Nanobiotechnology in Diagnosis, Drug Delivery and Treatment. Группа авторов

folate‐modified SeNPs showed a significant anti‐proliferative effect against 4T1 cells, significantly increased lifespan, and also prevented tumor growth (Shahverdi et al. 2018). In other study, SeNPs loaded with ferulic acid (FA‐SeNPs) were reported to cause damage of tumor cells as a result of apoptosis induction and direct interaction with DNA. Although the antitumor effect of both ferulic acid and SeNPs singly is relatively weak, the combination of these two biologically active ingredients exhibits high antitumor activity. It was shown that FA‐SeNPs induced intracellular overproduction of ROS and destruction of mitochondrial membrane potential by activating caspase‐3/9 to trigger HepG‐2 cell apoptosis through the mitochondrial pathway. The antitumor activity of FA‐SeNPs has also been associated with their binding to DNA (Cui et al. 2018).

      SeNPs functionalized with walnut peptides and having average size diameter of 89.22 nm showed high antitumor activity. These modified SeNPs were also reported to show excellent selectivity between cancer cells and normal cells. Targeted induction of apoptosis in human mammary adenocarcinoma cells (MCF‐7) was confirmed by cell‐cycle arrest in the S‐phase, nuclear condensation, and DNA disruption (Liao et al. 2016). Similarly, in another study chitosan‐stabilized iron oxide nanoparticles decorated with selenium having size diameter of 5–9 nm, zeta potential 29.59 mV, and magnetic properties of 35.932 emu g⁻¹ were prepared. Further, the authors evaluated their anticancerous activity using breast cancer cells MB‐231. After one day of incubation the viability of breast cancer cells was reduced to 40.5% in the presence of 1 μg ml⁻¹ of these composite nanoparticles without using chemotherapeutic pharmaceutical drugs (Hauksdóttir and Webster 2018). Chen et al. (2018) evaluated the possibility of SeNPs as new radio‐sensitizers in MCF‐7 breast cancer cells. Nano‐Se enhanced the toxic effects of radiation which resulted in high tumor cell death compared to any separate treatment causing cell cycle arrest in G2/M phase and activation of autophagy, and increasing the formation of both endogenous and radiation‐induced active oxygen forms (Chen et al. 2018). Similar findings were reported against lung cancer cell lines by Cruz et al. (2019).

      Biocompatible crystalline nanoparticles which release antitumor non‐organic elements are promising therapy for bone tumors. Selenium‐doped hydroxyapatite nanoparticles were reported to cause apoptosis of bone cancer cells in vitro with the help of caspase‐dependent apoptosis pathway and inhibit tumor growth in vivo while reducing systemic toxicity (Wang et al. 2016). Thus, all these studies performed in the last decade demonstrate the prospect of SeNPs for cancer therapy, which forms an actively progressing field for anticancer agent development.

2.4 Nanoselenium As a Part of Drug Delivery System

      One of the important applications of nanotechnology in medicine is the delivery of active ingredients and diagnostic agents to certain cells or tissues using nanoparticles. Many reports available proposed that various complexes of SeNPs can be used as potential delivery systems. To date, many studies have been devoted to the use of SeNPs in drug delivery systems for cancer and diabetes treatment (Guan et al. 2018). For this purpose, SeNPs are modified by functional ligands to achieve specific affinity for certain cells or organelles, in particular targeting cancer cells and mitochondria of various cells. A lot of diseases are associated with mitochondria dysfunction including cancer, cardiovascular diseases, diabetes, and neurological disorders. Some of the organic cations can penetrate the mitochondrial membrane and deliver therapeutic agents to mitochondria (Hou et al. 2017).

Functionalized SeNPs loaded with various chemotherapeutic drugs offer new prospects for cancer treatment. Due to their own anticancer activity and good responsiveness in the formation of complex forms, SeNPs are widely used for the systemic delivery of different antitumor drugs. Bioactivity in combination with higher selectivity toward cancer cells promises stable delivery with reduced systemic toxicity and higher chemotherapeutic efficacy (Chen et al. 2008). Nanomaterials tend to accumulate in cancer cells via the process of passive targeting (Yang et al. 2012) and often serve as “nanocarriers” for chemotherapy (Kano et al. 2007; Cho et al. 2010; Yang et al. 2010; Liu et al. 2012; Ramamurthy et al. 2013). It is well known that SeNPs have higher selectivity toward cancer cells compared to normal cells than selenite in similar concentrations (Chen et al. 2008). SeNPs can selectively penetrate cancer cells more than normal cells (Faghfuri et al. 2015) and they have rather low toxicity, high bio‐accessibility, convenient routes of administration, and good passive targeting. Also, SeNPs can maintain a prolonged release of selenium and have the ability to target the tumor, thereby reducing the distribution of selenium in normal tissues and increasing the accumulation in tumor tissues. This provides favorable conditions for the use of the fine‐line selenium drug (Menon et al. 2018).

