In the present mini-review silver nanoparticles (AgNPs) due to their superior physicochemical, and biological properties are intensively dealt with. The proper knowledge of these characteristics is essential to maximize their potential applications in many areas while minimizing their hazards to humans and the environment. This manuscript aims to critically review AgNPs synthesized via different approaches, its utilization in cancer treatment and future challenges.

Keywords: anti-cancer activities, AgNPs, IC50, Plasmon, HepG2, MCF-7, MDAMB231, SKBR3, rosa indica

Silver nanoparticles (AgNPs) constitute a class of materials with sizes in the range 1-100 nm. The interest in the study of AgNPs concerning their various behaviours has recently increased because of their unique and attractive physical, chemical, and biological properties.^1-7 AgNPs are also known to have particular functions regarding toxicity, surface plasmon resonance, and electrical resistance. Based on these, intensive research works have been conducted to investigate their properties and potential applications for several purposes such as antimicrobial agents in wound dressings, anticancer agents, electronic devices, and water treatment as well.^8-15

Cancer is a group of diseases, generating various pathological and metabolic changes in cellular environments. It is developed through diverse signaling mechanisms including cell proliferation, angiogenesis, and metastasis.^16,17 Cancer cells have abnormal metabolic activities in aerobic glycolysis, mitochondrial DNA depletion, and alterations in respiratory chains and genomic expressions. The physical and chemical treatments of cancer are limited at different stages. However, currently available therapies have an adverse effect and affect normal cell functions while giving excess drug and radiation exposures.^18,19

A marginal increase in cancer cases within the last few years ends up mostly, with death.²⁰ In several cancer types, we have to manipulate satisfactory medicine carriers similar to drug delivery to be applied as adequate chemotherapeutic agents.^21,22 Recently, AgNPs are reported to modulate the Pgp activity and therefore enhance the chemotherapeutic efficacy against multi-drug resistant cancer cells, thus, further emphasizing their excellent potential as combinational partners.²³ Moreover, the genotoxicity of AgNPs is supported by the generation of double-stranded DNA breaks along with chromosomal instability that drives the initiation of apoptotic execution.^24,25 This acting mechanism implies that AgNPs can be mutually associated with a great many DNA-targeting anticancer drugs (Figure 1).

Figure 1 Mechanism of action of silver nanoparticles against cancer cells.

There is several review papers published to address the issues associated with AgNPs regarding their toxicology properties during their use as antimicrobial agents for textiles, dental biomaterials, and bio-detectors, as well as during their syntheses.^26-34 For instance, toxicity properties including cytotoxicity and genotoxicity of capped or uncapped AgNPs have been reviewed in detail.³⁵ Their toxicity mechanisms after oral exposure were also thoroughly discussed.³⁶ Also, a recent review of AgNPs had focused on their synthesis using plant extracts for antimicrobial applications.³⁷ Most of the above studies concentrate chiefly on the different synthesis methods and their bactericidal activities. The reviews on the anticancer activity are somewhat seldom. Therefore, this review aims to present the anticancer activities for silver nano-particles synthesized from different sources.

Anticancer activity of silver nanoparticles

The Metallo-pharmaceuticals were included within the research field that was previously dominated by organic compounds and natural products. Many platinum and platinum-based compounds including carboplatin and oxaliplatin were approved as antitumor agents.³⁸ However, numerous drawbacks of platinum-based pharmaceuticals were reported proving, therefore, their curative effects.

Many cancer types are not susceptible to platinum drugs, and there are many toxic side effects, including gastrointestinal and haematological toxicity.³⁹ Moreover, several cancer cells have either intrinsic or acquired resistance to other platinating agents and cisplatin.⁴⁰ Consequently, current anticancer research has been devoted to the discovery of novel transition metal compounds. While silver was initially investigated because of its advantageous antimicrobial activity, there has been a recent interest in its anticancer functions (Table 1).

