million, with approximately 1.6 million fatalities. Conventional treatment regimens are ineffective because they are unable to eradicate lung cancer stem cells (LCSCs). LCSCs are known to be highly resistant to treatment, induce relapse, strengthen metastasis, preserve tumorigenicity, and self-renewal. This demonstrates the necessity of a novel treatment modality that can specifically target lung cancer and its progenitor cells. Nanomaterials (NMs) handle unique challenges with outstanding solutions in a variety of industrial and scientific applications. Silver nanoparticles (AgNPs) are among the most commonly used NMs in drug delivery, medical diagnostics, energy harvesting devices, sensors, lubricants, and bioremediation. Notably, they have demonstrated strong antibacterial, anticancer, and antiviral capabilities in the biomedical sector. The literature analysis reveals a selective cytotoxic impact on cancer cells compared to healthy cells, highlighting its potential utility in cancer treatment and emphasizing the necessity to investigate the potential risk of their use to the environment and human health.

Keywords: Silver nanoparticles, Antitumor potential, Lung cancer, Nanomedicine, Treatment

Introduction

Silver (Ag) is a d-block element and is used as an active metal for the synthesis of silver nanoparticles (AgNPs). Various other nanoparticles are also available, but Ag has an advantage due to its highly efficient biomedical nature i.e., it acts as an antiviral, antifungal, and antibacterial agent. Therefore, Ag is being actively used in the synthesis of metal-based nanoparticles (Takac et al. 2023). AgNPs due to their modifiable shape, size, high drug capacity and high surface to volume ratio, make them suitable to be used as antitumor agents and as a drug carrier for cancer treatment in conjugation with adjutants, capping agents, bioconjugate and reducing agents. AgNPs also act as a carrier for proteins against lung cancer, breast carcinoma and neural cancer by activation of pro-apoptotic genes such as caspase-3, Bax, p53 and downregulation of anti-apoptotic genes Bcl-2. The physico-chemical properties of AgNPs vary according to their size and it has been found that the particle size ranging from 70–200 nm is suitable for cancer treatment as it becomes easier for them to penetrate the cell membrane for the intracellular drug delivery (Jayachandran et al. 2023).

According to the American Cancer Society, cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. The molecular causes of cancer include mutations, alterations in the normal cell cycle, exposure to UV radiations, DNA damage, activation of oncogenes or proto-oncogenes, whereas alcohol consumption, smoking, tobacco chewing, cosmetic products, carcinogenic agents and drug overdose are also one of the major causes in the present scenario (Foulkes et al. 2019). Cancer has become one of the leading causes of deaths worldwide. Nearly a millions of people die annually due to cancer and the most common ones are breast cancer, lung cancer, and colon cancer. There are various cell lines related to each type of cancer, such as lung cancer- A549 cells, breast cancer- MCF-7 cells, colon cancer- HT29, cervical cancer- HeLa cells and Dalt in lymphoma ascites cancer.

Lung cancer is a tumor developed within the lungs or the airways. As per WHO, lung cancer is a type of cancer that is developed when abnormal cells grow uncontrollably in lungs as described in Fig. 1. The major causes include smoking, chewing tobacco, cigar use, exposure to harmful chemicals, radon gas, and pollutants, as well as factors such as age, family history, and pre-existing respiratory or pulmonary diseases (Emphysema, COPD) (Malik and Mukherjee 2018). Lung cancer, in fact, is a significant public health concern, causing a considerable number of deaths globally. Lung cancer is mainly categorized into two types—Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC). The SCLC arises from central regions of the lung, which is approximately 10–15% of total lung cancers. Nearly 70% of SCLC is caused due to mutation in the p53 genes. It is generally metastatic in nature, shows resistance to drugs and has a chance of relapse. The NSCLC occupies nearly 80–85% of total lung cancers and is further classified into Adenocarcinoma, Large cell carcinoma and squamous cell carcinoma. All the major causes associated with lung cancer mainly lead to NSCLC (Rozalen et al. 2020). Number of treatments are available for lung cancer varying from traditional to advanced methods such as surgery (removal of affected area or cancer cell mass), chemotherapy (administration of drugs such as cisplatin, temozolomide, dacarbazine and cyclophosphamide), radiotherapy (high-powered X-ray, protons are used to damage the genetic material of cancer cells), immunotherapy and drug delivery systems. However, the main problem associated with the above treatments are their adverse side effects (hair loss, weight loss, skin allergies, inflammation), limited specificity in case of tumor cell recognition, resistance to antitumor drugs over a period of time and possibility of relapse (Noorbazargan et al. 2021; Jin et al. 2020).

