Abstract
BackgroundOtotoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy. To date, no FDA approved agents to alleviate or prevent this ototoxicity are available. However, ototoxicity is generally believed to be produced by excessive generation of reactive oxygen species (ROS) in the inner ear, thus leading to the development of various antioxidants, which act as otoprotective agents. Astaxanthin (ATX) is an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies, owing to its unique antioxidant capacity.Methods and resultsIn this study, we aimed to evaluate the potential antioxidant properties of ATX in the inner ear by using the HEI-OC1 cell line, zebrafish, and guinea pigs. Because ATX has poor solubility and cannot pass through round window membranes (RWM), we established lipid-polymer hybrid nanoparticles (LPN) for loading ATX. The LPN enabled ATX to penetrate RWM and maintain concentrations in the perilymph in the inner ear for 24 h after a single injection. ATX-LPN were found to have favorable biocompatibility and to strongly affect cisplatin-induced generation of ROS, on the basis of DCFHDA staining in HEI-OC1 cells. JC-1 and MitoTracker Green staining suggested that ATX-LPN successfully reversed the decrease in mitochondrial membrane potential induced by cisplatin in vitro and rescued cells from early stages of apoptosis, as demonstrated by FACS stained with Annexin V-FITC/PI. Moreover, ATX-LPN successfully attenuated OHC losses in cultured organ of Corti and animal models (zebrafish and guinea pigs) in vivo. In investigating the protective mechanism of ATX-LPN, we found that ATX-LPN decreased the expression of pro-apoptotic proteins (caspase 3/9 and cytochrome-c) and increased expression of the anti-apoptotic protein Bcl-2. In addition, the activation of JNK induced by CDDP was up-regulated and then decreased after the administration of ATX-LPN, while P38 stayed unchanged.ConclusionsTo best of our knowledge, this is first study concluded that ATX-LPN as a new therapeutic agent for the prevention of cisplatin-induced ototoxicity.
Highlights
Ototoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy
The present study aimed to evaluate the protective effect of ATX against CDDP-induced ototoxicity in the House Ear Instituteorgan of Corti 1 (HEI-OC1) cell line, zebrafish, and guinea pigs, and to explore the underlying molecular mechanisms
To overcome the limitations associated with the inner ear application of ATX noted above, we developed a formulation of lipid-polymer nanoparticle (LPN) carriers to protect ATX’s antioxidant activity and allow for both homogenous dispersion in aqueous solution and strong interactions with hair cells via electrostatic effects
Summary
Ototoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy. No FDA approved agents to alleviate or prevent this ototoxicity are available. Astaxanthin (ATX) is an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies, owing to its unique antioxidant capacity. CDDP treatment is associated with a high incidence of severe ototoxicity. CDDP-induced ototoxicity in children ranges from 22 to 77% [2], among which 63%–77% of children experience permanent sensorineural hearing loss [3, 4]. Children are at greater risk of CDDP-induced ototoxicity than adults, resulting in severe negative consequences in their neurocognitive ability and psychosocial development [5]. Exploring new agents or strategies to combat the ototoxicity induced by CDDP is crucial
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