Preparation and in Vitro Antimicrobial Activity of Silver-Bearing Degradable Polymeric Nanoparticles of Polyphosphoester-block-Poly(l-lactide)

Abstract

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 ten 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.

Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery

“…Interestingly, our group has recently reported a similar behavior for the hydrolytic degradation of a related carboxylate-functionalized PPE- b -PLLA copolymer upon incubation in buffered aqueous systems. 34 In the present case, the fast drop in surface charge (Figure 4B) would support the hypothesis that main chain scissions are occurring predominantly over side chain cleavage. In a seminal study, Baran and Penczek showed, using NMR spectroscopy and titration techniques, that incubation pH value exerts a profound influence on the relative rate of hydrolysis of main chain versus side groups in methoxy-substituted polyphosphoesters.…”

“…Despite the apparent similarity in behavior at both pH values, it should be noted that macroscopic precipitation was observed within 20 h upon incubation at pH = 7.4, whereas it took 5 d at pH = 5.0. The major effect exerted by the pH of the incubation medium over the kinetics of degradation of polyphosphoesters has been previously reported in the literature 34,37,39−43 and is discussed further below, in light of the DLS data. At lower temperature (4 °C) the polyphosphoester backbone was substantially more stable at both pH values and most of the degradation that occurred was imputable to the fact that the NMR experiments were run at room temperature, which led to a faster apparent degradation.…”

“…The degradation of polyphosphoesters has been studied extensively in the literature and occurs spontaneously in aqueous buffers 34,37 but can also be mediated by enzymes. 38 Recent reports from our laboratory have investigated the degradation of self-assembled amphiphilic diblock copolymers made up of at least one polyphosphoester-based block using a range of characterization techniques (NMR spectroscopy, DLS, and mass spectrometry) and shown that the degradation rate was highly dependent on the nature of the side chain, 34,39 as previously reported in the literature. In this work, the hydrolytic stability of polymer assemblies generated from phosphonium-functionalized amphiphilic diblock copolymers was evaluated in detail by multinuclear NMR spectroscopy, dynamic light scattering, and zeta potential measurements at acidic and neutral pH values (pH = 5.0 and pH = 7.4, at 37 °C) using polymer Me 60 as a model compound.…”

“…29 With the desire to move toward fully degradable polymer nanoparticle systems, we have recently reported the straightforward synthesis of versatile and degradable polymer platforms making use of polyphosphoester (PPE)-based block copolymers 30−32 and demonstrated their potential use as drug delivery vehicles in biomedical applications, such as the in vivo delivery of paclitaxel 33 and antimicrobial agents to the lungs. 34,35 We now report on the development of fully degradable phosphonium-functionalized amphiphilic diblock copolymers and their self-assembly into well-defined micellar systems for siRNA intracellular delivery.…”

Urinary Tract Infection: Pathogenesis and Outlook

“…, Yersinia pestis ). Direct application to the bladder luminal surface of nanoparticles, perhaps coated with the FimH adhesin [85], has also been explored in mice as a means to accomplish targeted delivery of novel therapeutics to the host [86]. …”