Selenium nanoparticles: A potent chemotherapeutic agent and an elucidation of its mechanism

https://doi.org/10.1016/j.colsurfb.2018.06.006Get rights and content

Highlights

  • Binding selenium nanoparticles with specific ligands helps in specificity.

  • Size, dose and chemical form are important determinants in the chemoprevention.

  • Enhanced anti-tumor activity when being conjugated to anti-tumor drug.

  • The fate of the nanoparticle depends on the physicochemical and its chemical properties.

  • Cytotoxicity mainly due to apoptosis or cause cell cycle arrest being induced.

Abstract

Selenium nanoparticles have at present picked up a vital prospect in the field of medicine, due to their inquisitive properties when compared to other selenium compounds. They are comparatively better as anticancer, non- toxic, and biocompatible operators than selenite (SeO3−2) and selenate (SeO4−2) compounds. The mechanism behind the anticancerous property of SeNps is primarily due to the invasion of the apoptotic pathways and cell cycle arrest, which eventually lead to blockage of other pathways. Conjugation or surface modification of selenium nanoparticles enhances its anticancer adequacy by antibiotics, biomolecules or phytochemical compounds present in microbes or plants. Selenium, being an integral part of enzyme like glutathione peroxidase (GPx) and other seleno-chemical compounds, can enhance the chemotherapeutic activity by acting as a functional division of redox center and inhibiting the tissues from cellular damage by ROS. SeNps can open ways to new regular strategies for treating illnesses like malignancy, and this audit expresses the reasons why these nano measured medications can be the following huge achievement as chemotherapeutic operators.

Introduction

Nanotechnology has elevated the standards in treatment and diagnostics, and is considered as a standout amongst the most encouraging exploration introduction for oncotherapy. Cancer stays one of the greatest threats to human life. Although great efforts have been attempted to overcome cancer over the previous decades, it is as yet difficult to overcome the sickness. Chemotherapy is the generally connected approach for tumor administration, yet the poisons and the reactions influence chemotherapy to end up plainly troublesome. The most basic deterrents for malignancy chemotherapy are the limited availability of effective delivery systems for hydrophobic anticancer drugs, since low drug solvency in watery media limits their intravenous administration. To overcome the hurdles faced, researchers are opting for simpler technique or agents that are cost effective and can fulfill all the voids faced specifically by chemotherapeutic treatments, one such field is cancer nanotechnology, which is an emerging technique that displays application potential in cancer-targeted chemotherapy, molecular diagnosis and molecular imaging [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Nanodrug delivery systems have been found to improve the cellular targeting of anticancer drugs and exhibited radio-sensitization activities [12], [13], [14], [15], [16]. So, it is of extraordinary centrality to develop nanodrug conveyance frameworks for anticancer medications to upgrade their solubility and action efficacy [17], [18]. The National Cancer Institute has more than 400 potential operators under chemopreventive examination and has sponsored more than 65 clinical intervention trials [19].

As of now, much exertion has been given to create restorative uses of metal nanoparticles. While, critical advances have been made in the use of metal nanoparticles for the purpose of diagnosis, imaging and drug delivery, only less significant uses of nanoparticles have been reported [20], [21], [22], [23], [24]. One of such nanoparticles is the selenium nanoparticles (Nano-Se), which are attracting in expanding consideration because of their excellent biological activities, better biocompatibility and low toxicity. Selenium is an essential trace element for mammalian life, which additionally displays disease preventive properties due to their low toxicity, particularly, it shows improved antitumor activity contrasted with inorganic and organic selenium compounds [25], [26], [27]. Se at wholesome measurements, underpins cell cycle progression, prevents cell death, and is basic for ideal resistant reaction [28], [29], [30]. Adequate Se supplementation is co-identified with a diminished danger of growth, cardiovascular infections, diabetes and male fertility, while Se insufficiency brings about an expanded danger of mortality or poor insusceptible capacity. Consequences of epidemiological, preclinical and clinical examinations have demonstrated Se diminishing the risk of cancer, for example, mammary, prostate, lung, colon and liver malignancy [30], [31], [32], [33], [34]. Some molecular Se compound, for example, selenomethionine (SeMet), sodium selenite, methylselenocysteine and so on, have more successful anticancer action at high measurement [31], [35], [36], [37]. Nonetheless, high doses of selenite offer great concern about its toxicity as it exhibits a narrow margin between beneficial and toxic effects. Therefore, toxicity examination is always a crucial concern for development of Se-based anticancer drugs [38], [39], [40]. Many studies have demonstrated that SeNps have less toxicity, higher bioavailability, stronger biological activities like inducing seleno proteins, scavenging of free radicals, preventing oxidative DNA damage through potent antioxidant activity and strong cancer prevention than inorganic or organic selenocompound [41], [42], [43], [44], [45], [46]. Reports have shown that Se nanoparticles have magnificent bioavailability which shows as a novel cancer prevention agent exercising In-vitro and In-vivo. And, most evidences showed that selenium supplementation are a popular and broadly adopted complementary oncological treatment option [51], [52], [53].

