PMID- 38065412 OWN - NLM STAT- MEDLINE DCOM- 20240131 LR - 20240206 IS - 1873-4995 (Electronic) IS - 0168-3659 (Linking) VI - 365 DP - 2024 Jan TI - Injectable dexamethasone-loaded peptide hydrogel for therapy of radiation-induced ototoxicity by regulating the mTOR signaling pathway. PG - 729-743 LID - S0168-3659(23)00788-5 [pii] LID - 10.1016/j.jconrel.2023.12.004 [doi] AB - 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 RADA(32)-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. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Liu, Jingyu AU - Liu J AD - Cancer 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. FAU - Zhu, Lisheng AU - Zhu L AD - The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China. FAU - Bao, Yuqing AU - Bao Y AD - Cancer 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. FAU - Du, Zhouyuan AU - Du Z AD - Cancer 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. FAU - Shi, Liangliang AU - Shi L AD - Cancer 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. FAU - Hong, Xiaohua AU - Hong X AD - Cancer 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. FAU - Zou, Zhenwei AU - Zou Z AD - Cancer 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. Electronic address: zouzhenwei@hust.edu.cn. FAU - Peng, Gang AU - Peng G AD - Cancer 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. Electronic address: penggang1977@aliyun.com. LA - eng PT - Journal Article DEP - 20231214 PL - Netherlands TA - J Control Release JT - Journal of controlled release : official journal of the Controlled Release Society JID - 8607908 RN - 7S5I7G3JQL (Dexamethasone) RN - 0 (Hydrogels) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Mice MH - Animals MH - *Dexamethasone/pharmacokinetics MH - Hydrogels/chemistry MH - Reactive Oxygen Species MH - *Ototoxicity/drug therapy MH - Signal Transduction MH - TOR Serine-Threonine Kinases MH - Mammals OTO - NOTNLM OT - Dexamethasone OT - Drug delivery OT - Peptide hydrogel OT - Radiation-induced ototoxicity COIS- Declaration of Competing Interest None. EDAT- 2023/12/09 05:43 MHDA- 2024/01/31 06:42 CRDT- 2023/12/08 19:29 PHST- 2023/08/23 00:00 [received] PHST- 2023/11/19 00:00 [revised] PHST- 2023/12/02 00:00 [accepted] PHST- 2024/01/31 06:42 [medline] PHST- 2023/12/09 05:43 [pubmed] PHST- 2023/12/08 19:29 [entrez] AID - S0168-3659(23)00788-5 [pii] AID - 10.1016/j.jconrel.2023.12.004 [doi] PST - ppublish SO - J Control Release. 2024 Jan;365:729-743. doi: 10.1016/j.jconrel.2023.12.004. Epub 2023 Dec 14.