Fig. 1.

Fig. 1

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Global cancer statistics: representation of data through pie chart depicting the percentage of cases in various types of Cancer

Therefore, nanotechnology has been an area of interest for cancer treatment. Nanoparticles, due to their smaller size, high penetration power, reactivity and efficient catalytic activity, are being exploited as antitumor particles. Silver nanoparticles are one such NP which have been proven to be an effective remedy for the treatment of lung cancer (Raja et al. 2020). Silver nanoparticles are preferred over any other metal nanoparticles, such as Cu, Au, C and quantum dots, due to their good conductivity, stability, antimicrobial activity, anti-inflammation and anti-tumor activities. In addition, these nanoparticles were reported to be non-toxic to humans at low dosage as compared to platinum, gold or other metal nanoparticles. Hence, silver nanoparticles are considered to be more effective in lung cancer treatment (Gul et al. 2021; Huy et al. 2020; Kim et al. 2021).

Synthesis of silver nanoparticles

Silver nanoparticles (AgNPs) are molecules synthesized in the nano range with Ag as an active metal. AgNPs are being used in nanomedicine recently for the treatment of cancer through a drug delivery system and immune therapy. Therefore, the demand has increased to a greater extent for the synthesis of AgNPs. They can be synthesized by various means, including physical, chemical and biological methods, whereas the physical and chemical methods are more popular for the synthesis of nanoparticles as they are easy to perform, require less time and have the ease of availability of chemicals. However, owing to some of the disadvantages associated with them, biological methods such as green synthesis have been accepted more widely as they involves an eco-friendly way of synthesizing AgNPs (Nguyen et al. 2023; Ahmed et al. 2023).

Chemical synthesis of silver nanoparticles

One of the most commonly adopted chemical method includes chemical reduction of silver nitrate solution containing silver in its ( + 1) oxidation state (Ag+1), which is boiled at high temperature followed by the addition of a reducing agent namely tri-sodium citrate (Na3C6H5O7) to the solution drop-wise and is applied to a continuous vigorous agitation or stirring. Upon stirring, the Ag ion reduces from the oxidative state and color change in the solution has been observed. The resultant mixture is then allowed to cool at room temperature and subjected to purification and the purified silver nanoparticles are used for various purposes (Dhaka et al. 2023). The chemical equation for the above process is given as:

(Ag+1) + Sodium citrate (complex)Ag0 + Sodium citrate (ppt)

There are plenty of other physical & chemical methods, such as polyol method, hydrothermal method, salvation method and co-precipitation method, to synthesize AgNPs. However, the major disadvantages associated with these methods are very costly, including the use of certain toxic chemical compounds that are hazardous to the environment. Therefore, a method that is environmentally and economically stable is required and that is where the biological or green synthesis of nanoparticles came into play (Ahmed et al. 2023; Raj et al. 2023).

Green synthesis of silver nanoparticles

The biological synthesis includes the use of either bacterial strains or plant extracts to obtain AgNPs. Various bacterial strains such as Escherichia coli DH5α, Pseudomonas fluorescens, Shewanella oneidensis and High GC rich Gram positive bacteria are grown on culture plates and allowed to uptake the silver ions from their surrounding media and during their metabolism, they produce secondary metabolites containing COOH, CHO−, OH groups that stabilizes silver and through enzymatic action, and converts silver into its elemental state from the ionic state, thus producing a large number of silver nanoparticles either by intracellular or extracellular method (Singh et al. 2022c). Through extracellular production, the microbes grown on petri plates containing silver nitrate are centrifuged upon growth and secondary metabolites secreted by bacteria are thus present in the supernatant containing enzymes that catalyze the reaction. Whereas in the case of intracellular production, the microbes are incubated with a silver ion solution, which adheres to the cell wall of bacteria. The enzymes are produced by bacteria as monoclusters catalyzing the reduction of silver ion to its ground state and the change in color is observed i.e. from pale yellow to brown, indicating the formation of AgNPs. Further, through cell lysis and purification techniques AgNPs are characterized (Jabeen et al. 2021).

