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Cisplatin‐induced ototoxicity remains a clinical dilemma with limited mechanistic understanding and no food and drug administration (FDA)‐approved therapies. Despite emerging roles of small extracellular vesicles (sEV) in drug ototoxicity, their molecular cargo profiles and causal roles to cisplatin‐induced ototoxicity are unexplored. This study systematically investigates sEV derived from cochlear explants treated with cisplatin (Cis‐sEV) and controls (Ctrl‐sEV) using multi‐omics profiling. Through small RNA sequencing, 83 differentially expressed microRNAs (miRNAs) are identified in Cis‐sEV compared to Ctrl‐sEV. Notably, mmu‐miR‐34a‐5p, mmu‐miR‐140‐5p, mmu‐miR‐15b‐5p, mmu‐miR‐25‐3p, and mmu‐miR‐339‐5p are significantly upregulation in Cis‐sEVs. Predicted target pathways of these differentially expressed miRNAs are enriched in apoptosis, inflammation, and cellular damage, indicating their potential involvement in cisplatin‐induced cochlear damage. LC‐MS/MS analysis reveals 90 upregulated and 150 downregulated proteins in Cis‐sEV, with many involved in damage response. Specifically, CLTC, CCT2, ANXA6, and HSPA8 are uniquely upregulated proteins in Cis‐sEV, and CLTC and ANXA6 are exclusively co‐localized in hair cells (HCs) post‐cisplatin exposure, suggesting that Cis‐sEV originate primarily from damaged HCs. Moreover, CLTC in sEV may serve as a potential biomarker for cisplatin‐induced ototoxicity as verified in both in vitro and in vivo models. This study provides novel insights into the molecular mechanisms of cisplatin‐induced ototoxicity and identifies potential biomarker and therapeutic targets. Cisplatin causes reactive oxygen species accumulation, leading to apoptosis and inflammation in cochlear hair cells. Small extracellular vesicles primarily derived from the damaged hair cells likely contribute to cisplatin‐induced ototoxicity, carrying a variety of microRNAs and proteins. These differentially expressed components found in these cisplatin‐derived small extracellular vesicles may serve as biomarkers and potential targets for mitigating cochlear damage.

Cisplatin is widely used for the treatment of a number of solid malignant tumors. However, ototoxicity induced by cisplatin is an obstacle to effective treatment of tumors. The basis for this toxicity has not been fully elucidated. It is generally accepted that hearing loss is due to excessive production of reactive oxygen species by cells of the cochlea. In addition, recent data suggest that inflammation may trigger inner ear cell death through endoplasmic reticulum stress, autophagy, and necroptosis, which induce apoptosis. Strategies have been extensively explored by which to prevent, alleviate, and treat cisplatin-induced ototoxicity, which minimize interference with antitumor activity. Of these strategies, none have been approved by the Federal Drug Administration, although several preclinical studies have been promising. This review highlights recent strategies that reduce cisplatin-induced ototoxicity. The focus of this review is to identify candidate agents as novel molecular targets, drug administration routes, delivery systems, and dosage schedules. Animal models of cisplatin ototoxicity are described that have been used to evaluate drug efficacy and side effect prevention. Finally, clinical reports of otoprotection in patients treated with cisplatin are highlighted. For the future, high-quality studies are required to provide reliable data regarding the safety and effectiveness of pharmacological interventions that reduce cisplatin-induced ototoxicity.

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 H 2 O 2 ON/OFF stimulated model. Enhanced release profiles stimulated by H 2 O 2 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. Graphical Abstract

Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from has abundant activity against CIO. In this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin-induced HEI-OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence. It was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy. These findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.

Background Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk. Results We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGS HL ) and a biologically informed PGS for CIO (PGS CIO ). The PGS CIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGS CIO demonstrated superior performance ( P  = 5.54 × 10 − 5 ) relative to PGS HL ( P  = 2.93 × 10 − 3 ). PGS CIO was also associated with CIO in our test cohort ( P  = 0.04), while the PGS HL did not show a significant association with CIO ( P  = 0.52). Conclusion This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

In this study, in order to address the drawback of cisplatin (CDDP)-induced ototoxicity, we propose a straightforward strategy based on the delivery of a sulfur-based antioxidant, such as lipoic acid (LA), to HEI-OC1 cells. To this aim, hybrid liposomes (LA@PCGC) with a spherical shape and a mean diameter of 25 nm were obtained by direct sonication of LA, phosphatidylcholine and a gelatin-curcumin conjugate in a physiological buffer. LA@PCGC were found to be stable over time, were quickly (i.e., by 1 h) taken up by HEI-OC1 cells, and guaranteed strong retention of the bioactive molecule, since LA release was less than 20%, even after 100 h. Cell viability studies showed the efficiency of LA@PCGC for stabilizing the protective activity of LA. Curcumin residues within the functional liposomes were indeed able to maintain the biological activity of LA, significantly improving (up to 2.19-fold) the viability of HEI-OC1 cells treated with 5 μM CDDP. Finally, LA@PCGC was incorporated within an alginate-based injectable hydrogel carrier to create a formulation with physical chemical features suitable for potential ear applications.

