Astaxanthin-loaded polymer-lipid hybrid nanoparticles (ATX-LPN) Assessment of potential otoprotective effects

Abstract

Background Ototoxicity 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 Results In 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. Conclusions To best of our knowledge, this is first study concluded that ATX-LPN as a new therapeutic agent for the prevention of cisplatin-induced ototoxicity.

Use of zebrafish larvae lateral line to study protection against cisplatin-induced ototoxicity: A scoping review

“…Several studies have reported that mechanotransducer (MET) channels mediate the entry of cisplatin into cochlear hair cells, but it remains unclear whether MET channels are blocked during that process. 30,46,53 A study using larval zebrafish confirmed that cisplatin-induced damage to the hair cells relies on functional MET channels. 19 Furthermore, the effect of platinum (II) complexes on adult zebrafish auditory system suggested that cisplatin, and to a limited extent phenanthriplatin, can induce hair cells loss in particular regions of the saccule but not the utricle, 56 suggesting either various regional susceptibility to cisplatin or its distinct diffusion or transport pattern.…”

“…Overproduction of ROS can activate the signal transducer and activator of transcription 1 (STAT1), inducing the inflammation. 46 Previous studies have shown that ROS might induce autophagy, which, depending on the stimulation context, can promote either cell survival or lead to cell death. 54,55 The critical step responsible for the ototoxic properties of cisplatin is its transport inside the sensory cell.…”

“…28,31 The third otoprotective strategy involves blocking the entry of toxic substances into the inner ear and, in particular, into hair cells. 31,46 Lateral line hair cells share mechanisms of mechanotransduction (MET) with hair cells of the inner ear. 19 Data in the literature suggest that blocking MET channel prevents the intracellular accumulation of cisplatin.…”