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

J Nanobiotechnology. 2022 Jun 10;20(1):268. doi: 10.1186/s12951-022-01485-8.

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.

Keywords: Astaxanthin; Cisplatin-induced ototoxicity; Poly(propylene sulfide); ROS-responsive.

MeSH terms

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

Substances

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

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