It is assumed, that selenium can also enhance the activities of seleno-chemical and glutathione peroxidase (GPx), which can be counted as chemopreventive and chemotherapeutic operators upheld by countless, preclinical and clinical investigations [50], [51], [52]. As a segment of glutathione peroxidase, it can assist in scavenging of intracellular free radicals, it could also enhance the activity of the selenoenzyme such as glutathione peroxidase which acts as a function of redox centers and could prevent tissues from cell damage induced by free radicals [53].

Several mechanisms have been proposed to illustrate the anticancer activity of selenium, which incorporate acceptance of cell apoptosis, restraint of cell multiplication, regulation of redox state, detoxification of cancer-causing agent, stimulation of immune system, and inhibition of angiogenesis [54], [55], [56]. Among these potential systems of anticancer exercises of selenium, apoptosis gets most consideration and has been proposed to be basic for tumor chemoprevention by selenocompounds. As apoptosis is an essential mechanism to suppress malignancy development, and caspases are basic for actuating apoptosis, hence, Xueyun Gao et al. evaluated apoptosis and detected the activated caspases forms in human ileocecal adenocarcinoma HCT-8 cells. The tumor silencer p53 intervene various natural elements of apoptosis, cell cycle capture and DNA repair by interfacing with different proteins [57], [58]. They can be internalized into malignancy cells through endocytosis due to higher density, in this manner initiating cell demise by activating mitochondria-interceded apoptosis [59], [60]. The primary test stays for focusing on methodologies that reduce or maintain strategies to avoid toxicity towards the ordinary tissue. The anticancer mechanism of selenium is still controversial, but many reports testified that selenium could promote the growth of normal cells while inhibiting the growth of cancerous cells [61], [62]. The mechanism of Se action is mainly ascribed to a selective and substantial Se accumulation, which causes drastic elevation of ROS in peritoneal cancer cells, but not in normal tissues [63].

Numerous engineered frameworks have been created for the manufacture of Nano-Se over the previous decade. Be that as it may, a reproducible however basic strategy for preparation of Nano-Se with great stability is as yet a test. The preparation of nanoparticles is possible by either chemical or biological methods, which follows the principle of reduction of complex chemical to non toxic elemental form of nanoparticles. The only difference between both the methods is the use of reagents or chemicals, which are hazardous to the environment or human health, which is the case of chemical reduction. The chemical reduction methods involves the presence of modifiers or stabilizers which provide an excellent route to synthesize Nano-Se [64], [65]. Techniques for integrating selenium nanoparticles including chemical reduction, sono-chemical process, radiolytic lessening and wet chemical method. On the other hand, the eco-friendly green synthesis involves formation of nanoparticles which involves phytochemicals or bio-molecular reduction agents with better control over the shape and size having no side effects [66], [67], [68], [69], [70], [71], [72].

