Dual stimuli-responsive and sustained drug delivery NanoSensoGel formulation for prevention of cisplatin-induced ototoxicity

Abstract

Cisplatin (CisPt)-induced ototoxicity (CIO) is delineated as a consequence of CisPt-induced intracellular generation of reactive oxygen species (ROS) which can be circumvented by Bucillamine (BUC; an antioxidant drug with sulfhydryl groups) and Diltiazem (DLT, L-type calcium channel blocker). However, its effective accumulation in the Organ of Corti and cell cytoplasm is desired. Therefore, a biocompatible BUC- and DLT-nanoparticles (NPs)-impregnated dual stimuli-responsive formulation (NanoSensoGel) presented here with ROS- and thermo-responsive properties for the sustained and receptive delivery of drugs. The ROS-responsive polypropylene sulfide- methyl polyethylene glycol-2000 (PPS-mPEG₂₀₀₀) polymer was rationally designed, synthesized, and characterized to fabricate BUC- and DLT-loaded PPS-mPEG₂₀₀₀-NPs (BUC- and DLT-NPs). The fabricated BUC- and DLT-NPs showed efficient cellular uptake, intracellular delivery, ROS responsiveness, and cytoprotective effect which was characterized using cellular internalization, intracellular ROS, mitochondrial superoxide, and Caspase 3/7 assays on the House Ear Institute-Organ of Corti-1 (HEI-OC1) cells. The composite NanoSensoGel (i.e., ROS-responsive BUC- and DLT-NPs suspended in the thermo-responsive hydrogel) present in a sol state at room temperature and turned to gel above 33°C, which could be essential for retaining the formulation at the target site for long-term release. The NanoSensoGel showed sustained release of BUC and DLT following Fickian release diffusion kinetics. Overall, a novel NanoSensoGel formulation developed in this study has demonstrated its great potential in delivering therapeutics in the inner ear for prophylactic treatment of CIO, and associated hearing loss.

Keywords: Chemotherapy; Hearing loss; Inner ear drug delivery; Long-term release; ROS-responsive nanoparticles; Thermo-responsive hydrogel.