The crude plant extracts are also used to prepare silver nanoparticles in a cost effective and eco-friendly manner. Acalypha indica, Alternanthera sessilis, Andrographis paniculata and Aloe vera are certain plant species by means of which silver nanoparticles can be synthesized. From plants, the crude extract (natural compound) is obtained through solvent extraction using ethanol or methanol, soxhelt extraction, or decoction extraction. The phytochemicals produced by the plants resist fungi, bacteria, or virus growth i.e. flavonoids, carotenoids, terpenoids, alanoids and phenolic compounds act as reducing agent and reduce the silver ion into its ground state (Vanlalveni et al. 2021; Yousaf et al. 2020; Shaaban et al. 2021). The AgNPs are generally characterized using various techniques such as UV–visible spectroscopy, XRD, FTIR spectroscopy, X-Ray photoelectron spectroscopy (XPS), DLS analysis, SEM, EDX/EDS, AFM, TEM, SAED, and thermal gravimetric analysis (TGA) to achieve size, shape, crystallinity, zeta potential, hydrodynamic size, surface area, porosity, solubility, aggregation, adsorption potential of nanoparticles (Ingale and Chaudhari 2013; Mali et al. 2019, 2017). The brownish tint produced by the interaction of silver metal salt with plant extract confirms AgNP production. An SPR peak often develops in the 400–500 nm range due to the combined electron vibration in the synthesised NPs conduction band, which is in resonance with the light waves and may be detected by a UV–Vis spectrophotometer (Sundeep et al. 2017; Reddy et al. 2019). FTIR is a sophisticated approach for studying the role of phytochemicals in AgNP reduction and stabilization, such as flavonoids, terpenoids, alkaloids, phenolic acids, and proteins. Silver ions oxidized active organic functional groups in plant extracts, may include −OH, −NH2, and −CHO groups. The reduction of the metal precursor and the synthesis of NPs are governed by a little shift in the bands (Koduru et al. 2018; Bala and Rani 2020).

Lung cancer and its types

Cancer is a disease developed by uncontrolled division of cells in any part of the body. Normally, cells grow and multiply by the means of cell division (a controlled process) and when grow old or there is any mechanical damage, cells die through a process called apoptosis (programmed cell death) but some cells fail to follow the pathway of cell cycle and enter a state of uncontrolled growth and division which leads to the development of cancer (Minna et al. 2002). It is generally of 2 types: malignant in which the tumor cells can migrate to nearby tissues and organs or benign in which the cancer is restricted to a particular place. Cancer has become one of the major causes of death worldwide. There are different types of cancers developed in humans and lung cancer is one of the major types of cancer causing a number of deaths globally. Symptoms of lung cancer includes: shortness of breath, weight loss, cough (worse, vomiting blood, chest pain and feeling tired or weak (Foldbjerg et al. 2011).

Lung cancer is a type of cancer in which cells of lungs or airways undergo division and multiplication at an abnormal rate leading to develop a mass of cells which may not spread to nearby areas. There are 2 major categories of lung cancer non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) as described in Fig. 2. The non-small cell lung cancer is the major type of lung cancer, occupying 80–85% of it, while small cell lung cancer occupies only 10–15% of the cases diagnosed with lung cancer. The NSCLC mainly consists of adenocarcinoma (40%), squamous cell carcinoma (30%) and large cell carcinoma (15%) and SCLC so far can be diagnosed up to 10–15% (He et al. 2016).

Fig. 2.