Increase in the weight of the tumor mice was observed when elucidating the antitumor activity of the Hyaluronic Acid-Selenium nanoparticle in the Heps tumor mouse model on oral administration and the result of it was that Ha-Se nanoparticle exhibited anti-oxidant activity and could protect the organ especially the liver from free radicals and could impede the progress of diseases in mice, and HA is biocompatible in the body since it is a nonsulfated glycosaminoglycan present throughout the connective, epithelial as well as the connective tissue which is formed in the cytoplasm and a important component of the extracellular matrix [35] Nanoparticle above micromolar size are biologically inert [73], [74]. The selenium nanoparticles@ Anisomycin show good dispersibility, stability and superior biocompatibility [75]. Nano-Se exhibited an excellent bioavailability because of its high catalytic efficiency, strong adsorbing ability and low toxicity [76]. The selenium nanoparticles surface modified with Baicalin and Folic Acid targeting moeities showed appropriate particle size distribution, high aqueous solubility and biocompatibility [77]. Selenium supplementation may have some protective effects against some types of cancer in populations where the average dietary selenium levels are low. The selenium nanoparticles have been proved to be biocompatible to humans by various reports. One such study which was conducted to check about the role of selenium as a protective agent against where people were administered with low dose of antioxidant vitamins and minerals that included Vitamin E, Vitamin C, β-carotene, selenium and zinc on a daily basis and after a certain period of time it was reported that people who were given these antioxidant vitamins and minerals had a reduced incidence of prostrate cancer compared to the people who received placebo. Another study reported that the intake of selenium in the diet led to a reduced incidence of lung cancer and also seem to have some protective effects I case of lung cancer in humans [78].

Specifically, disease focused on ligands could be conjugated to the surface of nanoparticles, which could give particular aggregation of nanoparticles in the tumor-bearing organ, improve the selective killing capacities against growth cells, and in the meantime, reduces the toxicities toward ordinary cells. Researchers have demonstrated that selenium nanoparticles can be delivered when conjugated with protein BSA, l-cysteine, glucose, sucrose, chitosan and sulfated polysaccharides as stabilizer in the redox framework with mean molecular size measurement going from 24 nm to 200 nm [78], [79], [80], [81], [82], [83], [84].

The major drawback in cancer treatment is that the drugs exhibit growth inhibition over tumor cells as well as that of normal cells, thus the normal cells were also inhibited in their growth and therefore, they have started to develop drugs, keeping selectivity as a major criteria which had been achieved by conjugating the nanomaterial to a targeting compound on to its surfaces, thus, providing preferential accumulation of the nanomaterials in tumor cells and not in the non-tumorogenic cells. The tumor targeting ability of nanoparticles might be due to the combination of an Enhanced Permeation and Retention (EPR) effect as well as receptor- mediated uptake of nanoparticle. Targeting conjugates like Mesoporous selenium loaded with Doxorubicin could specifically target MCF-7 [85], [86], in another paper, Folate (FA) were used for targeting the tumor cells which over express Folate Receptor [87], RGD peptide (ArginylGylcylaspartic acid) inhibited MCF-7 tumor growth and angiogenesis in nude mice through down-regulation of VEGF-VEGFR2 [88], Human Serum Albumin (HSA) incorporation significantly improve the cellular uptake and tumor cell targeting ability [89]. Transferrin/Transferrin Receptors mediated endocytosis has been found as a useful strategy to enhance the entrapped drug concentration in tumor sites, and keep them away from non-targeted tissues and cells that hardly express Transferrin Receptors. Transferrin Receptors mediated pathway is the major pathway for the Doxorubicin loaded selenium nanoparticles as well as other therapeutic agents. In vitro treatment of selenium-curcumin nanoparticle exhibited a significant reduction in cell viability in cancer cells as compared to normal HaCaT cells, indicating the selectivity of the nanoparticles towards the cancer cells [74]. Therefore, nano-selenium as such exhibits a broad spectrum of inhibition against various cancer cells including HepG2, MCF-7 and can even exhibit great selectivity for early stage breast cancer compared to metastatic breast cancer cells [47], [48], [90]. Moreover, Selenium could promote the growth of normal cells, while inhibiting the growth of cancerous cells. Lysosomes are the primary target for the Baicalin-SeNps-Folic Acid (B-SeNp-FA) rather than the nucleus. Lysosomes are the primary target for the Baicalin-SeNps-Folic Acid (B-SeNp-FA) rather than the nucleus and this type of targetting system is also beneficial because the nanosystem B-Senp-FA (Baicalin- Selenium nanoparticles- Folic Acid) exploded into smaller particles under the influence of the acidic environment of the lysososme which helped in metabolism of the selenium nanoparticles as well as the release of the Biacalin. As, optimum conditions for release of the nano complex is lacking in nucleus, lysosomal targeting is always preferable over nuclear targeting [77].

