Exploiting shape-selected iron oxide nanoparticles for the destruction of robust bacterial biofilms - active transport of biocides via surface charge and magnetic field control.

Biofilms that form on reusable medical devices are a cause of hospital acquired infections; however, sanitization of biofilms is a challenge due to their dense extracellular matrix. This work presents an innovative strategy using biocide-loaded iron oxide nanoparticles transported within the matrix via a magnetic field to eradicate biofilms. Results show that the active delivery of the biocide to underlying cells effectively penetrates the extracellular matrix and inactivates Methicillin resistant Staphylococcus aureus (MRSA) biofilms (responsible for several difficult-to-treat infections in humans). To optimize this treatment, the loading of spherical, cubic and tetrapod-shaped nanoparticles with a model biocide, CTAB (cetyltrimethylammonium bromide) was studied. Biocide loading was determined to be dependent on the shapes' surface charge density instead of the surface area, meaning that biocide attachment is greater for nanoparticles with sharp edges (e.g. cubes and tetrapods). These results can be used to optimize treatment efficacy, and help further understanding of biofilm and nanoparticle surface zeta potentials, and the nanoparticle-biofilm interactions.

EDTA-Na3 functionalized Fe3O4 nanoparticles: grafting density control for MRSA eradication.

We report a synthesis strategy to simplify often cumbersome post-synthesis ligand exchange protocols and use that approach to synthesize EDTA-Na3 (N-(trimethoxysilylpropyl)ethylenediaminetriacetate, trisodium salt) functionalized hydrophilic and biocompatible Fe3O4 nanoparticles. The grafting density of EDTA-Na3 has been controlled from 0.07-0.37 µmol m-2 by varying the time at which EDTA-Na3 was added to the reaction. The success of EDTA-Na3 surface functionalization has been verified using Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and Mössbauer spectroscopy techniques. Mössbauer spectroscopy results showed the evidence of Fe-EDTA monomer and dimer formation signifying covalent bonding between Fe ions and EDTA-Na3. The earliest addition of EDTA-Na3 resulted in the most stable dispersion of nanoparticles in water and phosphate buffered saline (PBS) which remained stable for more than a month. In addition, our results suggest that these nanoparticles can have useful applications in magnetic hyperthermia and eradication of methicillin-resistant Staphylococcus aureus (MRSA) bacteria in presence of an ac magnetic field.

Simple, Hackable, Size-Selective, Amine-Functionalized Fe-Oxide Nanoparticles for Biomedical Applications.

A facile one-pot method for synthesizing amine-functionalized nonspherical Fe3O4 nanoparticles in gram-scale quantities is presented using just a single source of iron (iron(II) chloride) and an amine (triethylamine). The amine not only transforms iron salt to Fe3O4, but also directs the morphology of the nanoparticles along with the temperature of the reaction and functionalizes them, making the synthesis very economical. By modifying the surface further, these nanoparticles promise to offer useful biomedical applications. For example, after biocide coating, the particles are found to be 100% effective in deactivating methicillin-resistant Staphylococcus aureus (MRSA) bacteria in 2 h. Cellular-uptake studies using biocompatible EDTA-Na3 (N-(trimethoxysilyl-propyl)ethylenediaminetriacetate, trisodium salt)-coated nanoparticles in human glioblastoma U-251 cells show that the majority of the particles are internalized by the cells in the presence of a small dc-magnetic field, making these particles a potential candidate as drug carriers for magnetic field-targeted delivery and hyperthermia.

Differential internalization of brick shaped iron oxide nanoparticles by endothelial cells.

Nanoparticles targeting endothelial cells to treat diseases such as cancer, oxidative stress, and inflammation have traditionally relied on ligand-receptor based delivery. The present studies examined the influence of nanoparticle shape in regulating preferential uptake of nanoparticles in endothelial cells. Spherical and brick shaped iron oxide nanoparticles (IONPs) were synthesized with identical negatively charged surface coating. The nanobricks showed a significantly greater uptake profile in endothelial cells compared to nanospheres. Application of an external magnetic field significantly enhanced the uptake of nanobricks but not nanospheres. Transmission electron microscopy revealed differential internalization of nanobricks in endothelial cells compared to epithelial cells. Given the reduced uptake of nanobricks in endothelial cells treated with caveolin inhibitors, the increased expression of caveolin-1 in endothelial cells compared to epithelial cells, and the ability of IONP nanobricks to interfere with caveolae-mediated endocytosis process, a caveolae-mediated pathway is proposed as the mechanism for differential internalization of nanobricks in endothelial cells.

Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood-brain barrier.

PURPOSE: The present study examines the use of an external magnetic field in combination with the disruption of tight junctions to enhance the permeability of iron oxide nanoparticles (IONPs) across an in vitro model of the blood-brain barrier (BBB). The feasibility of such an approach, termed magnetic field enhanced convective diffusion (MFECD), along with the effect of IONP surface charge on permeability, was examined. METHODS: The effect of magnetic field on the permeability of positively (aminosilane-coated [AmS]-IONPs) and negatively (N-(trimethoxysilylpropyl)ethylenediaminetriacetate [EDT]-IONPs) charged IONPs was evaluated in confluent monolayers of mouse brain endothelial cells under normal and osmotically disrupted conditions. RESULTS: Neither IONP formulation was permeable across an intact cell monolayer. However, when tight junctions were disrupted using D-mannitol, flux of EDT-IONPs across the bEnd.3 monolayers was 28%, increasing to 44% when a magnetic field was present. In contrast, the permeability of AmS-IONPs after osmotic disruption was less than 5%. The cellular uptake profile of both IONPs was not altered by the presence of mannitol. CONCLUSIONS: MFECD improved the permeability of EDT-IONPs through the paracellular route. The MFECD approach favors negatively charged IONPs that have low affinity for the brain endothelial cells and high colloidal stability. This suggests that MFECD may improve IONP-based drug delivery to the brain.