Fig. 2

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Classification of NSCLC and SCLC types of lung cancers that develop from lung epithelial cells

Causes of lung cancer and risk factors

Cigarette smoking

There are numerous causes of lung cancer and cigarette smoking is the number one because that develops cancer in lungs. The smoke contains nearly about 5000 harmful chemical substances such as nicotine, hydrogen cyanide, cadmium, acrolein, acetaldehyde, lead, ethylene oxide, etc. and once inhaled they settle down in the lungs and interact with the cells to cause a change in the physiology of cell and cell cycle by interacting with both sympathetic and parasympathetic nervous system causing the release of epinephrine and cholinergic respectively. Epinephrine enters the cell through β- andrenergic receptor and interacts with adenylate cyclase and enters the phosphorylation cascade and activate the MLCP (Myosin Like Chain Phosphatase) to cause bronchodilation whereas cholinergic enters the cell through cholinergic receptor and interacts with guanylate cyclase to ultimately affect the MLCK (Myosin Like Chain Kinase) for broncho constriction as given in Fig. 3 (Malik and Mukherjee 2018; Gowda et al. 2018; Mejia-Mendez et al. 2023; El-Hussein and Hamblin 2017). As per the studies conducted in the United States of America, there are nearly 80–90% of deaths caused by lung cancer due to smoking. While tobacco and its products, such as cigar, pipes increase the risk factor of lung cancer.

Fig. 3.

Fig. 3

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Effect of smoke exposure from tobacco products inducing cellular responses of the nervous system

Second-hand smoke

Second-hand smoking is also known as passive smoking and is inhaled indirectly i.e. from the cigar, pipes and cigarettes of another person. Even though it is harmful but people who are smoking at present or have smoked for years, are at a higher risk of developing lung cancer (Rozalen et al. 2020) than second-hand smokers or non-smokers (Fig. 4).

Fig. 4.

Fig. 4

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Incidence of lung cancer and risk factors associated with immune system

Air pollutants

The air we breathe contains number of molecules that are once inhaled; enter the respiratory tract and lungs. Therefore, it is very important to breathe fresh air which is free from any pollutant because they tend to settle in the lung cells. The main pollutant that enters the lung and settle in alveoli are particulate matter with a range of 2.5–10 mu. Due to their extreme small size when inhaled, these are pushed into the alveoli and starts accumulating (Sharma et al. 2024). Such pollutants are released from industries, thermal power plants, automobiles and household appliances. Air pollutants result in 36% of deaths caused globally and that’s why they are referred as ‘invisible killers’. Pollutants like PM (particulate matter), SO2, NO2, O3, etc. can enter the cell and cause DNA damage by methylation of DNA or histone modification (Singh et al. 2022a).

Radon gas

The exposure to radon gas released from soil and rocks by the breakdown of radioactive metals like uranium and radium causes lung cancer. Nearly 20,000 deaths every year is caused by exposure to radon gas (Singh et al. 2022b). There are other harmful chemical substances and carcinogenic agents which can lead to lung cancer such as arsenic, silica, asbestos, diesel, ultraviolet radiations, benzene, aflatoxin (a fungus that contaminates food) etc.

Treatment of lung cancer

Surgery

It involves the surgical removal of the affected area based upon the type, cause and spread of cancer within the lung tissues. The surgeon evaluates the patient initially to gather information about age, overall health, family history and the stages of lung cancer. The surgery for lung cancer is performed where a part of the lung i.e. lung tissue, lobe, or the whole lung is removed from the human body. The major drawback of this method is that there is a chance of cells being left behind after surgery or reoccurrence along with bleeding and pain. In such a scenario, the doctor suggests either to go for radiotherapy or chemotherapy (Wyld et al. 2015; Strobel et al. 2019). Types of surgical removal performed have been described in Fig. 5.

Fig. 5.

Fig. 5

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Surgical methods for removal of affected cells in lung cancer therapy

Chemotherapy

It is one of the treatments which includes the use of old drugs like alkylation agents (drugs which were used initially for cancer treatment, such as DMS (N, N-dimethylsphingosine), EMS (electrical muscle stimulation), anti-metabolites, plant alkaloids, anti-tumor antibiotics, mitotic inhibitors (stops the mitotic division of cells), etc. These drugs are given to the patients in combination with each other to increase the effectiveness either intravenously or orally with specific doses at a fixed interval of time depending upon the spread of lung cancer (Wang et al. 2023). In people with advanced stages of lung cancer, it is given in combination with radiotherapy to increase the effectiveness and to provide relief from pain as given in Fig. 6 (Okem et al. 2023). The major side effects linked to this treatment are the extreme hair loss, anemia, fatigue, bruising and bleeding, loss of appetite, etc.