The synthesis method of nanoparticle by using plant extracts is green, single step, simple, eco-friendly, bio-reductive, cost-effective, requiring less reaction time and takes place at ambient condition and the various parameters that affect their synthesis are metal salt concentration, reducing agents, temperature, pH and reaction time. Nanoparticles are usually formed within 15 min of incubation and the rate of synthesis gradually increases with time [91]. Biomolecules present in the plants such as proteins/enzymes, polysaccharides, alkaloids, flavonoids, terpenoids, phenolic compounds and vitamins are generally involved in bio-molecular reduction, formation, protection and stabilization of metal nanoparticles with better over the shape and size having no toxicity [92]. The bio molecular reduction involves the reduction of mettalic ions into metal nanoparticles. Biomolecules like acids, monosaccharides and polysaccharides can also be used for the synthesis of selenium nanoparticles in the most simple, convenient way and can be carried out under ambient conditions like Acetic Acid was being used by C. Dwidevi et al. [93] and H. Chen et al. glucose which is a simple reducing agent can also be used. Glucose although being a simple reducing agent can also be used in the biomolecular reduction of mettalic ions into metal nanoparticles [94]. Plant extract are more preferably used compared to that of fungal and bacterial broths because the plant mediated synthesis is preferred over microbial synthesis due to its properties such as easy availability of plant resources, safer to handle due to the use of physical requirements like pressure, energy, temperature and constituent materials are trivial, more environment friendly, use of safer solvents, milder response conditions, cost-effective since it usually involves only one-simple process composed of various metabolites that aid in the reduction, rapid rate of synthesis, could have a better control over the size and the shape of the nanoparticle being synthesized, more stable nanoparticles and finally best suited for the medicinal, surgical and pharmaceutical applications [95], [96], [97]. Naturally-originated polysaccharides exhibit unique properties including excellent biocompatibility, biodegradability, stability, and non-toxicity, which are the basic characteristics for polymers used as biomaterials [98] and those polysaccharides are considered to be the appropriate template for the synthesis of selenium nanoparticles compared to that of phenolics and proteins because proteins are prone to enzymatic degradation and requires high temperatures and phenolics are auto-oxidized and gets aggregated in the pH of the stomach [99]. (Fig. 1) demonstrates the reaction between the precursor sodium selenite and curcumin which produces Se-CuNps, using a catalyst ascorbic acid at RT for 24 h.

Surface functionalization of selenium nanoparticles with various compounds, biomolecules or anti-cancer drugs which targets them to their specific site of action show enhanced anti-tumor activity by synergistically combining the effects of the nanoparticles with that compound to which it is bound. Anti-cancer drug Adriamycin (ADM) and Nano selenium were both able to inhibit Bel 7402 cell proliferation in a dose dependent manner but their combined treatment were more effective in inhibiting cancer cell growth and their velocity of cell apoptosis process was also high, than each of the 2 drugs alone on hepatic cancer cell lines [41]. Selenium nanoparticles combined with 5-fluorouracil enhanced anti-tumor outcome on various cell lines like A375 human melanoma cells [1], Human Serum Albumin (HSA), Mesoporous Selenium (MSe) coated with DOX, prominently induces cancer cell toxicity by synergistically enhancing the effects of MSe and DOX, where MSe exhibited a high DOX loading capacity [86]. Effects of FA-selenium nanoparticles on cancer cells were much higher than those on normal cells because Folic Acid was overexpressed at the surface of the cancer cells, thus, increasing its anti-cancer effects. Those selenium nanoparticles that expanded to snowflake structures under acidifying stimulus, led to an enhanced drug release over a prolonged period [87] but, when the size of the tumor increases, the growth-inhibitory effect of selenium nanoparticle decreases [90]. When the size of the nanoparticle is small, it is significantly more efficient than the large sized nanoparticles with low perceived toxicity and enhanced cytotoxicity [45]. After the treatment using SeHAN particles, more cancerous cells were necrotized [38]. Moreover, Selenium nanoparticles could also attenuate the side effects of subsequent routine chemotherapy without disturbing the chemotherapeutic efficacy [81] and decrease the side effects associated with anti-cancer drugs like Doxorubicin (DOX) [86]. The cytotoxicity of Ru-Se (Ruthenium(II)modified- Selenium nanoparticle) increased approximately 2–6 fold compared to non-ruthenium polypyridyl complexes binding selenium in which study they found out that the Ru-Se nanoparticles inhibited the activation of FGFR1 and their downstream protein kinases such as ErK and AKT. The Ru-Selenium nanoparticles significantly inhibited Human Umbilical Vascular Endothelial Cell Proliferation (HUVEC), migration and tube formation [25], [88].

