期刊
JOURNAL OF NANOBIOTECHNOLOGY
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12951-022-01485-8
关键词
ROS-responsive; Poly(propylene sulfide); Astaxanthin; Cisplatin-induced ototoxicity
资金
- National Natural Science Foundation of China [81970874]
- Natural Science Foundation of Shanghai [21ZR1437600, 19ZR1429400]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX05]
- Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases [14DZ2260300]
- Innovative research team of high-level local universities in Shanghai
This study proposes a drug delivery system combining the antioxidant astaxanthin (ATX) and ROS-responsive/consuming nanoparticles (PPS-NP) to combat cisplatin-induced ototoxicity. The system effectively inhibits the accumulation of reactive oxygen species (ROS) and protects cells in the cochlea, thus having potential for prevention of cisplatin-induced hearing loss.
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 1 H 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.
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