An Increased Efficiency of Triclosan Delivery by Novel Acrylate-Based Nanoparticles

Recently, polymeric nanoparticles (NPs) have been widely investigated as carriers for drug delivery [1-5]. There are several routes to introduce the molecule of interest into the polymer-through physical adsorption (loading), covalent attachment, molecular imprinting, etc. The first route takes advantage of the finished polymer as fishing net, in a manner that the desired molecule gets entangled between the polymeric chains and released upon matrix-hydrolysis or an external stimulus (i.e, change in the pH, electric current, solvent preference, etc.) [6]. Alternatively, one can derivatize the molecule of interest into a monomer and then polymerize it. This route greatly increases the potency of the drug, because of its enhanced presence inside the polymer on the one hand, and diminishes the leaching problem on the other hand. There are several methods to perform polymerization, through suspension, emulsion, dispersion and precipitation polymerization. We have focused on dispersion polymerization in order to optimize the conditions to synthesize the NPs with specific properties. Briefly, dispersion polymerization involves an initially homogeneous system of a monomer, an organic solvent, an initiator, and a particle stabilizer. The system becomes heterogeneous during polymerization because the polymer is insoluble in the solvent. Polymer particles are stabilized by adsorption of the particle stabilizer on the surface [7]. The process proceeds in the polymer particles as they absorb the monomer from the continuous phase, leading to the formation of spherical particles in the region of about 0.1–10 μm in diameter [8,9]. Particle size is governed by the temperature of polymerization, concentrations of the monomer and the initiator, the type and concentration of the stabilizer, and the type of the polymerization medium [10]. In order to synergize the advantages of the molecule of interest with nanomaterials and discard their disadvantages as well, one can physically or covalently link them into one molecular entity. A new system is thus created. Physical entrapment assures a slow release over a certain period of time, and protection from the harsh extra and intracellular environments. Covalent linkage assures these properties and also prevents spontaneously leaking by providing a new sort of control over the system and increases its content in the chosen formulation. One can tailor the properties of the hybrid material as one sees fits. The antimicrobial agent that was chosen to serve as a model was triclosan (Irgasan®). It is a well-known commercial and a Food and Drug Administration (FDA) approved, synthetic, non-ionic, broad- spectrum antimicrobial agent, possessing mostly antibacterial, but also some antifungal and antiviral properties [11]. Numerous studies conducted on different bacteria strains showed that triclosan acts on a defined bacterial target in the bacterial fatty acid biosynthetic pathway, the NADH-dependent enoyl-[acyl carrier protein] reductase (ENR) [12-15]. Several studies have already shown that triclosan could be loaded into an organic matrix, such as polystyrene, β-cyclodextrin, and several copolymers and still exhibit its antibacterial properties [16-24]. Nevertheless, the “free” triclosan released from these composites has several disadvantages. It may undergo chlorination under conditions typical to water treatment [25]; it may undergo photolytic, hydrolytic, and degradative transformations (into dioxins) at various wavelengths and at various pH values [26]; and if accumulated, either in the environment or on the human tissue, it may be harmful [27]. To reduce the creation of undesirable triclosan derivatives, a polymer and various copolymers (polyurethane based coatings containing tethered triclosan groups) have also been prepared out of triclosan, though it was never synthesized as nanospheres, only as a bulk [28-31]. Synthesizing a nanosphered polymer composed of covalently bound triclosan as the basic ingredient, combines the various advantages of the single systems. The polymer assures better protection against both hydrolytic and photolytic degradation and prevents the active compound from leaching. Moreover, the nanometer scale increases the overall surface area per gram of the particles and so diminishes the amount of triclosan needed, making the overall composition less toxic. The covalent bond between the polymeric backbone and the biocide is designed to be broken by enzymes, subsequently releasing the active triclosan, which will act upon its target inside the cell. Basically, the enzymes produced by the bacteria themselves will be responsible for the release of the antimicrobial agent. Our group has already reported on an analogous system, namely nanosized particulate SiO2 matrix that upon enzymatic degradation could release triclosan, in a controlled manner [32]. The system possessed enhanced antibacterial properties as compared to the free biocide. Herein a facile and convenient route to prepare polymeric NPs, containing covalently-bound triclosan, is reported. This system is of a chemically different nature, than the one reported before, and intrinsically biodegradable. Optimization experiments were conducted and subsequently the NPs were fabricated according to the chosen synthetic pathway, using dispersion polymerization. Full characterization of the polymeric NPs and the effects of various parameters (i.e., monomer and surfactant concentrations) on the polymerization process are described. Furthermore, we have tested these novel NPs against common pathogens and observed a high antibacterial activity triggered by enzymatic cleavage of triclosan from the polymeric matrix.