The enhanced cytotoxicity was due to the augmentation of the apoptosis and autophagy in the cancer cells [74]. Biomolecules like polysaccharide and sialic acid significantly enhanced the anti-proliferative activities of Selenium nanoparticles [4], [100]. The surface decoration of Gallic Acid (GA) and the presence of Ruthenium further improves the anti-tumor activities in HeLa cells [28]. Nanoparticles functionalized with bioadhesive polysaccharides could prolong residence time and therefore increase absorption of the loaded drugs [98]. (Fig. 2) demonstrates the anti-tumorous effects of selenium nanoparticles conjugated with Irinotecan on HCT-8 tumors.

By altering the surface chemistry of the selenium nanoparticles, cancer targeting ligands can be conjugated to those nanoparticles and thus, this complex could bind to the receptor of the cancer cell membrane, enhancing the selective uptake and accumulation of nanomaterial in tumor bearing organs and reducing the toxicity towards normal cells at the same time. The capping group of the nanoparticle may be used to conjugate various drugs molecules to achieve the targeted drug delivery system and thus, can be used as vehicles for drug delivery [63]. Surface decorators are important contribution to the cellular uptake of the nanoparticles in the cancer cells [10]. Transferrin (Tf) a targeting ligand, is a brilliant guide to deliver numerous therapeutic drugs into malignant sites which overexpress Tf receptors, whereas, Transferrin could be conjugated to the nanoparticle and can be utilized to target different stages of cancers, such as primary and metastatic cancers [1]. Selenium nanoparticles coated with ATP increases the cellular uptake, stability and great selectivity between cancer and normal cells [37]. Nanomaterials tend to accumulate in cancer cells through passive targeting process and often serve as “nanocarriers” for chemotherapeutics but this strategy has limitations due to its random delivery [100]. The pH difference between normal and cancer cells can also be used for targeted drug delivery to reduce side effects in normal cells since pH of the cancer cells will be much lower than the normal cells [101].

Most of the selenium nanoparticle complexes were found to be accumulated in the tumor tissue followed by the liver and the kidneys. Ru-MUA@Se coated selenium could target and migrate to the liver cancer cells In vivo and this nanomaterial was found clustered in the cellular compartment that appear to the nuclear membrane, the nuclear membrane were more likely to fold in order to absorb the material from outside, suggesting the delivery of nanoparticle carrying Ruthenium complexes was nuclear targeting in the tumor tissue [25]. Animal studies also show the same that the liver is the major target organ of selenium toxicity [49]. When the selenium nanoparticles was conjugated with Curcumin, this nanomaterial when treated with tumor tissue the cell membrane was intact where as the cell organelles were disorganized including mitochondria, lipid droplets as well as endosomes after treatment duration of 2h–6 h and localization of Cytochrome C (which is major indicator of apoptosis) was seen in the mitochondria which was swollen with expanded and transparent matrices with disorganized cristae [74]. Target distribution of selenium only in cancer cells and not in normal tissues did not trigger any apparent host toxicity, but did result in ROS burst in cancer cells and strong suppressive effect on cancer cell growth [45]. Selenium was mainly concentrated in the cancer cells when compared to selenium retention in normal tissues, thus the selective distribution resulted in strong proliferative suppression without perceived host toxicity on application of the synthesized selenium nanoparticles in the peritoneal cavity [81].

