title: Polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to prevent cisplatin-induced ototoxicity.
abstract: 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 (16mg/kg). The protective agents are based on polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate as anti-inflammarory and anti-apoptotic molecules. Dexamethasone and α-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-1β 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.
  
  
  
  100% of the cancer patients receiving ultra-high doses of CDDP (16mg/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 α-tocopheryl succinate to palliate the cisplatin ototoxicity derived from chemotherapy treatment. These new nanoparticles, that encapsulate, transport, and deliver dexamethasone or α-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.
authors.affiliation: Department of Otorhinolaryngology, Puerta de Hierro Majadahonda University Hospital, C/ Manuel de Falla, 1, 28222 Majadahonda, Spain; Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Martín-Saldaña
authors.affiliation: Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Palao-Suay
authors.affiliation: Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain. Electronic address: mraguilar@ictp.csic.es.
authors.forename: María Rosa
authors.initials: MR
authors.lastname: Aguilar
authors.affiliation: Department of Otorhinolaryngology, Puerta de Hierro Majadahonda University Hospital, C/ Manuel de Falla, 1, 28222 Majadahonda, Spain; Universidad Autónoma de Madrid, Cantoblanco Campus University, 28049 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ramírez-Camacho
authors.affiliation: Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/ Juan de la Cierva, 3, 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: San Román
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000737:chemistry; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003907:Dexamethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008422:Materials Testing; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000893:Anti-Inflammatory Agents; D001672:Biocompatible Materials; D053583:Interleukin-1beta; D003907:Dexamethasone; D020169:Caspases; D024502:alpha-Tocopherol; D002945:Cisplatin
keywords: Cisplatin; Dexamethasone; Nanoparticles; Otoprotection; α-Tocopheryl succinate