Saratale et al.⁴¹ developed AgNPs from common medicinal plant dandelion, Taraxacum officinale and showed their high cytotoxic effect against human liver cancer cells (HepG2).⁴¹ The AgNPs Synthesized by Kuppusamy et al.⁴² Using Commelina nudiflora L⁴² aqueous extract showed a reduced cell viability and increased cytotoxicity against HCT-116 colon cancer cells. Biofunctionalized silver nanoparticles synthesized within different plant extracts of guava and clove showed the satisfactory anti-cancer effect against four different cancer cell lines; human colorectal adenocarcinoma, the human kidney, human chronic myelogenous, leukaemia, bone marrow, and human cervix.⁴³ The developed silver nanoparticles using a proteinaceous pigment phycocyanin extracted from Nostoc linckia as reducing agent exhibited effective cytotoxic activity against MCF-7. The inhibitory concentration (IC50) was 27.79± 2.3μg/mL.³¹ Moreover, the chemically synthesized AgNPs composites possessed promising anticancer activity against the A549 (Human lung carcinoma), HeLa (Human cervical adenocarcinoma), MCF7 (Human breast adenocarcinoma), MDAMB231 (Human breast adenocarcinoma), and SKBR3 (Human breast adenocarcinoma) cells.⁴⁴ Kuppusamy et al.⁴² successfully bio-synthesized silver nanoparticles using the ethanolic extract of rose (Rosa indica) petals. The Ag functionalized extract proved potential anticancer activity against human colon adenocarcinoma cancer cell line HCT 15.⁴²

Effect of silver nanoparticles size on their anticancer activity

The biological effects of various metal nanoparticles in p53-deficient tumor cells as well as in vitro tumor stroma and in vivo metastasis models were investigated.⁴⁵ A higher cytotoxicity was recorded for the smaller, 5 nm sized silver nanoparticles compared to their larger counterparts. Additionally, it was concluded that silver nanoparticles could induce apoptosis-dependent programmed cell death in the absence of the tumor suppressor p53. Conventional cancer therapy often fails to cause cell death in p53-deficient cancer cells. The unique chemotherapeutic potential of such developed AgNPs was proved. Moreover, it was concluded that nanoparticles of size 5-35 nm primarily induced cell death through the mitochondrial structure and function targeting. Although the smaller Ag nanoparticles are more cytotoxic, the apoptotic action mechanism of both 5 and 35 nm was identical.⁴⁶ Interestingly, the cytotoxic features of silver and silver hybrid nanoparticles are cell-type dependent. In this domain, a higher cytotoxicity was recorded against cancer cells compared to non-cancerous fibroblasts. Conclusively, the stimulation of tumor-associated fibroblast cells with metal nanoparticles represents a typical therapeutic strategy. Since the treatment by Ag and Ag hybrids suppress the cancer cell promoting the activity of a tumor associated fibroblasts. Additionally, the in vivo results proved the ability of Ag/hybrids to inhibit the 4T1 tumor metastatic spreading in mice. Impressively, Ag hybrids can enhance the therapeutic efficacy of intravenous doxorubicin treatment.⁴⁷

The silver nanoparticles proved unique anticancer activity against different types of cancer cells. The several syntheses approaches significantly affect the cytotoxic activity of the achieved Ag nanoparticles. Future challenges on AgNPs synthesis and their release into the environment other than scaling up production, assess several potential avenues for future works are to promote a safer and more efficient utilization of these nanoparticles.

None.

The author declares no conflict of interest.

