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Biomaterials. 2018 Jul;171:133-143. doi: 10.1016/j.biomaterials.2018.04.038. Epub 2018 Apr 16.

Optimized phospholipid-based nanoparticles for inner ear drug delivery and therapy.

Author information

1
Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea.
2
Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
3
Department of Otolaryngology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea. Electronic address: cider12@catholic.ac.kr.
4
Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Catholic Photomedicine Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: hbkoo@catholic.ac.kr.

Abstract

To develop efficient carriers for inner ear drug delivery, we prepared four kinds of phospholipid-based nanoparticles: neutral, anionic, cationic, and cationic-PEG (polyethyleneglycol) particles. PEG was used to maintain long-term particle circulation in the perilymph, avoiding non-specific binding of particles to proteins. All four nanoparticles were about 200 nm in diameter, and their zeta potentials were -4.32, -26.0, +25.8, and -0.28, respectively, for neutral, anionic, cationic, and cationic-PEG nanoparticles. To test particle efficacy in vitro, we used an artificial mucosa 100 μm in thickness to model the round window membrane (RWM) and HEI-OC1 cells, which were treated with particles containing Nile Red dye. Based on the levels of particle penetration and cellular uptake in this model system, we selected an optimal particle for further study. We also observed the movement of particles in ex vivo organotypic cultures of the organ of Corti. In mice, we analyzed the biodistribution of dexamethasone (Dex) in the inner ear after intratympanic injection of Dex-loaded nanoparticles. Then, we tested the therapeutic utility of the Dex-loaded nanoparticles in a mouse model of ototoxicity. In the auditory brainstem response (ABR) test, particle provided improved hearing loss recovery at all tested frequencies, more so than did the Dex sodium phosphate (Dex-SP) solution in current clinical use. Furthermore, quantitative PCR showed that nanoparticles reduced the levels of pro-inflammatory cytokines, exhibiting anti-inflammatory effects superior to those of Dex-SP. Thus, the surface properties of nanoparticles play pivotal roles in particle penetration and distribution after intratympanic injection. Our in vitro screening system using an artificial mucosa will also be valuable in the development of carriers for inner ear drug delivery.

KEYWORDS:

Dexamethasone; Drug delivery; Hearing loss; Inner ear; Nanoparticle; Ototoxicity

[Indexed for MEDLINE]

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