Novel drug delivery approach may protect against cisplatin-related hearing loss
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Key takeaways:
- Cisplatin can permanently damage sensory hair cells in the inner ear and cause hearing loss.
- A novel drug delivery construct may protect the cochlea from cisplatin.
A novel drug delivery construct may protect individuals against cisplatin-induced ototoxicity and associated hearing loss.
The prophylactic intratympanic injection — comprised of hydrogel, nanoparticles and a drug combination — shields the hair cells of the cochlea from cisplatin, according to results of early research.
“The clinical impact is high. There is no drug treatment available for hearing loss,” Vibhuti Agrahari, PhD, assistant professor at University of Oklahoma College of Pharmacy, told Healio. “Cisplatin saves lives. You cannot stop giving cisplatin to the patient, but it comes with this segregation from the environment. Auditory wellness is also important. You have to cope in the environment every day. It creates a lot of stress.”
Background
Cisplatin — a platinum-based chemotherapy drug administered via IV — is used to treat a variety of malignancies, such as head and neck cancer, bladder cancer and cervical cancer. The drug also is used frequently as part of treatment for children with cancer.
As cisplatin makes its way through the body, it can be retained in the inner ear for long periods.
It can damage the hair cells in the cochlea that convert sound waves to mechanical waves, Agrahari said. It also inactivates glutathione enzymes that maintain the inner ear’s microenvironment, causing substantial and progressive hearing deficiencies.
As Healio previously reported, one study showed 78% of cancer survivors who had no hearing issues prior to cisplatin therapy experienced everyday listening problems afterward. Additionally, 54% of participants had clinically significant functional impairment.
Agrahari started studying the subject about 4 years ago. She had previously evaluated diseases in the back of the eye, but later realized that the similar approach can also be used to prevent hearing diseases.
She began investigating and found significant research and treatment gaps in this area.
“It’s really challenging to develop a product targeted for inner ear because of the ear’s anatomy and physiology,” Agrahari said. “It made me think that maybe I am the ‘someone’ who can start looking into it.”
‘Safe and protective environment’
Researchers have not found a way to clear cisplatin from the cochlea.
However, Agrahari and colleagues developed a drug delivery formulation that they believe could shield the inner ear from cisplatin.
It starts with a hydrogel — a fluid at room temperature, as it would be in a syringe, that transforms into a gel due to the body’s temperature.
The hydrogel matrix contains drug-loaded nanoparticles — which carry drugs to safeguard the ear — together.
Once the hydrogel formulation is injected, the nanoparticles carry those drugs to the cochlea through the round window membrane..
The nanoparticles break because of the specific environment of the inner ear once they reach the inner ear, releasing the drugs.
Researchers studied the approaching using calcium channel blockers — because calcium can damage the hair cells — and antioxidants, which preserves the inner ear’s homeostasis.
“When there is a signal from the inner ear that there is imbalance in the microenvironment and the reactive oxygen species (ROS) are generated, that triggers the formulation to release the drug and protect the sensory hair cells of the cochlea,” Agrahari said. “That is the logic behind designing ROS-responsive formulation, particularly nanoparticles.
“Our formulations make a safe and protective environment,” Agrahari added, noting preliminary results show cisplatin does not affect or kill auditory cell lines.
Broader use possible
Agrahari and colleagues continue to evaluate different drug levels in the formulation.
They also are investigating how long the compound will last and how often it would need to be administered to maintain protection.
Ex vivo studies are in progress, and preclinical testing will be initiated in the next year or so to generate in vivo data to support a pilot phase 1 trial in the next few years, Agrahari said.
However, she said she does not want this formulation used strictly with cisplatin. The delivery system could, in theory, be used to protect those in loud environments — such as the aviation industry or music industry — from noise-induced hearing loss, as well.
“The concept is beyond cisplatin-induced ototoxicity,” Agrahari said. “The concept is: How can we protect the sensory hair cells from being damaged? It could be cisplatin-induced ototoxicity, it could be noise-induced [or it could be] age-related hearing loss.”
References:
- Thakur NS, et al. J Control Release. 2024;doi:10.1016/j.jconrel.2024.02.005.
- Thakur NS, et al. J Nanobiotechnology. 2024;doi:10.1186/s12951-024-02686-z.
For more information:
Vibhuti Agrahari, PhD, can be reached at vibhuti-agrahari@ouhsc.edu.
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