Scheme 5.1 Schematic representation of the therapeutic approach by combining chemo- and photodynamic therapy
1.6 Selenium
Selenium (Se) is an essential trace element in the body, which is a member of non-metallic group of elements. Jon Jacob Berzelius discovered the Se in 1817, and the term “Selenium” was coined after greek ‘selene’ meaning
‘moon’.43 In human body, Se is a part of the proteins known as seleno-proteins.
The incorporation of the Se in seleno-proteins is assisted by the genetic code for seleno-cysteine. Se as a chemical species possess multiple properties.
Naturally, the role of the selenoproteins is to protect the body from oxidative stress. Antioxidant seleno-enzymes like glutathione peroxidase (GSH-P) and thioredoxin reductases reduce oxidative stress inside the cells. Some of the seleno-proteins are mentioned in Table 1.3.
Table 1.3 Selenoproteins and their functions.
Selenoprotein Function
Thioredoxin Reductases Reduction of oxidized thioredoxin, reduction of nucleotides,
Glutathione Peroxidases antioxidant defense, reduction of hydrogen peroxide and organic hydroperoxides, Iodothyronine
Deiodinases
Deiodination of T4 thyroid hormone into active T3 form.
Selenoprotein P Antioxidant defense
1.6.1 Involvement of Se in Cancer prevention
Geographical survey has shown that levels of Se in body and the tumor incidence were inversely related.44 Moreover, the studies carried out on animal models showed the selenium supplementation could inhibit tumor growth.45 Clark and co-workers carried out Nutritional Prevention of Cancer (NPC) trial, which showed that Se supplementation reduced the prostate cancer-related deaths.46 As mentioned earlier, Se at the nutritional levels serves as anti- oxidant by boosting the actions of the mentioned seleno-proteins.
Reports have also shown that Se regenerates the other anti-oxidant molecules like Q10, Vitamins C and E.47 Contrasting to this, Se at above the nutritional levels showed cytotoxic and anti-cell proliferative action.48 Similar studies performed to compare the effect of different chemical species selenium
confirmed that the therapeutic activity depends on the form of the Se species, redox status of the tissue and the metabolism pathway.49 Studies have also shown that the malignant cancer cells are more sensitive to Se, as compared to the non-cancerous cells.50
1.6.2 Selenium nanoparticles in cancer treatment
Se containing compounds studied for the therapeutic purpose include selenium dioxide, selenodiglutathione, selenomethionine, diselenides, and selnites. All these compounds have shown antiproliferative action against cancer cells. Along with these compounds, Se nanoparticles (SeNPs) have also gained attention of the researchers due to their cytotoxic properties. Multiple studies have shown the potential of the SeNPs for anticancer applications.
SeNPs can be prepared by biological, chemical, and physical methods. The biological or chemical method performs reduction of Se containing chemical species to elemental SeNPs. Chemical reduction of the Se involves use of the stabilizing and reducing agents. Similarly, green synthesis of the SeNPs involves the use of microorganisms or plant extract-based biomolecules. The physical method involves top-down approach where bulk materials are fragmented into nanomaterials using microwave, laser ablation and γ- irradiation.51 As the Se itself has anti-proliferative property, alone SeNPs, SeNPs loaded with drug or combination of the SeNPs and drugs may be used.
Chitosan polymer-stabilized SeNPs showed selective uptake in cancer cells and induced DNA fragmentation and apoptosis.52 Alone SeNPs treatment have shown induction of apoptosis via various mechanisms. In-vitro studies carried out on MDA-MB-231 and HeLa cells have shown dose-dependent (10-40µM) reduction in the cell viability; whereas the S phase arrest of the cell cycle led to the cell death.53 Another study reported that highly stable SeNPs prepared in
presence of polysaccharide isolated from fungus, induced cell apoptosis via DNA damage and cell cycle arrest at S phase.54
Figure 1.7 Surface modifications of the SeNPs for therapeutic applications (Conceptualized and redrawn).
1.6.3 Selenium NPs as drug carrier
Non-targeted delivery of the drug molecules results in the distribution of the drug molecules to the healthy cells, causing systemic toxicity. Thus, the nanocarriers mediated drug delivery becomes an important tool for targeted therapies. Use of SeNPs for drug delivery, could improve overall therapeutic response due to the contribution from cytotoxic properties of SeNPs.55 Surface modification can affect the physico-chemical properties of the nanocarriers for a therapeutic approach. Most of the nanoparticle shows destabilization in an aqueous medium; thus, the surface capping agents are helpful to prepare the stable nanoparticles. Similarly, surface capping can also modulate the uptake of the nanomaterials into the desired cells or by body’s clearance mechanism.
For example, surface capping with neutral polymers like PEG (poly-ethylene glycol) coating of the SeNPs can reduce the uptake and clearance of the SeNPs through reticulo-endothelial cells resulting in prolonged circulation.56,57 Additionally, the targeted delivery of the SeNPs can be achieved by
conjugating the targeting ligand on the surface by chemical modifications. The possible surface modification of the SeNPs are shown in Figure 1.7.
Transferrin conjugated SeNPs were prepared to target the cancer cells overexpressing the transferrin receptor. These TF-conjugated NPs selectively internalized through endocytosis in cancer cells avoiding the healthy cells.58 Similarly, Folic acid-conjugated SeNPs have also shown enhanced delivery to the folic acid receptor overexpressing cells.58 In another study, L-arginine capped drug-loaded NPs were used to deliver siRNA for MDR-1 inhibition. The fluorescent labeling of these NPs by ruthenium complexes renders the fluorescent NPs that can be tracked inside the cells.59 Multiple studies have shown that the synergistic response of the loaded drug and SeNPs making an effective treatment strategy. Recent studies have reported the synthesis of the stimuli-responsive nanocarriers for drug delivery after various stimuli, including temperature and pH.60