Nanoparticles used for drug delivery need to be degraded, absorbed and/or evenly excreted. The fate of a drug after administration In vivo fate depends mainly on the physicochemical properties of the drug and its chemical structure [37]. In drug delivery, degradation of nanoparticle can promote the drug delivery by enabling the release of encapsulated drugs [88]. PEG-Selenium nanoparticle entered and accumulated in the cells in a time-dependent manner, then became saturated [10]. RGD-Nanoparticle entered the cells by endocytosis, then accumulated in the lysosomes and finally dispersed in the whole cytoplasm [72]. likewise, Transferrin-Selenium nanoparticles also moved across the cell membrane, then accumulates in the lysosome and then it gets dispersed throughout the cytoplasm and the drug release from the complex was found to be 48% within 1 h and 90% was released within 48 h in the lysosomes but only 12% was released within 1 h and 40% was released within 48 h in the blood [1]. Most SeHAN particles were taken up by tumor cells, dissolved by lysosome and therefore, easily got degraded and excreted out from the system [38]. Energy plays an important role in the process of Ru-MUA coated Selenium entering the cells, Clathrin-mediated endocytosis is the main route of internalization and the internalized nanoparticle can escape from the endocytic vesicles (endolysosomes), resist the lysosomal degradation and then enter the nucleus to impart therapy with high efficacy [25]. Transferrin-selenium nanoparticles moved across the cell membrane, then accumulates in the lysosome and then it gets well dispersed throughout the cytoplasm. The drug release from the Tf-Se np complex was almost 48% within 1 h and 90% was released within 48 h in lysosome and only 12% was released within 1 h and 40% within 48 h in the blood [1]. PEG-Se np entered and accumulated in the cells in a time dependent manner, which became saturated after 6 h. Later PEG-Se np clusters were also found in the cells [10]. Paclitaxel-loaded polyphosphoester hybrid micelles exhibited higher affinity towards the liver compared to that of Transferrin modified Paclitaxel-loaded polyphosphoester hybrid micelles due to its small size that enabled to get through the small pores of the liver. The paclitaxel was primarily metabolized in the liver by CYP 3A4 and 2C8and underwent biliary excretion, the low liver disposition could extend the retention time of PTX in the brain [27]. DOX, DOX-LP, DOX-SeLP were the 3 complexes that were used and it was reported that the DOX-SeLP complex was the most effective among these in delivering the DOX in the therapeutic dose due to longer half-life, smaller clearance rate and also higher plasma peak concentration, while the other complexes were not effective enough because the DOX-LP were easily cleared from the circulation due to intense phagocytosis by the macrophages of the Rough Endoplasmic Reticulum and also due to the fragile nature of the liposomes which is being acted upon by the plasma components [32]. Paclitaxel-loaded polyphosphoester hybrid micelles exhibited higher affinity towards the liver compared to that of Transferrin modified Paclitaxel-loaded polyphosphoester hybrid micelles due to its small size that enabled to get through the small pores of the liver. The paclitaxel was primarily metabolized in the liver by CYP 3A4 and 2C8and underwent biliary excretion, the low liver disposition could extend the retention time of PTX in the brain [27]. After 2 h of treatment of the tumor with the Selenium-Curcumin nanoparticle there was a high increase in the vacuole number, degradation and reduction in size of the nanoparticles and were found in vacuoles. The degradation and reduction was due to erosion of the nanoparticle matrix and after 6 h of treatment they were spotted in the cytoplasm in intact state due to diffusion of the nanoparticle matrix [74].

