On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules.

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)2]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)2]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein. Absorbance and fluorescence titrations, mass spectrometry together with melting and viscometry tests show significant differences in the binding features between silver and gold compounds. [Au(EIA)2]Cl covalently binds BSA. It is here evidenced that the selectivity is high: low affinity and external binding for all polynucleotides and G4s are found. Conversely, in the case of [Ag(EIA)2]Cl, the binding to BSA is weak and relies on electrostatic interactions. [Ag(EIA)2]Cl strongly/selectively interacts only with double strands by a mechanism where intercalation plays the major role, but groove binding is also operative. The absence of an interaction with triplexes indicates the major role played by the geometrical constraints to drive the binding mode.

Silver carbene complexes: An emerging class of anticancer agents.

Cancer is a major global health problem with large therapeutic challenges. Although substantial progress has been made in cancer therapy, there still remains a need to develop novel and effective treatment strategies to treat several relapsed and refractory cancers. Recently, there has been growing demand for considering organometallics as antineoplastic agents. This review is focused on a group of organometallics, silver N-heterocyclic carbene complexes (SCCs) and their anticancer efficacy in targeting multiple pathways in various in vitro cancer model systems. However, the precise molecular mechanism of SCCs anticancer properties remains unclear. Here, we discuss the SCCs chemistry, potential molecular targets, possible molecular mechanism of action, and their application in cancer therapies.

A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization, and Biological Studies.

The silver(I) N-heterocyclic carbene (NHC) complex bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride ([Ag(EIA)2 ]Cl), bearing two anthracenyl fluorescent probes, has been synthesized and characterized. [Ag(EIA)2 ]Cl is stable in organic solvents and under physiological conditions, and shows potent cytotoxic effects in vitro toward human SH-SY5Y neuroblastoma cells. The interactions of [Ag(EIA)2 ]Cl with a few model biological targets have been studied as well as its ability to be internalized in cells. The in vitro anticancer activity is apparently related to the level of drug internalization. Notably, [Ag(EIA)2 ]Cl does not react with a few model proteins, but is capable of binding the C-terminal dodecapeptide of thioredoxin reductase hTrxR(488-499) and to strongly inhibit the activity of this enzyme. Binding occurs through an unconventional process leading to covalent binding of one or two carbene ligands to the C-terminal dodecapeptide with concomitant release of the silver cation. To the best of our knowledge, this mode of interaction is reported here for the first time for Ag(NHC)2 complexes.

Preparation and in vitro antimicrobial activity of silver-bearing degradable polymeric nanoparticles of polyphosphoester-block-poly(L-lactide).

The development of well-defined polymeric nanoparticles (NPs) as delivery carriers for antimicrobials targeting human infectious diseases requires rational design of the polymer template, an efficient synthetic approach, and fundamental understanding of the developed NPs, e.g., drug loading/release, particle stability, and other characteristics. Herein, we developed and evaluated the in vitro antimicrobial activity of silver-bearing, fully biodegradable and functional polymeric NPs. A series of degradable polymeric nanoparticles (dNPs), composed of phosphoester and L-lactide and designed specifically for silver loading into the hydrophilic shell and/or the hydrophobic core, were prepared as potential delivery carriers for three different types of silver-based antimicrobials-silver acetate or one of two silver carbene complexes (SCCs). Silver-loading capacities of the dNPs were not influenced by the hydrophilic block chain length, loading site (i.e., core or shell), or type of silver compound, but optimization of the silver feed ratio was crucial to maximize the silver loading capacity of dNPs, up to ca. 12% (w/w). The release kinetics of silver-bearing dNPs revealed 50% release at ca. 2.5-5.5 h depending on the type of silver compound. In addition, we undertook a comprehensive evaluation of the rates of hydrolytic or enzymatic degradability and performed structural characterization of the degradation products. Interestingly, packaging of the SCCs in the dNP-based delivery system improved minimum inhibitory concentrations up to 70%, compared with the SCCs alone, as measured in vitro against 10 contemporary epidemic strains of Staphylococcus aureus and eight uropathogenic strains of Escherichia coli. We conclude that these dNP-based delivery systems may be beneficial for direct epithelial treatment and/or prevention of ubiquitous bacterial infections, including those of the skin and urinary tract.

Mathematical modelling of Pseudomonas aeruginosa biofilm growth and treatment in the cystic fibrosis lung.

Lung failure due to chronic bacterial infection is the leading cause of death for patients with cystic fibrosis (CF). It is thought that the chronic nature of these infections is, in part, due to the increased tolerance and recalcitrant behaviour of bacteria growing as biofilms. Inhalation of silver carbene complex (SCC) antimicrobial, either encased in polymeric biodegradable particles or in aqueous form, has been proposed as a treatment. Through a coordinated experimental and mathematical modelling effort, we examine this proposed treatment of lung biofilms. Pseudomonas aeruginosa biofilms grown in a flow-cell apparatus irrigated with an artificial CF sputum medium are analysed as an in vitro model of CF lung infection. A 2D mathematical model of biofilm growth within the flow-cell is developed. Numerical simulations demonstrate that SCC inactivation by the environment is critical in aqueous SCC, but not SCC-polymer, based treatments. Polymer particle degradation rate is shown to be an important parameter that can be chosen optimally, based on environmental conditions and bacterial susceptibility.

Nanotechnology as a therapeutic tool to combat microbial resistance.

Use of nanoparticles is among the most promising strategies to overcome microbial drug resistance. This review article consists of three parts. The first part discusses the epidemiology of microbial drug resistance. The second part describes mechanisms of drug resistance used by microbes. The third part explains how nanoparticles can overcome this resistance, including the following: Nitric oxide-releasing nanoparticles (NO NPs), chitosan-containing nanoparticles (chitosan NPs), and metal-containing nanoparticles all use multiple mechanisms simultaneously to combat microbes, thereby making development of resistance to these nanoparticles unlikely. Packaging multiple antimicrobial agents within the same nanoparticle also makes development of resistance unlikely. Nanoparticles can overcome existing drug resistance mechanisms, including decreased uptake and increased efflux of drug from the microbial cell, biofilm formation, and intracellular bacteria. Finally, nanoparticles can target antimicrobial agents to the site of infection, so that higher doses of drug are given at the infected site, thereby overcoming resistance.