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.
J Control Release. 2012 Jan 10;157(1):112-7. doi: 10.1016/j.jconrel.2011.07.026. Epub 2011 Jul 23.
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.
纳米载体有可能减轻或预防化疗引起的副作用，促进纳米载体制剂向临床转化。迄今为止，纳米载体的器官特异性毒性仍需阐明。在这里，我们研究了聚合物胶束纳米载体预防耳毒性的潜力，耳毒性是高剂量顺铂（CDDP）治疗的常见副作用。在这项研究中，我们评估了载有 CDDP 的聚合物胶束（NC-6004）在豚鼠中的耳毒性，与顺铂进行了比较。在给药前和给药后 5 天，用它们对 2、6、12、20 和 30kHz 声音刺激的听觉脑干反应（ABR）进行了测量。用 NC-6004 治疗的组没有明显的 ABR 阈值变化，而用 CDDP 治疗的组表现出剂量依赖性的阈值变化，特别是在较高频率。与 ABR 结果一致，用 NC-6004 治疗的组表现出良好的毛细胞保留，而用 CDDP 治疗的组表现出明显的毛细胞损失（P<0.05）。同步辐射诱导的 X 射线荧光光谱成像表明，与用 CDDP 治疗的豚鼠相比，用 NC-6004 治疗的豚鼠耳蜗中铂的分布和浓度显著降低（P<0.01）。这些发现表明，CDDP 的胶束化通过避开内耳中的脆弱细胞来降低其耳毒性。
