Bioadhesive drug-loaded microparticles prolong drug retention in the middle ear and ameliorate cisplatin-induced hearing loss
Zhibin Zhou, Xue Bai, Zhi-Yong Zhou, Ziyue Lin, Bing Liao, Fei Gong, Mei-Qun Wang, Xu-Bo Chen, Yuehui Liu, Hongping Chen, Kai Xu
Abstract
Hearing loss represents a common adverse effect following platinum-based chemotherapy regimens. The therapeutic management of inner ear diseases is significantly constrained by the blood-labyrinth barrier, which restricts the penetration of drug molecules into the endolymphatic, thereby limiting their therapeutic efficacy. Local drug delivery has emerged as a safe and effective method for the treatment of inner ear diseases. Nevertheless, the suboptimal retention duration of therapeutic agents within the middle ear substantially compromises drug delivery efficiency. To overcome this limitation, we designed and synthesized a methacrylate-gelatin microsphere (GH) conjugate polydopamine (PDA) layer (GH@PDA) with excellent adhesion ability. This engineered platform demonstrates rapid loading kinetics for bioactive molecules, enabling precise localized delivery of therapeutic payloads. Based on our findings that calcium overload and ROS accumulation are important mechanisms for cisplatin-induced hearing loss, we functionalized GH@PDA with both the nitric oxide (NO) precursor L-arginine and calmodulin-dependent kinase II inhibitor KN93 to construct the multifunctional composite GH@PDA@LK. In vivo imaging analyses revealed that the GH@PDA can prolong the retention of the middle ear and significantly increase the drug uptake concentration of the inner ear. Notably, intratympanic administration of GH@PDA@LK conferred robust protection against cisplatin-induced auditory threshold shifts and reduced outer hair cell loss in rat models. These findings collectively demonstrate that injectable GH@PDA microspheres constitute a clinically translatable platform for inner ear drug delivery. More importantly, our work establishes a novel mechanistically grounded therapeutic paradigm for preventing chemotherapy-induced ototoxicity through dual-pathway modulation of calcium signaling and oxidative stress. • Construction of a microfluidic hydrogel microsphere delivery system for minimally invasive intratympanic administration. • Co-delivery of NO precursor L-arginine and small molecule inhibitor KN93 to achieve intracellular ROS clearance and inhibition of calcium overload pathways. • Dual drug delivery for the treatment of cisplatin-induced hearing loss model across across the round window membrane.