Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

Area of Science:

• Ototoxicology
• Cancer Therapeutics
• Preclinical Models

Background:

• Cisplatin is a vital chemotherapy drug but causes significant ototoxicity, leading to hearing loss in cancer survivors.
• Current preclinical models using systemic cisplatin delivery exhibit high morbidity and mortality, raising animal welfare concerns and increasing animal usage.
• Developing a more humane and reliable animal model for cisplatin ototoxicity is crucial for understanding and mitigating this adverse effect.

Purpose of the Study:

• To develop and validate a novel local delivery model for cisplatin ototoxicity in rodents.
• To compare the efficacy and safety of local versus systemic cisplatin delivery in inducing hearing loss.
• To establish a more ethical and efficient preclinical model for studying cisplatin-induced hearing loss.

Main Methods:

• A local delivery model was created by applying cisplatin solution directly into the otic bulla via a retroauricular approach in mice.
• Hearing loss was assessed by measuring auditory threshold shifts at various frequencies.
• Systemic cisplatin delivery was administered intraperitoneally as a control group.
• Platinum concentrations in cochlea, liver, and kidney were measured using mass spectrometry.
• Cochlear hair cell, neuron, and synapse loss were evaluated using immunohistochemistry.

Main Results:

• Local cisplatin delivery reliably induced significant hearing loss (10–30 dB shift), particularly at high frequencies (22 and 32 kHz).
• Mice in the local delivery group showed no significant morbidity or distress, unlike the systemic group which experienced severe weight loss and premature experiment termination.
• Mass spectrometry confirmed platinum accumulation was restricted to the cochlea in the local delivery group, with minimal systemic uptake.
• A strong correlation was observed between cochlear platinum concentration and the degree of hearing loss.
• Significant loss of outer hair cells, auditory neurons, and synapses was confirmed in the cochlea following local cisplatin delivery.

Conclusions:

• Local cisplatin delivery provides a robust and reliable method for inducing ototoxicity in a rodent model.
• This novel model demonstrates significantly improved animal welfare and reduced animal numbers compared to traditional systemic delivery methods.
• The local delivery model accurately mimics human cisplatin-induced hearing loss, offering a valuable tool for future research and therapeutic development.