Reduction as well as stabilization of the nanoparticle was achieved by flavonoids and phenolics where, on comparison the flavonoids are more effective than the phenolics. Stabilization of the nanoparticle was due to capping of the phytochemicals on the surface of the nanoparticles which prevents them from aggregation thus offering additional advantage of the stability in the green chemical synthesis [19]. Green synthesized nanoparticle was stable for a longer duration [90], while addition of chemicals like polyvinyl alcohol also contributed to its stability [63], where its stability depends on the conjugate to which it is bound with, its synthesis method, structure and the addition of chemicals. RGD-nanoparticle was found to be stable during blood circulation [88]. The prepared/synthesized Hyaluronic acid-Se nanoparticle (HA-Se) were stable for at least for 1 month at room temperature [35]. Tf-selenium nanoparticles dispersed in Phosphate Buffered Saline (PBS) solution kept stable within 21 days and this stability of the nanomaterial enabled it to enter the cells by endocytosis. To fabricate the stable and versatile nanoparticle, a 4-layer structure was formed by loading DOX and conjugating chitosan (CS) and Transferrin to selenium nanoparticles [1]. HSA coating of the Mesoporous (MSe) selenium enhanced of the stability, dispersibility of (MSe) and also prevented the premature drug release [86]. Undaria Pinnatifida when added to Nano-Selenium to prevent aggregation and to improve the stability, it remained stable for atleast 3 months [20]. B. Yu et al. revealed that the internalized Selenium nanoparticle can be easily degraded upon X-Ray exposure to estimate the enhanced cancer chemo-radiotherapy [10].

The size of the thus formed nanoparticle also affects the stability like in case of Gallic Acid-Selenium/Ruthenium nanoparticle were stable for 6 days when it was 70 nm in size. This nanoparticle was highly stable in both PBS and cell culture media because of the protective GA coating on their surface [28]. Processes like lyophilization also maintained the stability of the nanoparticle in Quercetin and Gallic Acid mediated synthesis of the nanoparticles remained stable for more than 9 months whereas the as such synthesized nanoparticle remained stable for 60 days in colloidal solution [19]. As such the biomolecules alone could provide stability like Sialic acid that prevents the growth of the nanoparticle [100]. Nano Selenium remained stable as long as 3 months when stored at 4° C but, when SeNps preserved using aqueous polysaccharide often form aggregates [79]. As shown in (Fig. 3) the morphology of selenium nanoparticles can be done using electron microscopes like TEM or SEM, DLS, visual colour change from colourless to reddish brown solution and stability of synthesized nanoparticles is also monitored.

Endocytosis being the major mechanism of intracellular uptake of the nanoparticle by the cells is cell-type and size dependent and those nanoparticles got easily aggregated in aqueous solution to form bigger size, thus prevented their endocytosis [100]. So to enhance the cellular uptake of the nanoparticles it has to be conjugated to a biocompatible polymer which also enhances the selectivity of the nanosystem. Small size of ATP coated selenium nanoparticle (40 nm) contributed to the development of highly stable nanostructures and due to its small size it could escape the reticulo-endothelial system and prevented uptake by macrophages, and thus, exhibited a time-dependent and dose dependent cellular uptake of the nanoparticle [37]. The cellular uptake could take place through any one the endocytic pathway, deliver the drug and then can get degraded or eliminated. Folic Acid (FA) surface conjugation on the surface of the nanoparticle significantly enhanced the cellular uptake through FA- receptor mediated endocytosis through nyasin dependent lipid raft mediated pathway and clathrin mediated pathways [87], Ruthenium (II)-Selenium nanoparticles interacts with proteins in the cytoplasm and were grouped in intracellular compartments of the cells like the perinuclear compartments and vesicular structure close to the cell nucleus of HepG2 cells whose uptake and accumulation increased in a time-dependent manner, it may enter the nucleus by endocytosis and interfere with certain signalling pathways [67]. RGD peptide recognises and binds to integrins overexpressed on the cell membrane and then internalizes by receptor-mediated endocytosis, then disassembles under acidic condition with the presence of lysosome and cell lysate, leading to bioresponsive triggered drug release [88]. The Transferrin-Selenium nanoparticle was internalised by the cells through energy-dependent endocytosis (either through Clathrin mediated or Lipid-raft mediated), thus moved across the cell membrane, accumulated in the lysososme finally being dispersed in the cytoplasm with no traces of the nanomaterial in the nucleus [1]. Coating the surface of Mesoporous Selenium coated DOX with HSA generated a unique redox-responsive nanoparticle transported into the cells by endocytic pathway, localized with lysosome, which demonstrated glutathione dependent drug release, increase in tumour targeting effects and enhanced cellular uptake through nanoparticle interact with SPARC in MCF-7 cells [86]. Ruthenium(II)-polypyridyl complex with 11-mercaptoundecanoic acid modified selenium nanoparticles (Ru-MUA@Se) efficiently enhances the cellular uptake [25]. Anti-cancer drugs like Adriamycin (ADM) penetrated easily the cell membrane whereas the selenium nanoparticle internalization required more time [22]. Nanoparticles functionalized with bioadhesive polysaccharides could prolong residence time and therefore increase absorption of the loaded drugs [98].