Fig.6.

Fig.6

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Chemotherapy for lung cancer and side effects

Radiation therapy

The use of radiation to kill cancer cell is one of the treatments available for lung cancer where surgery is not an option. The use of ionizing radiations like X-rays, protons and magnetic resonance induction are exposed to specific body parts and the cancer cells can be killed to a certain extent (Wu et al. 2023). Through PET Scan and CT scan the cancer can be identified with its stage and spread in lungs. A linear beam of X-rays is exposed to the tumor and nearby lung tissues and lymph nodes and these radiations cause changes in genetic material, cell lysis, apoptotic genes and ultimately death of cells. Radiotherapy is provided in many ways either with chemotherapy, before and after the surgery, or to stop metastasis as shown in Fig. 7 (Spohn et al. 2023). There are number of advanced radiotherapies available across the world, such as IMRT (Intensity-modulated radiation therapy), HDR (High dose rated radiation therapy) and 3D-CRT (3D conformational radiotherapy.

Fig.7.

Fig.7

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Precision radiotherapy for lung cancer and promising strategies

The disadvantages associated with this are that there is a high risk of damage to nearby cells of the affected area by radiations and there are some side effects of radiations, including fatigue, skin color change, headache, blurry vision and many more (Roeder et al. 2020; Chow et al. 2021).

Immunotherapy

This treatment includes the use of agents that helps our immune system to fight against the cancerous cells. The cancer cell releases certain proteins and toxins that help them hide from the immune cells and additionally they secrete certain chemicals to damage the cells of the immune system. Therefore, anti-tumor antibodies are employed such as ipilimumab, tremelimumab, nivolumab, durvalumumab, avelumumab, atezolizumumab (Esfahani et al. 2020). These are a group of monoclonal antibodies specific against tumor cells which are given to the patients to boost up the immune system and to generate an effective immune response against these cancerous cells. This method of treatment is generally adopted in case of benign tumor where the cancer has spread to other parts of the body. Their release into the bloodstream will help the patient fight the cancer throughout the body (Kennedy and Salama 2020; Banstola et al. 2020). The major drawback related to this method is that it takes a lot of time for our body to recognize those cells and produce antibodies on their own plus it is very costly to generate monoclonal antibodies (Chhabra and Kennedy 2021).

Mechanism involved in immunotherapy

The immune cells have a property to kill the defective cells, while they do not attack the normal cells of the body. The main immune cells of the body are T-cells and they have some protein molecules expressed on their surface called “checkpoints” (Akkın et al. 2021). Cancer cells use these checkpoints to prevent themselves from being recognized and attacked by T-cells. There are certain drugs, such as nivoliumab, cemiplimab and permbrolizumab, which block the PD-1 protein present on the surface of T-cells to detect the cancer cells within the human body and target the cells to suppress the tumor as shown in Fig. 8 (Spohn et al. 2023; Zeng et al. 2021).

Fig.8.

Fig.8

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Current landscape of therapeutic resistance; T-cell design and functional mechanism in lung cancer

In addition, the body is administered with monoclonal antibodies like durvulumab and atezolizumab, which target the cancer cells and block the PD-L1 protein expressed on the surface of cancer cells. These monoclonals bind and block the receptor-like protein molecules and further lead to the generation of an active immune response against tumor cells (Li et al. 2021). Various other methods that are presently considered suitable for treatment of lung cancer are targeted drug therapy, stereotactic body radiotherapy and palliative care (Tan et al. 2020). While all of the above metes have certain disadvantages related to them as mentioned above in each. Certainly a new area in medicine called nanomedicine has been developed and it’s found to be very effective in the treatment of cancer with minimum side effects. Therefore, AgNPs are being used widely due to their anti-tumor properties (Igarashi and Sasada 2020).

