A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration

Abstract

This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of −26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.

Coenzyme Q10 plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats

“…In our rat model, Acu-Qter was able completely quench Cpt ototoxicity, whereas in previous in vitro and in vivo studies using antioxidants and anti-inflammatory drugs a complete neutralization of Cpt toxicity was never achieved [ 5 , 17 – 26 , 41 – 44 ].…”

The feasibility of an encapsulated cell approach in an animal deafness model

“…A few models of encapsulated cells for inner ear treatment such as alginate capsules [24] or devices based on nanoparticles [25] , [26] , [27] have been presented in the last decade. In the present study, the device contained encapsulated cells (EC) that were genetically modified for long-term overexpression of BDNF or GDNF.…”

Auditory disorders and future therapies with delivery systems

“…31 It was demonstrated that fluorescent dye-tagged NPs that were PEGylated exhibited significantly higher fluorescence levels in OHCs of the organ of Corti compared with those without PEGylation. 32 As an applicable example of drug delivery, PEG-coated polylactic acid (PEG-PLA) NPs loaded with dexamethasone were locally injected on the surface of the RWM 33 to promote survival of the hair cells in the presence of cisplatin-induced ototoxicity and the maintenance of auditory function in guinea pigs.…”