A novel nanodialysis platform for inner ear detoxification

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Despite being the first-line therapy for many types of cancer, Cisplatin can alter the course of chemotherapy through ototoxicity as well as decrease a patient's quality of life. Cisplatin-induced ototoxicity represents an important challenge to patient care because of the lack of effective treatment. Based on extensive studies in our laboratory, the Principle Investigator (PI) has developed a stable, safe, regulated, and controllable hydrogel-based delivery system of drugs, biomaterials, or nanoparticles to the inner ear from the middle ear. The application is performed simply by applying a hydrogel on the round window membrane (RWM) with a flexible otoscope in the outpatient setting. This platform also has the advantage of an enzymatic “off-switch,” which allows for controlled degradation of the hydrogel and rapid cessation of payload delivery to the inner ear. Magnetic nanoparticles (NPs) composed of superparamagnetic iron oxide (SPIO) have been widely used for many biomedical applications. These SPIO NPs (SPIONs) are typically encased in biocompatible coatings, such as polymers or lipids, which increase retention time of the particle within the organism and allow for surface functionalization. The resulting “MultiFunctional NanoParticles (MFNPs)” can be conjugated to a multitude of targeting ligands (forming targeted (t)MFNPs) to sequester any number of identified toxins. The proposed study is to develop an inner ear nanodialysis detoxification platform for drug-induced ototoxicity. Synthesized glutathione-conjugated tMFNPs (G-tMFNPs) are capable of binding with cisplatin. During the detoxification process, G-tMFNPs will be noninvasively delivered to the inner ear through the RWM by a chitosan glycerophosphate (CGP) hydrogel system. With a rotatory magnetic device (RMD), these G- tMFNP will then be distributed from the base to the apex of the entire cochlea consequently sequestering cisplatin in the perilymph and endolymph. Once cisplatin has entered the inner ear, G-tMFNAs will bind to cisplatin and form G-tMFNP-cisplatin complexes; The G-tMFNP-cisplatin complexes will be safely removed from the inner ear by RMD and external magnet application. Furthermore, this proposed system is modular and easily modifiable; therefore, it can be used for the elimination of a variety of ototoxic agents. The proposed study will be evaluated in an animal model with cisplatin-induced ototoxicity in clinical settings. The PI believes that the proposed inner ear nanodialysis system, to our knowledge, is the first system that serves as a platform for detoxification in cisplatin-induced ototoxicity. If this innovative system proves effective and safe, it will represent a major breakthrough in the prevention and treatment of drug-induced ototoxicity, where a noninvasive inner ear dialysis system is desperately needed.