title: Micellization of cisplatin (NC-6004) reduces its ototoxicity in guinea pigs.
abstract: Nanocarriers potentially reduce or prevent chemotherapy-induced side effects, facilitating the translation of nanocarrier formulation into the clinic. To date, organ-specific toxicity by nanocarriers remains to be clarified. Here, we studied the potential of polymeric micelle nanocarriers to prevent the ototoxicity, which is a common side effect of high-dose cisplatin (CDDP) therapy. In this study, we evaluated the ototoxicity of CDDP-incorporating polymeric micelles (NC-6004) in guinea pigs in comparison with that of cisplatin. Their auditory brainstem responses (ABRs) to 2, 6, 12, 20, and 30kHz sound stimulation were measured before and 5 days after the drug administration. Groups treated with NC-6004 showed no apparent ABR threshold shifts, whereas groups treated with CDDP showed dose-dependent threshold shifts particularly at the higher frequencies. Consistent with the ABR results, groups treated with NC-6004 showed excellent hair-cell preservation, whereas groups treated with CDDP exhibited significant hair-cell loss (P<0.05). Synchrotron radiation-induced X-ray fluorescence spectrometry imaging demonstrated that the platinum distribution and concentration in the organ of Corti were significantly reduced (P<0.01) in guinea pigs treated with NC-6004 compared with guinea pigs treated with CDDP. These findings indicate that micellization of CDDP reduces its ototoxicity by circumventing the vulnerable cells in the inner ear.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Faculty of Medicine, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-Ku, Tokyo, 113-8655, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Baba
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Akinori
authors.initials: A
authors.lastname: Kashio
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004337:Drug Carriers / Q000008:administration & dosage / Q000633:toxicity*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage / Q000633:toxicity; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D004337:Drug Carriers; D008823:Micelles; D053769:Nanocapsules; D009944:Organoplatinum Compounds; D011099:Polyglutamic Acid; C557897:demplatin pegraglumer; D002945:Cisplatin