MINIREVIEW Silver Nanoparticles: Therapeutical Uses, Toxicity, and Safety Issues CAROLINA ALVES DOS SANTOS, 1 MARCELO MARTINS SECKLER, 1 AVINASH P. INGLE, 2 INDARCHAND GUPTA, 2,3 STEFANIA GALDIERO, 4 MASSIMILIANO GALDIERO, 5 ANIKET GADE, 2,6 MAHENDRA RAI 2 1 Department of Chemical Engineering, Polytechnic School, University of Sao Paulo, Brazil 2 Department of Biotechnology, SGB Amravati University, Amravati 444 602, Maharashtra, India 3 Department of Biotechnology, Institute of Science, Aurangabad 431004, Maharashtra, India 4 Department of Pharmacy, CIRPEB, University of Naples, “Federico II” and Istituto di Biostrutture e Bioimmagini, CNR, Naples 80314, Italy 5 Department of Experimental Medicine, Division of Microbiology – II University of Naples, Via De Crecchio 7, 80138, Naples Italy 6 Department of Biology, Utah State University, Logan, Utah 84322 Received 11 February 2014; revised 7 April 2014; accepted 9 April 2014 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24001 ABSTRACT: The promises of nanotechnology have been realized to deliver the greatest scientific and technological advances in several areas. The biocidal activity of Metal nanoparticles in general and silver nanoparticles (AgNPs) depends on several morphological and physicochemical characteristics of the particles. Many of the interactions of the AgNPs with the human body are still poorly understood; consequently, the most desirable characteristics for the AgNPs are not yet well established. Therefore, the development of nanoparticles with well-controlled morphological and physicochemical features for application in human body is still an active area of interdisciplinary research. Effects of the development of technology of nanostructured compounds seem to be so large and comprehensive that probably it will impact on all fields of science and technology. However, mechanisms of safety control in application, utilization, responsiveness, and disposal accumulation still need to be further studied in-depth to ensure that the advances provided by nanotechnology are real and liable to provide solid and consistent progress. This review aims to discuss AgNPs applied in biomedicine and as promising field for insertion and development of new compounds related to medical and pharmacy technology. The review also addresses drug delivery, toxicity issues, and the safety rules concerning biomedical applications of silver nanoparticles. C  2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci Keywords: nanotechnology; silver nanoparticles; therapeutics; antimicrobials; toxicity; drug delivery; coating; synthesis; biomaterials INTRODUCTION Metal nanoparticles in general and silver nanoparticles (Ag- NPs) in particular have attracted much attention in scien- tific research because of their versatility in different areas as engineering, medicine, chemistry, and physics. 1–4 Now- a -days, with the fast development of microbial resistance against traditional antimicrobials and the difficult insertion of new drugs/compounds, there is a need to search for promising alter- natives, which is an important question of public health safety. 5 The development of antimicrobial-resistance mechanisms im- pact in public health system is responsible for excessive time in the treatment of diseases, longer duration of hospitalization, and due costs involved with equipment’s and facilities. The bio- cidal activity of AgNPs depend on several morphological and physicochemical (e.g., size, shape, and surface) characteristics that influence directly in the success of these compounds as an- timicrobial agents. Enhanced antibacterial action of the AgNPs has been shown for the smallest particles within the nanome- ter size range that seems to improve the permeability of Ag ions in microbial cells facilitating the cell death. 6 Moreover, the presence of certain capping agents also improve their biocidal effectiveness. Initially, it was believed that polymeric systems used were biologically inert and that they have the ability to (1) Correspondence to: Mahendra Rai (Telephone: +91-9422857196; Fax: +91- 721-2662135; E-mail: mkrai123@rediffmail.com, mahendrarai7@gmail.com) Journal of Pharmaceutical Sciences C  2014 Wiley Periodicals, Inc. and the American Pharmacists Association protect the drug, (2) increase the half-life of these in vivo compo- nents, and (3) facilitate their diffusion. However, this paradigm has been modified because of recent evidence that these poly- meric materials can drastically change the cellular response of microorganisms. 7,8 Application of AgNPs in biomedical de- vices should possess other features related to their interac- tion with the human body: they should be biofilm-inhibiting, noncytotoxic, and nonthrombogenic. 9 The prevention of biofilm formation has been shown for catheters coated with AgNPs 10,11 and their cytotoxicity against human cells is significantly lower than prokaryotic organisms. 12,13 Unfortunately, many of the in- teractions of the AgNPs with the human body are still poorly understood; consequently, the most desirable characteristics for the AgNPs are not yet well established. 14 Therefore, the de- velopment of nanoparticles with well-controlled morphological and physicochemical features for application in the human body is still an active area of interdisciplinary research. Many routes have been proposed for the synthesis of AgNPs, the most straightforward ones being those based on the chem- ical reduction of the Ag + ions from aqueous solution. Citrate, D-glucose, ascorbic acid, aldehydes, amines, 15 polysaccharides including chitosan, 16 and leaf extracts 17 have been used as re- ducing agents. The elementary steps in the formation of AgNPs are thought to be the generation of a neutral silver atom that subse- quently forms positively charged precursors Ag 2 + , Ag 4 2+ , and larger clusters, which upon further aggregation, form the fi- nal nanoparticles. 18 Challenges in chemical route are related Dos Santos et al., JOURNAL OF PHARMACEUTICAL SCIENCES 1