Accumulative evidence has suggested that the size, dose and chemical form are important determinants of chemopreventive activities of selenium compounds [20]. Particle size is an important parameter for suppressing the cancer cell growth, depending upon the size and the dose, the nanoparticles can directly affect the physical stability, cellular uptake and distribution of nanoparticle [37]. Anti-tumorogenic effect of selenium have been associated with supranutritional levels of the element which is usually >1 mg/kg Se diet [102]. Small-sized selenium nanoparticles are more effective in inhibiting cancer cell growth where on an average 12.5 nm of the nanoparticle is equivalent to methylselenininc acid in inducing apoptosis in several cancer cell lines where due to its small size it can easily escape the reticulo-endothelial removal in diseased organs [28], whereas the large-sized selenium nanoparticle did not suppress cell number accumulation [45]. In case of ultra small sized PEG-selenium nanoparticles exibited growth inhibition on drug-resistant heptacellular carcinoma cells [103]. A dose of about 0.4 mg/kg/day was found to suppress tumor growth in breast cancer cell lines when K.K. Vekariya et al. wanted to test the Erα dependent anticancer mechanism in MDA-MB231 breast cancer cell lines [90]. Nano Selenium alone could effectively inhibit the growth of HCT-8 cells in concentration higher than 50 μm in vitro and thus high concentration of Nano selenium induces high levels of apoptosis [12]. Particle size is one of the most important parameters determining biocompatibilities and bioactivities of materials with therapeutic importance. The more cell permeability of the nanoparticle will enable to have more drug bioavailability at target site for better therapeutic property and also reduced the dose of drug required for recovery and reduces the adverse effect of the drug [104]. It has been proved that higher intake of selenium will help to prevent the incidence of pancreatic cancer [105]. The (Fig. 4) demonstrated SeNps coated with ligands and the fate of larger or smaller size nanoparticles when they enter the cells of cancerous or non-cancerous cells through targeted receptors.

Section snippets

Mechanism

Selenium nanoparticles and anti-cancer drugs mainly exhibit their cytotoxic effects by inducing apoptosis of cells and/or inducing cell cycle arrest at different phases of cell cycle [1]. Oxidative stress and ROS formation was found to be the major mechanism for selenium induced cytotoxicity [20], [87], [90] where, ROS modulates apoptosis by regulating the activities of enzymes involved in cell-death pathways. Apoptosis – an active mode of cell death is a genetically regulated suicide mechanism

Toxicity

Toxicity examination is crucial concern for development of selenium based anti-cancer drugs. The toxicity of the selenium was mainly found to be due to the generation the ROS and it is strongly influenced by its metabolism [105]. Selenium nanoparticles exhibited low, acute toxicity for In vivo analysis, and exhibited much lesser toxicity compared to that of selenomethionine and selenite. Selenium nanoparticles demonstrated decreased toxicity, increased bioavailability and stronger activity than

Clinical trials

Numerous clinical tests have been reported that selenium as such can be used as a protective agent against various types of cancers. Chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals which include vitamin-C, Vitamin-E, β-carotene, selenium and zinc. The trial comprised of 5141 middle-aged men free of severe health conditions, that took place over a period of 8.8 years for men treated with placebo and almost 9 years for men who was

Conclusion

Numerous sorts of nanomaterials have been integrated and applied in cancer therapy. Among of them, SeNps have increased noteworthy effect because of their anticancer action and low toxicity to normal cells and its selectivity towards tumor cells have pulled in a lot of consideration as a novel anticancer agent and drug carrier. Although the combination of various chemotherapeutic agents is regularly utilized to prevent drug resistance in cancer patients, the ability of the malignancy cells to

Acknowledgement

The authors did not face any discrepancy while doing the work, and would like to thank It is Vellore Institute of Technology, Tamilnadu, India for encouragement and support bestowed upon us.

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