1. Mohammed Fayaz A, Balaji K, Girilal M, et al. Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria. Nanomedicine: Nanotechnology, Biology and Medicine. 2010;6(1):103–109.
2. Sharma VK, Yngard RA, Lin Y. Silver nanoparticles: green synthesis and their antimicrobial activities. Adv Colloid Interface Sci. 2009;145(1-2):83–96.
3. Kwak JI, An YJ. Trophic transfer of silver nanoparticles from earthworms disrupts the locomotion of springtails (Collembola). J Hazard Mater. 2016;315:110–116.
4. Huang Z, Chen G, Zeng G, et al. Toxicity mechanisms and synergies of silver nanoparticles in 2,4-dichlorophenol degradation by Phanerochaete chrysosporium. J Hazard Mater. 2017;321:37–46.
5. Sun X, Shi J, Zou X, et al. Silver nanoparticles interact with the cell membrane and increase endothelial permeability by promoting VE-cadherin internalization. J Hazard Mater. 2016;317:570–578.
6. Desireddy A, Conn BE, Guo J, et al. Ultrastable silver nanoparticles. Nature. 2013;501(7467):399–402.
7. Kumar A, Praveen Kumar Vemula, Pulickel M Ajayan, et al. Silver-nanoparticle-embedded antimicrobial paints based on vegetable oil. Nature Materials. 2008;7(3):236–241.
8. Habiboallah G, Mahdi Z, Majid Z, et al. Enhancement of gingival wound healing by local application of silver nanoparticles periodontal dressing following surgery: a histological assessment in animal model. Modern Research in Inflammation. 2014;3(3):128–138.
9. Kaur J, Tikoo K. Evaluating cell specific cytotoxicity of differentially charged silver nanoparticles. Food Chem Toxicol. 2013;51:1–14.
10. Chen D, Qiao X, Qiu X, et al. Synthesis and electrical properties of uniform silver nanoparticles for electronic applications. Journal of Materials Science. 2009;44(4):1076–1081.
11. Dankovich TA, Gray DG. Bactericidal paper impregnated with silver nanoparticles for point-of-use water treatment. Environ Sci Technol. 2011;45(5):1992–1988.
12. Mangala Praveena S, Suk Han L, Lung Than LT, et al. Preparation and characterisation of silver nanoparticle coated on cellulose paper: evaluation of their potential as antibacterial water filter. Journal of Experimental Nanoscience. 2016;11(17):1307–1319.
13. Mthombeni NH, Mpenyana-Monyatsi L, Onyango MS, et al. Breakthrough analysis for water disinfection using silver nanoparticles coated resin beads in fixed-bed column. J Hazard Mater. 2012;217-218:133–140.
14. Zhang H, Oyanedel-Craver V. Comparison of the bacterial removal performance of silver nanoparticles and a polymer based quaternary amine functiaonalized silsesquioxane coated point-of-use ceramic water filters. J Hazard Mater. 2013;260:272–277.
15. Syafiuddin A, Salmiati Salim MR, Beng Hong Kueh A, et al. A review of silver nanoparticles: research trends, global consumption, synthesis, properties, and future challenges. Journal of the Chinese Chemical Society. 2017;64(7):732–756.
16. Jason R Mann, Raymond N DuBois. Cancer chemoprevention: myth or reality? Drug Discovery Today: Therapeutic Strategies. 2004;1(4):403–410.
17. Seigneuric R, Markey L, Nuyten DS, et al. From nanotechnology to nanomedicine: applications to cancer research. Curr Mol Med. 2010;10(7):640–652.
18. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741–1750.
19. Wu X, Patterson S, Hawk E. Chemoprevention--history and general principles. Best Pract Res Clin Gastroenterol. 2011;25(4-5):445–459.
20. Raghunandan D, Ravishankar B, Sharanbasava G, et al. Anti-cancer studies of noble metal nanoparticles synthesized using different plant extracts. Cancer Nanotechnology. 2011;2(1-6):57–65.
21. Wafa I Abdel-Fattah, Abdel Sattar M Sallam, Nagwa A Atwa, et al. Functionality, antibacterial efficiency and biocompatibility of nanosilver/chitosan/silk/ phosphate scaffolds 1. Synthesis and optimization of nanosilver/chitosan matrices through gamma rays irradiation and their antibacterial activity. Mater Res Express. 2014;1(3):035024.
22. Abdel-Fattah WI, Eid MM, Abd El-Moez SI, et al. Synthesis of biogenic Ag@Pd Core-shell nanoparticles having anti-cancer/anti-microbial functions. Life Sci. 2017;183:28–36.
23. Igaz N, Kovács D, Rázga Z, et al. Modulating chromatin structure and DNA accessibility by deacetylase inhibition enhances the anti-cancer activity of silver nanoparticles. Colloids Surf B Biointerfaces. 2016;146:670–677.
24. Jiang X, Foldbjerg R, Miclaus T, et al. Multi-platform genotoxicity analysis of silver nanoparticles in the model cell line CHO-K1. Toxicol Lett. 2013;222(1):55–63.
