Micellization of cisplatin (NC-6004) reduces its ototoxicity in guinea pigs Miyuki Baba a, b , Yu Matsumoto a, b , Akinori Kashio a , Horacio Cabral c , Nobuhiro Nishiyama b , Kazunori Kataoka b, c, d, e , Tatsuya Yamasoba a, ⁎ a 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 b Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-Ku, Tokyo, 113–8655, Japan c Department of Bioengineering, Graduate School of Engineering, Hongo 7-3-1, Bunkyo-Ku, Tokyo, 113–8655, Japan d Department of Materials Engineering, Graduate School of Engineering, Hongo 7-3-1, Bunkyo-Ku, Tokyo, 113–8655, Japan e Center for NanoBio Integration, University of Tokyo, Hongo 7-3-1, Bunkyo-Ku, Tokyo, 113–8655, Japan abstract article info Article history: Received 3 February 2011 Accepted 17 July 2011 Available online 23 July 2011 Keywords: Auditory brainstem response Cisplatin Guinea pig Hair cell Polymeric micelle Ototoxicity 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 b 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 b 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. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Recently, nanocarrier-mediated drug delivery has received great attention in cancer therapy since nanocarriers carrying chemother- apeutic agents have shown to enhance antitumor activity with reduced side effects [1–4]. The antitumor activity is enhanced because the tumor accumulation is augmented in the nanocarriers via the enhanced permeability and retention (EPR) effect [5], which is based on the following pathophysiological characteristics of solid tumors: hypervascularity, incomplete vascular architecture, secretion of vascular permeability factors stimulating extravasation within the cancer tissue, and the absence of effective lymphatic drainage. However, the reduction or prevention of chemotherapy-induced side effects, especially organ-specific toxicity, by nanocarriers remains to be completely clarified. The mechanisms of nanocarrier-mediated reduction of chemotherapy-induced organ-specific toxicity must be shown to facilitate the translation of nanocarrier formulation into the clinic. Polymeric micelles, which are self-assemblies of block copolymers, have gained increasing popularity as nanocarriers for chemothera- peutic agents since their critical features, including size and drug loading and release, can be modulated by engineering block copolymers. Polymeric micelles carrying chemotherapeutic agents can selectively and effectively accumulate in the solid tumors, thereby leading to enhanced antitumor activity. Currently, our micelle formulations of paclitaxel (PTX), SN-38 (a biologically active metabolite of CPT-11), cisplatin (cis-dichlorodiammineplatinum(II), CDDP), and 1,2-diaminocyclohexane (DACHPt) are being tested in clinical trials. Regarding chemotherapy-induced side effects, polymeric micelles have been revealed to restrain the neurotoxicity of PTX and CDDP [6,7], intestinal toxicity of CPT-11 [8], and the nephrotoxicity of CDDP [7]. CDDP is a common chemotherapeutic agent used to treat many different types of cancer, including lung, gastrointestinal, bladder, and head and neck cancer. The major dose-limiting factors in CDDP therapy is the nephrotoxicity, which can be reversed to some extent by increasing the saline hydration and by using diuretic agents. As aforementioned, micellization of CDDP can prevent the nephrotoxicity, Journal of Controlled Release 157 (2012) 112–117 ⁎ Corresponding author at: Department of Otolaryngology and Head and Neck Surgery, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113–8655, Japan. Tel.: +81 3 5800 8924; fax: +81 3 3814 9486. E-mail address: tyamasoba-tky@umin.ac.jp (T. Yamasoba). 0168-3659/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2011.07.026 Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel NANOMEDICINE