Silver nanoparticles in treatment of lung cancer

Nanomedicine is being developed recently, which can create a newer era in the world of life sciences. One such nanomedicine is AgNPs as these can be used as a drug carrier in cancer therapy as many changes are observed in cells at the proteomics; genomics and transcriptomic level with the use of AgNPs (Taefehshokr et al. 2020). There are various methods by which silver nanoparticles can act as anti-tumor agents. At the molecular level, AgNPs of varying sizes can provoke DNA fragmentation, protein carbonylation, and lipid membrane peroxidation in cancer cells via enhancing ROS generation (Jabeen et al. 2021). Similarly, biosynthesized silver nanoparticles have the ability to change the transmembrane potential of mitochondria. This is accomplished by producing an excessive production of free radicals, specifically hydrogen peroxide, which ultimately leads to the death of cells through the process of apoptosis (Hembram et al. 2018). A treatment with silver nanoparticles (AgNPs) can also inhibit the motility of cancer cells by means of their interaction with metalloproteinases (MMPs), halt the progression of the cell cycle, cause multiple morphological changes (such as blebbing of cytoplasm and chromatin condensation), and modulate the expression of proteins that promote and inhibit apoptosis [Abass Sofi et al. 2022, Kanipandian et al. 2019]

The active targeting of nanoparticles, achieved by conjugating a ligand to their surface, is more effective. This unique ligand can selectively bind to receptors or antigens that are overexpressed on the surface of cancer cells. This method enhances selectivity, hence increasing drug absorption and retention at the tumour location, which in turn lowers systemic toxicity. Active targeting enhances passive targeting by increasing the cellular internalisation of nanoparticles by target cells; nevertheless, tumour localisation remains unaffected and continues to rely on passive diffusion (Gomes et al. 2021).

Moreover, translocation is a common nonspecific way for ultrasmall NPs (less than 5 nm in size) to pass across cellular barriers. However, bulk transport mechanisms such as phagocytosis, pinocytosis, or specific/nonspecific transport mechanisms allow bigger NPs to enter cells. Because of their efficient transport and increased permeability and retention (EPR) properties, nanoparticles (NPs) with a diameter of 10–100 nm may generally be regarded as appropriate for anticancer treatment. Smaller NPs (less than 10 nm in size) may be released from regular arteries quickly and harm healthy cells and tissue before the kidneys can metabolize them (Sukhanova et al. 2018). Consequently, the researcher also found that silver coated with Trimesic Acid (Ag@TMA) (less than 5 nm in size) had the maximum toxicity. Additionally, Ag@TMA1’s action is less selective and can kill any kind of cell, which restricts its use in targeted therapy. Because of their bigger size (30–50 nm), potential EPR impact, and enhanced selectivity towards cancer cells, silver nanocomposites are the most promising candidates for anticancer treatment, according to available data (Nel et al. 2006). In many other findings, graphene oxide coated with silver nanocomposite (Choi et al. 2018) and PVP coated with silver nanoparticles (Hotaby et al. 2017) have been prepared to form a desired nanostructure to have enhanced therapeutic efficiencies. There are various conjugating agents with silver nanoparticles, which include anticancer drugs (Benyettou et al. 2015), antibacterial (Kaur and Kumar 2019), PEG and PVP (Zhao et al. 2019), cellulose (Lin et al. 2015), amino acids (Kumar et al. 2018), proteins (Tai et al. 2014), fatty acids (Rajendran et al. 2019). In the field of biomedical science and therapies, these conjugating agents make it possible for silver nanoparticles to have a wide range of applications (Pucelik et al. 2022).

AgNPs were shown to enhance the expression level of ATM, ATR, CHK1, and CHK2, all of which are genes that are associated with DNA damage in cancer cells. This was discovered in the same investigation. Embelin, a powerful anticancer chemical that is found in Embelia ribes, was utilized in another study as a reducing and capping agent for the manufacture of silver nanoparticles (AgNPs). In the same publication, embelin-AgNPs were found to reduce the growth of A549 cells while also causing their death by apoptosis. This inhibition was observed in a dose-dependent manner, ranging from 10 to 200 μg/ML (Jagtap et al. 2022). In a separate investigation, AgNPs produced from stem extracts of medicinal plants, including Commiphora gileadensis, exhibited cytotoxicity against colon cancer cell lines HCT116, HT29, and SW620 in a dose-dependent manner (10–100 μg/mL) (Al-Zahrani et al. 2022). In a separate investigation, AgNPs (~ 10–30 nm) made from Salvia species (i.e., Salvia coccinea, Salvia leucantha, and Salvia splendens) led to the apoptotic death of A549 cells at concentrations of 402, 364, and 418 μg/mL, respectively (Rajendran et al. 2022).

