Polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to prevent cisplatin-induced ototoxicity

The aim of this work is the development of highly protective agents to be administered locally within the middle ear to avoid cisplatin-induced ototoxicity, which affects to 100% of the clinical patients at ultra-high concentrations (16 mg/kg). The protective agents are based on polymeric nanoparticles loaded with dexamethasone or alpha-tocopheryl succinate as anti-inflammarory and anti-apoptotic molecules. Dexamethasone and alpha-tocopheryl succinate are poorly soluble in water and present severe side effects when systemic administered during long periods of time. Their incorporation in the hydrophobic core of nanoparticles with the appropriate hydrodynamic properties provides the desired effects in vitro (lower cisplatin-induced toxicity, decreasing of caspase 3/7 activity, and lower IL-1 beta release) and in vivo (reducing the hearing loss at the local level). The local administration of the nanoparticles by bullostomy provides an adequate dose of drug without systemic interference with the chemotherapeutic effect of cisplatin. Statement of Significance 100% of the cancer patients receiving ultra-high doses of CDDP (16 mg/kg) suffer severe hearing loss, being a limiting factor in antineoplastic treatments. In this paper we describe the application of polymeric nanoparticles loaded with dexamethasone or alpha-tocopheryl succinate to palliate the cisplatin ototoxicity derived from chemotherapy treatment. These new nanoparticles, that encapsulate, transport, and deliver dexamethasone or alpha-tocopheryl succinate in the middle ear, are able to partially prevent ototoxicity derived from high doses of CDDP. This is an interdisciplinary study in which in vitro and in vivo experiments are described and extensively discussed. The importance of the results opens an excellent opportunity to the translation to the clinic. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.