No abstract

Purpose Supplementation of exogenous nerve growth factor (NGF) into the cochlea of deafened animals rescues spiral ganglion cells from degeneration. However, a safe and potent delivery of therapeutic proteins, such as NGF, to spiral ganglion cells remains one of the greatest challenges. This study presents the development of self-assembled cubic lipid-based crystalline nanoparticles to enhance inner ear bioavailability of bioactive NGF via a round window membrane route. Methods A novel nanocarrier-entrapped NGF was developed based on phytantriol by a liquid precursor dilution, with Pluronic ® F127 and propylene glycol as the surfactant and solubilizer, respectively. Upon dilution of the liquid lipid precursors, monodispersed submicron-sized particles with a slight negative charge formed spontaneously. Results Biological activity of entrapped NGF was assessed using pheochromocytoma cells with NGF-loaded reservoirs to induce significant neuronal outgrowth, similar to that seen in free NGF-treated controls. Finally, a 3.28-fold increase in inner ear bioavailability was observed after administration of phytantriol lipid-based crystalline nanoparticles as compared to free drug, contributing to an enhanced drug permeability of the round window membrane. Conclusion Data presented here demonstrate the potential of lipid-based crystalline nanoparticles to improve the outcomes of patients bearing cochlear implants.

The aim of this study was to design novel mixed micelles as an ophthalmic delivery system for alpha-tocopherol (TOC) to prevent its degradation and improve ocular efficacy. The nonionic polymers, Polyoxyl 15 Hydroxystearate (Solutol® HS15) and Pluronic® F127, were discovered to be the most effective agents for retaining the activity and solubilization of TOC, respectively. Prepared by a thin-film hydration method, HS15/Pluronic® F127 yielded good encapsulation percentages of TOC, with a 27.7% drug loading efficiency. Incorporation of cetalkonium chloride (CKC) into HS15/Pluronic® F127 mixed micelles made the zeta potential of the micelles +17 mV, potentially prolonging the residence time of formulations on ocular surfaces. The optimized micelle preparation remained stable when diluted in a synthetic tear solution. It is known that the antioxidant ability of TOC in typical formulations reduces to around 85% of its initial value after 1 month when stored at 4 or 25 °C under an air atmosphere, which limits ophthalmic applications to less than 1 month. However, encapsulated TOC in investigated micelles remained stable for at least 6 months when sealed with N2. Finally, the cationic micelles were well tolerated after multiple administrations in rabbits, and they improved ocular accumulation of TOC. Taken together, these data suggest that the optimized micelle preparations described in this study may be suitable drug carriers for the treatment of ocular oxidant damage.