In Vivo Study of Entero- and Hepatotoxicity of Silver Nanoparticles Stabilized with Benzyldimethyl-[3-myristoylamine)-propyl]ammonium Chloride (Miramistin) to CBF1 Mice upon Enteral Administration.

Yurii A Krutyakov,Georgy V Lisichkin,Jaeho Pyee,Inna A Vasyukova,Alexander A Gusev,Olga V Zakharova,Alexey A Kudrinskiy,Vladimir A Kuzmin

doi:10.3390/nano11020332

Abstract

Silver nanoparticles (AgNPs) are the most widely studied antimicrobial nanomaterials. However, their use in biomedicine is currently limited due to the availability of data that prove the nanosilver toxicity associated primarily with oxidative stress development in mammalian cells. The surface modification of AgNPs is a potent technique of improvement of their biocompatibility. The synthetic or natural compounds that combine zero or low toxicity towards human and animal organisms with inherent antimicrobial properties are the most promising stabilizing agents, their use would also minimize the risks of microorganisms developing resistance to silver-based materials. We used a simple technique to obtain 30–60 nm AgNPs stabilized with benzyldimethyl[3-myristoylamine)-propyl]ammonium chloride monohydrate (BAC)—a well-known active ingredient of many antibacterial drugs. The objective of the study was to assess the AgNPs-BAC entero- and hepatotoxicity to CBF1 mice upon enteral administration. The animals were exposed to 0.8–7.5 mg/kg doses of AgNPs-BAC in the acute and to 0.05–2.25 mg/kg doses of AgNPs-BAC in the subacute experiments. No significant entero- and hepatotoxic effects following a single exposure to doses smaller than 4 mg/kg were detected. Repeated exposure to the doses of AgNPs-BAC below 0.45 mg/kg and to the doses of BAC below 0.5 mg/kg upon enteral administration also led to no adverse effects. During the acute experiment, the higher AgNPs-BAC dose resulted in increased quantities of aminotransferases and urea, as well as the albumin-globulin ratio shift, which are indicative of inflammatory processes. Besides, the relative mass of the liver of mice was smaller compared to the control. During the subacute experiment, the groups treated with the 0.25–2.25 mg/kg dose of AgNPs-BAC had a lower weight gain rate compared to the control, while the groups treated with the 2.25 mg/kg dose of AgNPs-BAC showed statistically significant variations in the blood serum transaminases activity, which indicated hepatosis. It should be noted that the spleen and liver of the animals from the groups treated with the 0.45 and 2.25 mg/kg dose of AgNPs-BAC were more than two times smaller compared to the control. In the intestines of some animals from the group treated with the 2.25 mg/kg dose of AgNPs-BAC small areas of hyperemia and enlarged Peyer’s patches were observed. Histological examination confirmed the initial stages of the liver and intestinal wall inflammation.

Highlights

Silver is the sixty third most common element in the Earth’s crust and silver compounds can be found on every continent
The obtained AgNPs-BAC is an aqueous dispersion of AgNPs capped with the biologically active cationic surfactant benzyldimethyl[3-(miristoylamino)-propyl]ammonium
The obtained AgNPs-BAC is an aqueous dispersion of AgNPs capped with the biologically active cationic surfactant benzyldimethyl[3-(miristoylamino)-propyl]ammonium chloride, which is an active ingredient of many antiseptic drugs

Summary

Introduction

Silver is the sixty third most common element in the Earth’s crust and silver compounds can be found on every continent. It is hard to say when people first discovered silver, but it is clear that it was known and used by prehistoric people. Silver alloys were actively used for producing coins, ornaments and various household items. The medical properties of the metal, especially its powerful antibacterial effects, were known to people at the time of Hippocrates. There were attempts to use silver for treatment of epilepsy, neonatal ophthalmic diseases, cholera, dysentery, sexually transmitted diseases, traumatic and other types of infections. One should mention surgical instruments, bone prostheses and catheters made of silver alloys [1,2]. Developments in biotechnology have allowed incorporation of ionizable silver into fabrics for clinical use to reduce the risk of nosocomial infections, and for personal hygiene [3,4]

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