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.
Jiayi Gu   #  1  2  3 ,  Xueling Wang   #  1  2  3 ,  Yuming Chen  1  2  3 ,  Ke Xu  1  2  3 ,  Dehong Yu  4  5  6  7 ,  Hao Wu  8  9  10
Affiliations
  • 1. Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases (14DZ2260300), Shanghai, China.
  • 4. Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 5. Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 6. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases (14DZ2260300), Shanghai, China. [email protected].
  • 7. Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai, China. [email protected].
  • 8. Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 9. Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 10. Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases (14DZ2260300), Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 35689218 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.
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