Mitochondria-targeting nanomedicine: An effective and potent strategy against aminoglycosides-induced ototoxicity.

Abstract

We report a proof-of-concept for the development of mitochondria-targeting nanoparticles (NPs) loaded with geranylgeranylacetone (GGA) to protect against a wide range of gentamicin-induced ototoxicity symptoms in a zebrafish model. The polymeric NPs were functionalized with a mitochondrial-homing peptide (d‑Arg‑Dmt‑Orn‑Phe‑NH2) and exhibited greater mitochondrial uptake and lower gentamicin uptake in hair cells via mechanotransduction (MET) channels and tuned machinery in the hair bundle than the ordinary NPs did. Blockade of MET channels rapidly reversed this effect, indicating the reversible responses of hair cells to the targeting NPs were mediated by MET channels. Pretreatment of hair cells with mitochondria-targeting GGA-loaded NPs exhibited a superior acute or chronic protective efficacy against subsequent exposure to gentamicin compared with unmodified formulations. Mitochondrial delivery regulating the death pathway of hair cells appeared to cause the therapeutic failure of untargeted NPs. Thus, peptide-directed mitochondria-targeting NPs may represent a novel therapeutic strategy for mitochondrial dysfunction-linked diseases.

• Authors: Shuang Zhou, Yanhui Sun, Xiao Kuang, Shanshan Hou, YinXian Yang, Zhenjie Wang, Hongzhuo Liu
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 126 Pg. 59-68 (Jan 01 2019) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 29684426 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Diterpenes
• Drug Carriers
• Gentamicins
• Oligopeptides
• poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer
• Polyglactin 910
• Polyethylene Glycols
• geranylgeranylacetone

Topics

• Animals
• Anti-Bacterial Agents (toxicity)
• Cell Death
• Diterpenes (administration & dosage)
• Drug Carriers
• Drug Liberation
• Gentamicins (toxicity)
• Hair Cells, Auditory (drug effects, pathology)
• Mechanotransduction, Cellular
• Mitochondria (metabolism)
• Nanomedicine
• Nanoparticles (chemistry)
• Oligopeptides (chemistry)
• Polyethylene Glycols (chemistry)
• Polyglactin 910 (chemistry)
• Proof of Concept Study
• Zebrafish