title: 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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China ; Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Jiangnan University, The Fourth People's Hospital of Wuxi City, Wuxi, People's Republic of China.
authors.forename: Changling
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for Modern Silk, Soochow University, Suzhou, People's Republic of China.
authors.forename: Zhaozhu
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China.
authors.forename: Dongye
authors.initials: D
authors.lastname: Chen
authors.affiliation: National Engineering Laboratory for Modern Silk, Soochow University, Suzhou, People's Republic of China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China.
authors.forename: Fuxin
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China.
authors.forename: Dehong
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000009:adverse effects*; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced / Q000188:drug therapy; D019344:Lactic Acid / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D012405:Round Window, Ear / Q000187:drug effects
chemical_list: D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D003907:Dexamethasone; D002945:Cisplatin
keywords: cisplatin-induced hearing loss; dexamethasone; single-dose administration; stealth nanoparticles