An enhanced antioxidant strategy of astaxanthin encapsulated in ROS-responsive nanoparticles for combating cisplatin-induced ototoxicity.

Abstract

BACKGROUND:

Excessive accumulation of reactive oxygen species (ROS) has been documented as the crucial cellular mechanism of cisplatin-induced ototoxicity. However, numerous antioxidants have failed in clinical studies partly due to inefficient drug delivery to the cochlea. A drug delivery system is an attractive strategy to overcome this drawback.

METHODS AND RESULTS:

In the present study, we proposed the combination of antioxidant astaxanthin (ATX) and ROS-responsive/consuming nanoparticles (PPS-NP) to combat cisplatin-induced ototoxicity. ATX-PPS-NP were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units, which scavenged ROS and disintegrate to release the encapsulated ATX. The ROS-sensitivity was confirmed by 1H nuclear magnetic resonance spectroscopy, transmission electron microscopy and an H2O2 ON/OFF stimulated model. Enhanced release profiles stimulated by H2O2 were verified in artificial perilymph, the HEI-OC1 cell line and guinea pigs. In addition, ATX-PPS-NP efficiently inhibited cisplatin-induced HEI-OC1 cell cytotoxicity and apoptosis compared with ATX or PPS-NP alone, suggesting an enhanced effect of the combination of the natural active compound ATX and ROS-consuming PPS-NP. Moreover, ATX-PPS-NP attenuated outer hair cell losses in cultured organ of Corti. In guinea pigs, NiRe-PPS-NP verified a quick penetration across the round window membrane and ATX-PPS-NP showed protective effect on spiral ganglion neurons, which further attenuated cisplatin-induced moderate hearing loss. Further studies revealed that the protective mechanisms involved decreasing excessive ROS generation, reducing inflammatory chemokine (interleukin-6) release, increasing antioxidant glutathione expression and inhibiting the mitochondrial apoptotic pathway.

CONCLUSIONS:

Thus, this ROS-responsive nanoparticle encapsulating ATX has favorable potential in the prevention of cisplatin-induced hearing loss.

• Authors: Jiayi Gu, Xueling Wang, Yuming Chen, Ke Xu, Dehong Yu, Hao Wu
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 20 Issue 1 Pg. 268 (Jun 10 2022) ISSN: 1477-3155 [Electronic] England
• PMID: 35689218 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antineoplastic Agents
• Antioxidants
• Reactive Oxygen Species
• Xanthophylls
• astaxanthine
• Hydrogen Peroxide
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Antioxidants (therapeutic use)
• Apoptosis
• Cisplatin (pharmacology)
• Guinea Pigs
• Hearing Loss (chemically induced, drug therapy, prevention & control)
• Hydrogen Peroxide
• Nanoparticles (chemistry)
• Ototoxicity
• Reactive Oxygen Species (metabolism)
• Xanthophylls