Bioadhesive drug-loaded microparticles prolong drug retention in the middle ear and ameliorate cisplatin-induced hearing loss

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.

Keywords: Calcium overload; Hearing loss; Local drug delivery; Microgel; Reactive oxygen species.