Magnetic Targeted Delivery of Dexamethasone Acetate Across the Round Window Membrane in Guinea Pigs

Abstract

Hypothesis Magnetically susceptible PLGA nanoparticles will effectively target the round window membrane (RWM) for delivery of dexamethasone-acetate (Dex-Ac) to the scala tympani. Background 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. Method 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. Results 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. Conclusion 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.

Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA

“…One aspect of this challenge is protecting and transfecting the siRNA into the desired target tissues. We have a developed a promising approach using a nontoxic, biodegradable PLGA polymer-based NP delivery platform (Barnes et al, 2007, Dormer et al, 2008, Du et al, 2013; Gao et al, 2010, Ge et al, 2007, Kopke et al, 2006, Mondalek et al, 2006, Wang et al, 2011, Wassel et al, 2007) . Saltzman et al .…”

“…Therefore, siRNA targeting of Hes genes may be an effective strategy for the post-traumatic regeneration of mammalian HCs in vivo in the future. PLGA NPs can cross the round window membrane of the inner ear in vitro and in vivo (Du et al, 2013; Gao et al, 2010; Ge et al, 2007), suggesting that PLGA NP-mediated inner ear delivery of siRNAs against these target genes may be a viable clinical approach to accomplish this aim.…”

Recent advances in local drug delivery to the inner ear

“…However, no long-term study of drug release from nanoparticles has been conducted 673 yet. PLGA SPION nanoparticlesenabled the entry of dexamethasone into the inner ear via magnetic 674 targeting through the round windowresulting in higher concentration of dexamethasone in 675 perilymph compared with passive diffusion (Du et al, 2013). 10% of the injected amount of 676 dexamethasone was delivered 60 min after injection.…”

Gene therapy for deafness

“…Methods for delivering viral vectors or small molecules using a trans-tympanic approach are being pursued. Using these approaches, delivery of dexamethasone 20 , antagonizing reactive oxygen species 19 or inducing a pharmaceutical elevation in the levels of HSPs 21 showed promise for a protective outcome. Ideally, protective therapy should be delivered via ear drops or systemic medication which could be administered under any conditions by the end user.…”