Multiple morphological alterations, including cytoplasmic blebbing, chromatin breakage, and nuclear swelling, were brought about by the presence of AgNPs in the same cell line (Veetil et al. 2024). AgNPs, which ranged in size from three to ten nanometres and were made by combining ethanol extracts from traditional herbal products like garlic (Allium sativum), were found to limit the growth of A549 cells in a dose-dependent manner. This phenomenon was related to the generation of reactive oxygen species (ROS) and other forms of cellular damage (Padmini et al. 2022). A similar finding was observed when 18–39 nm AgNPs was synthesized using the supernatant of Streptomyces hirsutus strain SNPGA-8. These AgNPs exhibited cytotoxicity against A549 cells, with an IC50 value of 31.4 μg/Ml. In the same study, treatment with AgNPs led to an increase in reactive oxygen species (ROS) production in the same cell line (Pallavi et al. 2022). The anticancer efficacy of metallic nanoparticles can fluctuate based on several aspects, including their size, morphology, ζ-potential, and synthesis conditions. Small nanoparticles (< 100 nm) are recognized as potent anticancer treatments because to their size, which facilitates efficient distribution, enhanced permeability and retention (EPR) effect, biocompatibility, and stability (Singh et al. 2017; Gavas et al. 2021). Conversely, big nanoparticles (> 200 nm) are inclined to agglomerate in the liver and persist in the bloodstream for extended durations (Alexis et al. 2008).

Photodynamic theory/ photosensitizers

The AgNPs due to their extreme small size can easily enter the tumor cell microenvironment through diffusion, phagocytosis or endocytosis. Upon uptake by tumor cells, the electromagnetic radiations generally in infrared wavelength are focused onto them (Kessel 2023; Algorri et al. 2021). Due to the hypothermal activity of silver nanoparticles, in the presence of light or photons, they get activated upon absorbing the chemical energy and convert the same into heat energy further causing hyperthermia in cells and ultimately leading to cell necrosis. Moreover, these AgNPs also form singlet oxygen species, which increase toxicity in cells as given in Fig. 9 (Niculescu and Grumezescu 2021).

Fig.9.

Fig.9

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Targeted photodynamic therapy for cancer using functionalized silver nanomaterials

Reactive oxygen species

Silver nanoparticles when invade the cell organelles of tumor cells, cause proteogenomic changes in tumor cells through redox metabolism. Mitochondria, nucleus and other redox reactive organelles provide microenvironment for the generation of reactive oxygen species (ROS) such as super radical O2, ozone O3, single oxygen [O], H2O2, peroxy radical and alkoxy radical etc. (Nakamura and Takada 2021).

Mechanism

Due to the presence of high levels of antioxidants in cancer cell, there is no generation of reactive oxygen species, therefore, silver nanoparticles reduce the antioxidant level and thus increase the formation of ROS and activates mitochondria-mediated apoptotic pathway. It causes the downregulation of Bcl-2 which is an anti-apoptotic gene and upregulation of Bax a pro-apoptotic gene (Sahoo et al. 2022; Zhang et al. 2021; Sarmiento-Salinas et al. 2021). Bioconjugated form of silver nanoparticles i.e. fructose-coated AgNPs lead to the opening of mitochondrial membrane and realease of cytochrome c, which will act upon procaspase, which further activates caspase 3 that regulates the p53 genes mediated apoptosis leading to the death of cancer cells. Peroxisomes, NADPH Oxidase, and warburg effect within cells promote the release of ROS. Not only the disruption of mitochondrial membrane, AgNPs cause organelle damage, oxidative stress, mRNA and DNA damage within the cells as described in Fig. 10. ROS also changes the cellular pH of cancer cells causing cellular stiffness. A cell differentiated to human skin is exposed to AgNPs causes the release of silver ions and increasing the cellular toxicity (Kotsafti et al. 2020; Harris and DeNicola 2020; Jomova et al. 2023).

