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Theranostics 2020, Vol. 10, Issue 20 possible mechanisms involving the anticancer effects of AgNPs have been proposed. AgNPs can cause apoptosis or necrosis by destroying the ultrastructure of cancer cells, inducing ROS production and DNA damage, inactivating enzymes, as well as regulating signaling pathways [27-29]. In addition, AgNPs can also block the invasion and metastasis of tumor cells by inhibiting angiogenesis [30-32]. Due to the enhanced permeability and retention (EPR) effect, tumor cells preferentially absorb NPs-sized bodies than normal tissues [33, 34]. While the poor lymphatic drainage in the tumor enables nanoparticles to stay and penetrate [35]. This may enhance the targeted drug delivery of AgNPs. Further studies of anticancer mechanisms of AgNPs are essential to develop economical, reliable, and broad-spectrum anticancer agents. Besides the most studied antimicrobial and anticancer activities, AgNPs have also received attention in other cutting-edge medical applications, including wound repair, bone healing, dental material filling, vaccine adjuvants, antidiabetic agents, and bioimaging. In this review, we will also briefly introduce these biomedical applications. Considering various products containing AgNPs, such as dressings, creams, solvents, and scaffolds, it seems necessary to assess the potential toxicity of AgNPs in cells, tissues, and organs. Generally speaking, primary exposure routes include skin contact, inhalation, ingestion, and injection [36-38]. These routes will distribute AgNPs to different tissues and organs, such as skin, respiratory, circulatory, nervous, hepatobiliary, urinary and reproductive systems [36-41]. The deposited AgNPs may be potentially toxic to these tissues or organs by inducing cell necrosis, apoptosis or genetic mutations [42-45]. For example, AgNPs deposited in the lungs can cause pneumonia and asthma [46]. AgNPs may cross the blood testis barrier (BTB) and reduce the fertility of model animals and cause teratogenicity in offspring [42]. Some toxicological studies on model animals have shown that the potential toxicity of AgNPs is related to the inherent properties [25, 47]. Large surface area may lead to increased silver ions (Ag+) released from AgNPs, which may enhance the toxicity of nanoparticles. Besides the unique properties, the potential toxicity of AgNPs is closely related to dose, concentration and exposure time [24, 48-50]. Exploring the pharmacodynamics of AgNPs in vivo may contribute to the development of bio- friendly and safe agents. In recent years, a considerable amount of researches involving AgNPs prove enough evidence of promising medical applications of silver nano- materials. However, the potential toxicities of AgNPs 8998 to mammals in vivo and cell lines in vitro alert us to be cautious about its utilization. This reminds us to carry out more researches to obtain safe, bio- friendly agents containing AgNPs. This article provides a review of the applications of AgNPs and potential toxicology from an objective stance with insights toward understanding deep implications for medicine. Synthesis of AgNPs The synthesis methods of nanoparticles (NPs) are mainly divided into two processes: top-down and bottom-up (Figure 1). The top-down approach refers to the formation of metal NPs from bulk materials using various physical forces to synthesis NPs, such as mechanical energy used in ball milling, crushing and grinding; electrical energy used in the electrical arc-discharge method and laser ablation method; and thermal energy used in vapor condensation method [51]. These approaches can obtain NPs between 10 and 100 nm in size. The top-down approach, mainly the physical method, may acquire pure nanoparticles without chemical additives. NPs synthesized by physical method may exhibit uniform particle size distribution and high purity. Though the physical approach does not contain chemical reagents which may harm human and environment, it brings a great challenge to prevent agglomeration due to absence of stabilizer or capping agents. Furthermore, these methods need complex equipment and external energy in the process. The bottom-up approach involves the construction of complex clusters to obtain NPs from molecular components by employing nucleation and growth processes [51, 52]. The commonly used bottom-up approaches include chemical synthesis and biological synthesis, both can obtain NPs by reducing the precursor salt [52]. The chemical synthesis can be coupled with alternative energies, such as photochemical [53], electrochemical [54], microwave-assisted [55] and sonochemical methods [12]. Though the chemical method is carried out to quickly obtain various shapes of NPs, the use of harmful chemical additives may limit the medical applications of NPs. To overcome the shortcomings of the chemical method, the biological method has been regarded as an alternative option. The biological method usually relies on macromolecular substances in bacteria, fungi, and algae [16], such as exopolysaccharide, cellulose, and enzymes, and organic components in plant extracts such as enzymes, alcohol, flavonoids, alkaloids, quinines, terpenoids, phenolic compounds [16, 56-59]. Biological synthesis is an economical, environmentally friendly, simple and reliable approach, but the components on the surface of http://www.thno.orgPDF Image | Silver nanoparticles Synthesis medical applications safety
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