Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Hartwig Meyer,^1,2 Timo Stöver,^1,3 Florian Fouchet,⁴ Guillaume Bastiat,⁴ Patrick Saulnier,⁴ Wolfgang Bäumer,² Thomas Lenarz,¹ Verena Scheper,<sup>1

1</sup>Department of Otolaryngology, Hannover Medical School, ²Institute for Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany; ³Department of Otolaryngology, Johann Wolfgang Goethe University, Frankfurt, Germany; ⁴Laboratoire d'Ingénierie de la Vectorisation Particulaire, University of Angers, Angers, France

Objective: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve–electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active.
Methods: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-α (TNF-α) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo.
Results: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-α in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results.
Conclusion: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects.

Keywords: rolipram, nanoparticle, hearing loss, spiral ganglion cell, inner ear