25. Souza TA, Franchi LP, Rosa LR, et al. Cytotoxicity and genotoxicity of silver nanoparticles of different sizes in CHO-K1 and CHO-XRS5 cell lines. Mutat Res Genet Toxicol Environ Mutagen. 2016;795:70–83.
26. Riaz Ahmed KB, Nagy AM, Brown RP, et al. Silver nanoparticles: Significance of physicochemical properties and assay interference on the interpretation of in vitro cytotoxicity studies. Toxicol In Vitro. 2017;38:179–192.
27. Maurer LL, Meyer JN. A systematic review of evidence for silver nanoparticle-induced mitochondrial toxicity. Environ Sci Nano. 2016;3:311–322.
28. Benjamin Le Ouay, Francesco Stellacci. Antibacterial activity of silver nanoparticles: A surface science insight. Nano Today. 2015;10(3):339–354.
29. Singh R, Shedbalkar UU, Wadhwani SA, et al. Bacteriagenic silver nanoparticles: synthesis, mechanism, and applications. Appl Microbiol Biotechnol. 2015;99(11):4579–4593.
30. Barbara Simončič, Danijela Klemenčič. Preparation and performance of silver as an antimicrobial agent for textiles: A review. Textile Research Journal. 2016;86(2):210–223.
31. Rajeshkumar S. Green Synthesis of Different sized antimicrobial silver nanoparticles using different parts of plants- a review. International Journal of ChemTech Research. 2016;9(4):197–208.
32. Mashwani ZU, Khan T, Khan MA, et al. Synthesis in plants and plant extracts of silver nanoparticles with potent antimicrobial properties: current status and future prospects. Appl Microbiol Biotechnol. 2015;99(23):9923–9934.
33. Nidhija Roy, Archana Gaur, Aditi Jain, et al. Green synthesis of silver nanoparticles: An approach to overcome toxicity. Environmental Toxicology and Pharmacology. 2013;36(3):807–812.
34. Tarun Kumar Sharma, Aradhana Chopra, Mahak Sapra, et al. Green Synthesis and antimicrobial potential of silver nanoparticles. International Journal of Green Nanotechnology. 2012;4(1):1–16.
35. De Lima R, Seabra AB, Durán N. Silver nanoparticles: a brief review of cytotoxicity and genotoxicity of chemically and biogenically synthesized nanoparticles. J Appl Toxicol. 2012;32(11):867–879.
36. Gaillet S, Rouanet JM. Silver nanoparticles: their potential toxic effects after oral exposure and underlying mechanisms--a review. Food Chem Toxicol. 2015;77:58–63.
37. Shakeel Ahmed, Mudasir Ahmad, Babu Lal Swami, et al. A review on plants extract mediated synthesis of silver nanoparticles for antimicrobial applications: A green expertise. Journal of Advanced Research. 2016;7(1):17–28.
38. Wilson JJ, Lippard SJ. Synthetic methods for the preparation of platinum anticancer complexes. Chem Rev. 2016;114(8):4470–4495.
39. Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33(1):9–23.
40. Galluzzi L, Senovilla L, Vitale I, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869–1883.
41. Saratale RG, Benelli G, Kumar G, et al. Bio-fabrication of silver nanoparticles using the leaf extract of an ancient herbal medicine, dandelion (Taraxacum officinale), evaluation of their antioxidant, anticancer potential, and antimicrobial activity against phytopathogens. Environ Sci Pollut Res Int. 2017;1–15.
42. Kuppusamy P, Ichwan SJ, Al-Zikri PN, et al. In Vitro Anticancer activity of au, Ag nanoparticles synthesized using commelina nudiflora l. Aqueous extract against HCT-116 colon cancer cells. Biol Trace Elem Res. 2016;173(2):297–305.
43. Raghunandan D, Ravishankar B, Sharanbasava G, et al. Anti-cancer studies of noble metal nanoparticles synthesized using different plant extracts. Cancer Nanotechnol. 2011;2(1-6):57–65.
44. El-Naggar NE, Hussein MH, El-Sawah AA. Bio-fabrication of silver nanoparticles by phycocyanin, characterization, in vitroanticancer activity against breast cancer cell line and in vivo cytotoxicity. Sci Rep. 2017;7(1):10844.
45. Melaiye A, Simons RS, Milsted A, et al. Formation of water-soluble pincer silver(I)-carbene complexes: a novel antimicrobial agent. J Med Chem. 2004;47(4):973–977.
46. Melaiye A, Sun Z, Hindi K, et al. Silver(I)-imidazole cyclophane gem-diol complexes encapsulated by electrospun tecophilic nanofibers: Formation of nanosilver particles and antimicrobial activity. J Am Chem Soc. 2005;127(7):2285–2291.
47. Kascatan-Nebioglu A, Melaiye A, Hindi K, et al. Synthesis from caffeine of a mixed N-heterocyclic carbene-silver acetate complex active against resistant respiratory pathogens. J Med Chem. 2006;49(23):6811–6818.