Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Abstract

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.

Advances in nano-based inner ear delivery systems for the treatment of sensorineural hearing loss

“…They showed that lipid NP-encapsulated rolipram led to higher SGC survival rates and neurite outgrowth than rolipram delivery alone [25]. While rolipram may be studied in the future as a potential therapeutic agent, the findings of this study could not be replicated in vivo , which the authors believe may be due to non-sustained and nonspecific rolipram delivery.…”

“…Thus, current research is aimed at finding biomaterials that will increase neuronal survival and potentiate neurite outgrowth as a means of treating specific forms of neural hearing loss. [25–28]. …”

Phosphodiesterase Type 4 Inhibitor Rolipram Improves Survival of Spiral Ganglion Neurons In Vitro

“…A previous study of our group demonstrated a protective effect on SGN in vitro only if Rolipram was delivered encapsulated in lipid nanocapsules [49]. However, this neuroprotective effect was not observed after treatment with pure Rolipram [49].…”

“…A previous study of our group demonstrated a protective effect on SGN in vitro only if Rolipram was delivered encapsulated in lipid nanocapsules [49]. However, this neuroprotective effect was not observed after treatment with pure Rolipram [49]. One explanation could be that the used Rolipram concentration induced an increase of cAMP too high to promote the protective effect demonstrated by cAMP analogues [28]–[30].…”

Growth factor-eluting cochlear implant electrode: impact on residual auditory function, insertional trauma, and fibrosis

“…However, even with the introduction of minimally traumatic “soft” surgical techniques (reviewed in [ 5 ] and [ 6 ]) and electrodes that have been modified to reduce intracochlear trauma during their insertion [ 7 ], residual hearing is lost or incompletely preserved in one-third of cases [ 8 ]. Some researchers have begun to explore the possibility that better hearing preservation may be achieved by the application of protective pharmacological agents to the inner ear at the time of surgery ([ 9 , 10 ] and [ 11 ], reviewed in [ 6 ]).…”