Micellization of cisplatin (NC-6004) reduces its ototoxicity in guinea pigs

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 30 kHz 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. (C) 2011 Elsevier B. V. All rights reserved.