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1.  Magnetic Targeted Delivery of Dexamethasone Acetate across the Round Window Membrane in Guinea Pigs 
Magnetically susceptible PLGA nanoparticles will effectively target the round window membrane (RWM) for delivery of dexamethasone-acetate (Dex-Ac) to the scala tympani.
Targeted delivery of therapeutics to specific tissues can be accomplished using different targeting mechanisms. One technology includes iron oxide nanoparticles, susceptible to external magnetic fields. If a nanocomposite composed of biocompatible polymer (PLGA), magnetite, and Dex-Ac can be pulled into and across the mammalian RWM, drug delivery can be enhanced.
In vitro targeting and release kinetics of PLGA-magnetite-Dex-Ac nanoparticles first were measured using a RWM model. Next, these optimized nanocomposites were targeted to the RWM by filling the niche in anesthetized guinea pigs. A permanent magnet was placed opposite the RWM for 1 hour. Cochlear soft tissues, perilymph, and RWM were harvested after euthanasia and steroid levels were measured using HPLC.
Membrane transport, in vitro, proved optimal targeting using a lower particle magnetite concentration (1 versus 5 or 10 mg/ml). In vivo targeted PLGA-magnetite-Dex-Ac particles had an average size of 482.8 ± 158 nm (DLS) and an average zeta potential −19.9 ± 3.3 mV. In 1 hour, there was significantly increased cochlear targeted delivery of Dex or Dex-Ac, compared with diffusion alone.
Superparamagnetic PLGA-magnetite-Dex-Ac nanoparticles under an external magnetic field (0.26 mT) for 1 hour significantly increased Dex-Ac delivery to the inner ear. The RWM was not completely permeated and also became loaded with nanocomposites, indicating that delivery to the cochlea would continue for weeks by PLGA degradation and passive diffusion.
PMCID: PMC3522431  PMID: 23187928
Dexamethasone acetate; Magnetic targeting; Poly(lactide-co-glycolide); Round window membrane; Sensorineural hearing loss
2.  Magnetic characterization of superparamagnetic nanoparticles pulled through model membranes 
To quantitatively compare in-vitro and in vivo membrane transport studies of targeted delivery, one needs characterization of the magnetically-induced mobility of superparamagnetic iron oxide nanoparticles (SPION). Flux densities, gradients, and nanoparticle properties were measured in order to quantify the magnetic force on the SPION in both an artificial cochlear round window membrane (RWM) model and the guinea pig RWM.
Three-dimensional maps were created for flux density and magnetic gradient produced by a 24-well casing of 4.1 kilo-Gauss neodymium-iron-boron (NdFeB) disc magnets. The casing was used to pull SPION through a three-layer cell culture RWM model. Similar maps were created for a 4 inch (10.16 cm) cube 48 MGOe NdFeB magnet used to pull polymeric-nanoparticles through the RWM of anesthetized guinea pigs. Other parameters needed to compute magnetic force were nanoparticle and polymer properties, including average radius, density, magnetic susceptibility, and volume fraction of magnetite.
A minimum force of 5.04 × 10-16 N was determined to adequately pull nanoparticles through the in-vitro model. For the guinea pig RWM, the magnetic force on the polymeric nanoparticles was 9.69 × 10-20 N. Electron microscopy confirmed the movement of the particles through both RWM models.
As prospective carriers of therapeutic substances, polymers containing superparamagnetic iron oxide nanoparticles were succesfully pulled through the live RWM. The force required to achieve in vivo transport was significantly lower than that required to pull nanoparticles through the in-vitro RWM model. Indeed very little force was required to accomplish measurable delivery of polymeric-SPION composite nanoparticles across the RWM, suggesting that therapeutic delivery to the inner ear by SPION is feasible.
PMCID: PMC1785374  PMID: 17204157
3.  The permeability of SPION over an artificial three-layer membrane is enhanced by external magnetic field 
Sensorineural hearing loss, a subset of all clinical hearing loss, may be correctable through the use of gene therapy. We are testing a delivery system of therapeutics through a 3 cell-layer round window membrane model (RWM model) that may provide an entry of drugs or genes to the inner ear. We designed an in vitro RWM model similar to the RWM (will be referred to throughout the paper as RWM model) to determine the feasibility of using superparamagnetic iron oxide (Fe3O4) nanoparticles (SPION) for targeted delivery of therapeutics to the inner ear.
The RWM model is a 3 cell-layer model with epithelial cells cultured on both sides of a small intestinal submucosal (SIS) matrix and fibroblasts seeded in between. Dextran encapsulated nanoparticle clusters 130 nm in diameter were pulled through the RWM model using permanent magnets with flux density 0.410 Tesla at the pole face. The SIS membranes were harvested at day 7 and then fixed in 4% paraformaldehyde. Transmission electron microscopy and fluorescence spectrophotometry were used to verify transepithelial transport of the SPION across the cell-culture model. Histological sections were examined for evidence of SPION toxicity, as well to generate a timeline of the position of the SPION at different times. SPION also were added to cells in culture to assess in vitro toxicity.
Transepithelial electrical resistance measurements confirmed epithelial confluence, as SPION crossed a membrane consisting of three co-cultured layers of cells, under the influence of a magnetic field. Micrographs showed SPION distributed throughout the membrane model, in between cell layers, and sometimes on the surface of cells. TEM verified that the SPION were pulled through the membrane into the culture well below. Fluorescence spectrophotometry quantified the number of SPION that went through the SIS membrane. SPION showed no toxicity to cells in culture.
A three-cell layer model of the human round window membrane has been constructed. SPION have been magnetically transported through this model, allowing quantitative evaluation of prospective targeted drug or gene delivery through the RWM. Putative in vivo carrier superparamagnetic nanoparticles may be evaluated using this model.
PMCID: PMC1475881  PMID: 16603066

Results 1-3 (3)