Fig.10.

Fig.10

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Continuous exposure of AgNPs or silver ions generate ROS overproduction, transcriptional reprogramming, and apoptosis mediated through p53 pathway

Cytotoxicity and genotoxicity

The cytotoxicity and genotoxicity can be generated by changing the concentration of AgNPs. The higher release of Ag+ ions in the cell can cause oxidative stress among the cells, which might lead to DNA damage, mRNA damage, change in the expression of cellular matrix and metal proteins. Initially, Ag2SO4, AgNO3 and AgClO4 were the chemicals that were used as a source of silver induced toxicity in cells but due to their adverse effects, limited specificity, development of drug resistance and possibility of relapse, the use of silver nanoparticles attracted significant attention of the scientific community. AgNPs coated with PVP can be used as cytotoxicity and genotoxicity agents along with a targeted drug delivery system and these combined properties make them as anti-tumor in nature (Foldbjerg et al. 2011; Swift and Golsteyn 2014; Zounkova et al. 2007).

Conclusion and future perspective

The role of nanotechnology in biomedical applications is vast, especially in the treatment of a wide variety of cancers. Cancer has been causing a number of deaths all around the globe and as per the recent estimation, around 29 million people are supposed to be diagnosed with cancer by 2040 with around 2.5 million cases recorded for lung cancer. But due to continuous advancements in medical science, the mortality rate can be decreased (Samarth et al. 2018). NPs are being currently exploited for their use in the clinical treatment of cancer. As compared to traditional methods like surgery, radiotherapy, chemotherapy, immunotherapy, combined therapies, NPs are found to be more effective. Both organic (carbon nanoparticles, DNA origami) and inorganic NPs (AuNPs, PtNPs, AgNPs, etc.) can be used for lung cancer treatment (Rai et al. 2014; Patra et al. 2014). Silver can generate cytotoxicity in cells, cause oxidative stress due to the generation of ROS, increased the expression of apoptotic genes such as p21, p53, Bax, activation of caspase 9, 6 and 3, etc. and hence Ag is used to generate metal nanoparticles. AgNPs are found to have improved physicochemical properties that can cure cancer to a greater extent. Also AgNPs with some conjugates like PEG, capping agents and in combination with advanced T-cell immunotherapies are associated with improved biocompatibility, pharmacokinetics and tumor targeting (Kar et al. 2024; Abdel-Fattah and Ali 2018). Apart from, chemical and biological approach, Bhasma in Ayurveda has also shown enormous support in formulating metal-based formulations, created by intricate pharmacological methods that integrate plants and transform them into an appropriate form. Recently, the fabrication of Rajat Bhasma has demonstrated proliferative activity against many malignant cell lines, beneficial interactions with HIV, and bactericidal effects (Sharma et al. 2016). The Rajat Bhasma was synthesized and characterized, showing a reddish-brown color, with the average particle size of 10–100 nm, and a quasi-spherical shape. The anticancer activity of Rajat Bhasma reveals the potent anticancer activity against MCF-7 cell lines (Naikare et al. 2022). Thus, metal-based nanomedicines can provide a scientific foundation by drawing on the fact that Bhasma contains submicronic or nanoparticles that improve bioavailability and could be the need of future research. Research is being carried out to develop hybrid NPs that are more suitable for drug targeting. Further studies about various biological characteristics of different cancers are underway so that more precise treatments can be made available in the near future and, moreover, one can engineer NPs that use targeting moieties for cancer cells. Nano vaccines are also into play to interact with the immune system and fight against tumors way better than traditional immunotherapies, but their clinical trial results are unsatisfactory. A further crosstalk between NPs based treatment and targeted immunity needs to be exploited.

Funding

No funding was received for the said study.

Declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Contributor Information

Manoj Singh, Email: manoj.singh@mmumullana.org, Email: lookformanoj@gmail.com.

Anil Kumar Sharma, Email: anibiotech18@gmail.com.

References:

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