RESUMO
Multidrug combination therapy in the inner ear faces diverse challenges due to the distinct physicochemical properties of drugs and the difficulties of overcoming the oto-biologic barrier. Although nanomedicine platforms offer potential solutions to multidrug delivery, the access of drugs to the inner ear remains limited. Micro/nanomachines, capable of delivering cargo actively, are promising tools for overcoming bio-barriers. Herein, a novel microrobot-based strategy to penetrate the round window membrane (RWM) is presented and multidrug in on-demand manner is delivered. The tube-type microrobot (TTMR) is constructed using the template-assisted layer-by-layer (LbL) assembly of chitosan/ferroferric oxide/silicon dioxide (CS/Fe3O4/SiO2) and loaded with anti-ototoxic drugs (curcumin, CUR and tanshinone IIA, TSA) and perfluorohexane (PFH). Fe3O4 provides magnetic actuation, while PFH ensures acoustic propulsion. Upon ultrasound stimulation, the vaporization of PFH enables a microshotgun-like behavior, propelling the drugs through barriers and driving them into the inner ear. Notably, the proportion of drugs entering the inner ear can be precisely controlled by varying the feeding ratios. Furthermore, in vivo studies demonstrate that the drug-loaded microrobot exhibits superior protective effects and excellent biosafety toward cisplatin (CDDP)-induced hearing loss. Overall, the microrobot-based strategy provides a promising direction for on-demand multidrug delivery for ear diseases.
RESUMO
Hearing loss is mainly due to outer hair cell (OHC) damage in three cochlear turns. Local administration via the round window membrane (RWM) has considerable otological clinical potential in bypassing the blood-labyrinth barrier. However, insufficient drug distribution in the apical and middle cochlear turns results in unsatisfactory efficacy. We functionalized poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) with targeting peptide A665, which specifically bound to prestin, a protein uniquely expressed in OHCs. The modification facilitated the cellular uptake and RWM permeability of NPs. Notably, the guide of A665 towards OHCs enabled more NPs perfusion in the apical and middle cochlear turns without decreasing accumulation in the basal cochlear turn. Subsequently, curcumin (CUR), an appealing anti-ototoxic drug, was encapsulated in NPs. In aminoglycoside-treated guinea pigs with the worst hearing level, CUR/A665-PLGA NPs, with superior performance to CUR/PLGA NPs, almost completely preserved the OHCs in three cochlear turns. The lack of increased low-frequencies hearing thresholds further confirmed that the delivery system with prestin affinity mediated cochlear distribution rearrangement. Good inner ear biocompatibility and little or no embryonic zebrafish toxicity were observed throughout the treatment. Overall, A665-PLGA NPs act as desirable tools with sufficient inner ear delivery for improved efficacy against severe hearing loss.