      SeNPs can be used as a carrier of 5‐fluorouracil (FU) to achieve anticancer synergism (Liu et al. 2012). Thus, SeNPs functionalized with 5‐fluorouracil showed anticancer activity against five human cancer cell lines (A375, MCF‐7, HepG2, Colo201, and PC3) with IC50 values ranging from 6.2 to 14.4 μM. It is worthy to note that despite the activity, the compound has high selectivity between cancer and normal cells. SeNPs loaded with 5‐fluorouracil in breast and colon cancer cell lines enhanced the chemosensitivity of FU‐NPs in MCF7 and Caco‐2 cells more than in MDA‐MB‐231 and HCT 116 cell lines. The effect was achieved by inhibiting the bioenergy of cancer cells by blocking the glucose uptake (Abd‐Rabou et al. 2019). SeNPs and irinotecan in combination dramatically inhibit tumor growth and significantly induce apoptosis of tumor cells in the HCT‐8 cell xenograft model; they also decrease systematic toxicity (Gao et al. 2014).

      A combination of SeNPs and doxorubicin (Dox) demonstrated better antitumor effect than treatment with each of the component separately (Ramamurthy et al. 2013). Se‐functionalized liposomes (SeLPs) for systemic Dox delivery were obtained by applying selenium in situ on liposomes. It was shown that Dox loaded Se‐functionalized liposomes have a long‐term release effect of Dox and they can increase cellular uptake of Dox compared to normal liposomes. Selenium cover increases the circulation time of liposomes in the body and, therefore, it prolongs the overall release of the drug in vivo. In addition, selenium attached to liposomes doubles the antitumor effect of liposomal Dox (Xie et al. 2018). Similarly, folic acid‐modified SeNPs were loaded with Dox for targeting the surface of tumor cells that overexpress receptors to folic acid (for example, HeLa cells). These nanocomposites can be easily absorbed by HeLa cells (folate receptor overexpression cells) compared to A54 cells of lung cancer (folate receptor deficient cells) and entered HeLa cells mainly through the clathrin‐mediated endocytosis pathway. The nanocomposite inhibited the proliferation of HeLa cells and induced cell apoptosis; it could specifically accumulate itself at the site of tumor which contributed to the significant antitumor efficacy of the nanocomposite in vivo (Xia et al. 2018a).

      In another study conducted by Xia et al. (2018b), SeNPs modified by cyclic peptide (Arg‐Gly‐Asp‐d‐Phe‐Cys [RGDfC]) and loaded with Dox were used in non‐small cell lung cancer therapy. This structure demonstrated effective uptake by A549 cells mainly through the clathrin‐mediated endocytosis pathway. Compared to free Dox, this compound showed more inhibiting proliferation and caused A549 cell apoptosis. This delivery system with active targeting showed high antitumor efficacy in in vivo studies (Xia et al. 2018b). Moreover, mesoporous SeNPs coated with human serum albumin, associated with Dox, showed the ability not only to target the tumor in mice but also to reduce the side effects associated with Dox, and they enhanced its antitumor activity (Zhao et al. 2017a). Cyclophosphamide is one of the most effective anticancer drugs, but it has serious toxic effects on normal host cells due to its nonspecific action. Coadministration of cyclophosphamide and SeNPs caused a significant decrease in tumor volume and number of viable tumor cells while providing increased survival in mice (Bhattacharjee et al. 2017).

Multiple drug resistance is one of the major challenges in cancer therapy. Liu et al. (2015) manufactured folate‐conjugated SeNPs loaded with ruthenium polypyridyl as a new nanotherapeutic system. This nanosystem provided direct uptake visualization of nanoparticles by cells and it was able to prevent multidrug resistance effectively in liver cancer. The authors noted that it is possible to overcome the multidrug resistance in R‐HepG2 cells using SeNPs by inhibiting the expression of the ABC family protein. Internalized SeNPs caused an overproduction of ROS in the