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Injectable dexamethasone-loaded peptide hydrogel for therapy of radiation-induced ototoxicity by regulating the mTOR
Jingyu Liu1, Lisheng Zhu2, Yuqing Bao1
1Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China.
Abstract:
Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA32-HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway.
Insights
A novel injectable hydrogel, RHD, delivers dexamethasone to protect against radiation-induced ototoxicity. This therapy preserves hair cells and auditory function by reducing inflammation and oxidative stress.
Area of Science:
- Biomaterials Science
- Otolaryngology
- Radiology
Background:
- Radiation therapy can cause ototoxicity, leading to hearing loss.
- Inner ear anatomical barriers and drug instability limit current treatments.
- There is a need for effective strategies to prevent radiation-induced hearing loss.
Purpose of the Study:
- To develop and evaluate an injectable hydrogel (RHD) for localized, sustained dexamethasone delivery.
- To assess the protective effects of RHD against radiation-induced ototoxicity in vitro and in vivo.
- To investigate the underlying mechanisms of RHD's therapeutic action.
Main Methods:
- Development of RADA32-HRN-dexamethasone (RHD) injectable hydrogel.
- In vitro studies using hair cell cultures and flow cytometry.
- In vivo studies using a mouse model of radiation-induced ototoxicity.
- Assessment of inflammation, reactive oxygen species, mitochondrial function, apoptosis, DNA damage, and auditory function.
- Analysis of mammalian target of rapamycin (mTOR) signaling pathway activity.
Main Results:
- RHD hydrogel demonstrated controlled and sustained release of dexamethasone.
- RHD gel protected hair cells from radiation-induced damage, reducing inflammation and oxidative stress.
- RHD treatment attenuated apoptosis and DNA damage, and improved mitochondrial function.
- Outer hair cell recovery and partial restoration of auditory function were observed in RHD-treated mice.
- RHD enhanced mTOR pathway activity, promoting hair cell survival.
- Intratympanic injection of RHD showed good biosafety and did not impede radiotherapy's anti-tumor effects.
Conclusions:
- Injectable RHD hydrogel is a promising therapeutic for radiation-induced hearing loss.
- RHD effectively mitigates ototoxicity by targeting inflammation, oxidative stress, and apoptosis via the mTOR pathway.
- RHD offers a safe and localized treatment strategy without compromising radiotherapy efficacy.
