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

• Published in: Journal of controlled release 2012-01, Vol.157 (1), p.112-117
• Main Authors: Baba, Miyuki, Matsumoto, Yu, Kashio, Akinori, Cabral, Horacio, Nishiyama, Nobuhiro, Kataoka, Kazunori, Yamasoba, Tatsuya
• Format: Article
• Language: English
• Subjects: Animals; Auditory brainstem response; Biological and medical sciences; Cisplatin; Cisplatin - administration & dosage; Cisplatin - toxicity; Drug Carriers - administration & dosage; Drug Carriers - toxicity; Evoked Potentials, Auditory, Brain Stem - drug effects; Evoked Potentials, Auditory, Brain Stem - physiology; General pharmacology; Guinea pig; Guinea Pigs; Hair cell; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - pathology; Hair Cells, Auditory - physiology; Male; Medical sciences; Micelles; Nanocapsules - administration & dosage; Nanocapsules - toxicity; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - toxicity; Ototoxicity; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyglutamic Acid - administration & dosage; Polyglutamic Acid - analogs & derivatives; Polyglutamic Acid - toxicity; Polymeric micelle
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2011.07.026

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. [Display omitted]