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of cisplatin-induced ototoxicity. Whether heat shock pretreatment could be utilized to up-regulate 70 kilodalton heat shock proteins (HSP70) expression in bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (HS-BMSC-Exo) to alleviate cisplatin-induced ototoxicity is deciphered in this study. Heat shock pretreatment was performed on BMSCs to induce HS-BMSC-Exo, which were further trans-tympanically administrated into cisplatin intraperitoneally injected C57BL/6 mice. Auditory brainstem response (ABR) was assessed to indicate auditory sensitivity at 8, 16, 24, and 32 kHz. Myosin 7a staining was utilized to detect the mature hair cells. The relative expressions of the NLRP3 inflammasome complex were determined with Western blot in the cochlea. Diminished auditory sensitivity and increased hair cell loss could be observed in the cisplatin exposed mice with increased content of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, NLRP3, ASC, cleaved caspase-1, and pro-caspase-1, and decreased content of IL-10, which could be reversed by HS-BMSC-Exo or BMSC-Exo administration. It was worth noting that HS-BMSC-Exo demonstrated more treatment benefits than BMSC-Exo in cisplatin-induced ototoxicity. Heat shock precondition may provide a new therapeutic option to produce exosomal HSP70, and HS-BMSC-Exo could be utilized to relieve cisplatin-induced ototoxicity.

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.

Cisplatin-induced hearing loss is experienced by a high percentage of patients with squamous cell carcinoma undergoing cisplatin chemotherapy. A novel nano-construct capable of sequestering extracellular cisplatin was developed to combat this problem. The nano-construct consisted of superparamagnetic iron oxide nanoparticles (SPIONs) entrapped within polymeric micelles, which were formed from a glutathione diethyl ester-conjugated amphiphilic diblock copolymer. The glutathione-micelles were analyzed at the cellular level and in an organotypic study for safety evaluation. All utilized methods indicated that the micelles do not cause cellular toxicity or organ damage. The micelles’ ability to reduce cisplatin-induced cytotoxicity was then probed in an in vitro model. Cisplatin was pre-treated with the novel nano-construct before being added to growing cells. When compared to cells that were exposed to untreated cisplatin, cells in the pre-treated cisplatin group showed a significant increase in cell viability. This clearly demonstrates that the construct is able to protect the cells from cisplatin cytotoxicity and makes it highly likely that the novel nano-construct will be able to play a role in the protection of the inner ear from cisplatin-induced ototoxicity.

Objective To evaluate the efficacy of the otoprotective transtympanic application of N-acetylcysteine in preventing chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy. Data sources PubMed, Scopus, Web of Science, Cochrane Central, and ClinicalTrials.gov were searched for the following concepts: ((“Acetylcysteine” [Mesh]) AND (“Ototoxicity” [Mesh]) AND (“Cisplatin” [Objective: To evaluate the efficacy of otoprotective transtympanic application of N-acetylcysteine in the prevention of chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy. [Mesh]). Study selection Inclusion: randomized controlled trials, Exclusion: (1) case reports or case series; (2) thesis; (3) review articles; (4) conference abstracts; (5) animal studies; (6) non-english studies; (7) studies whose population was other than patients on platinum-based chemotherapy. Data extraction: changes in hearing thresholds measured by pure tone tympanometry, covering high and low frequencies: 250, 500, 1000, 2000, 4000, and 8000 Hz. We used RevMan (Review Manager) version 5.3 to conduct the meta-analysis and GRADE to assess the quality of the evidence. Data synthesis: The literature search yielded 277 unique articles. After reviewing six full-text articles, three RCTs provided data available for meta-analysis. A total of 88 cisplatin-based chemotherapy candidates were included for final analysis. Hearing thresholds showed a significant threshold difference between the ear treated with N-acetylcysteine and the control ear (ear not treated with N-acetylcysteine), especially at high frequencies as high as 8000 Hz (pooled effect size − 10.67, 95% CI [-12.33, -9.02], P  < 0.00001). The data favored the Nac group in all frequencies as well, at 4000 Hz (pooled effect size − 2.13, 95% CI [-3.49, -0.77], P  = 0.002), at 2000 Hz (pooled effect size − 1.38, 95% CI [-2.69, -0.06], P  = 0.04), at 1000 Hz (pooled effect size − 1.58, 95% CI [-2.63, -0.53], P  = 0.003), at 500 Hz (pooled effect size − 1.58, 95% CI [-2.62, -0.54], P  = 0.003), and at the low frequency of 250 after solving the heterogeneity (pooled effect size − 0.96, 95% CI [-2.88, 0.95], P  = 0.32). Conclusions Current data justifies the transtympanic administration of N-acetylcysteine for otoprotection in chemotherapy patients, minimizing the enduring consequences of cisplatin-induced ototoxicity and auditory impairment. Given the results’ emphasis on the Sarafraz et al. (2018) study, more randomized controlled trials are necessary with an expanded sample size and standardization of N-acetylcysteine concentration, study population, and assessed outcomes.