Uchino H, Matsumura Y, Negishi T, Koizumi F, Hayashi T, Honda T, Nishiyama N, Kataoka K, Naito S, Kakizoe T
Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Br J Cancer. 2005 Sep 19;93(6):678-87. doi: 10.1038/sj.bjc.6602772.
In spite of the clinical usefulness of cisplatin (CDDP), there are many occasions in which it is difficult to continue the administration of CDDP due to its nephrotoxicity and neurotoxicity. We examined the incorporation of CDDP into polymeric micelles to see if this allowed the resolution of these disadvantages. Cisplatin was incorporated into polymeric micelles through the polymer-metal complex formation between polyethylene glycol poly(glutamic acid) block copolymers and CDDP (NC-6004). The pharmacokinetics, pharmacodynamics, and toxicity studies of CDDP and NC-6004 were conducted in rats or mice. The particle size of NC-6004 was approximately 30 nm, with a narrow size distribution. In rats, the area under the curve and total body clearance values for NC-6004 were 65-fold and one-nineteenth the values for CDDP (P<0.001 and 0.01, respectively). In MKN-45-implanted mice, NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP. Histopathological and biochemical studies revealed that NC-6004 significantly inhibited the nephrotoxicity of CDDP. On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the administration of NC-6004. Furthermore, rats given CDDP showed a significant delay (P<0.05) in sensory nerve conduction velocity in their hind paws as compared with rats given NC-6004. Electron microscopy in rats given CDDP indicated the degeneration of the sciatic nerve, but these findings were not seen in rats given NC-6004. These results were presumably attributable to the significantly reduced accumulation of platinum in nerve tissue when NC-6004 was administered (P<0.05). NC-6004 preserved the antitumour activity of CDDP and reduced its nephrotoxicity and neurotoxicity, which would therefore seem to suggest that NC-6004 could allow the long-term administration of CDDP where caution against hepatic dysfunction must be exercised.
尽管顺铂（CDDP）在临床上具有实用性，但由于其肾毒性和神经毒性，在许多情况下难以继续使用CDDP进行给药。我们研究了将CDDP掺入聚合物胶束中，看这是否能解决这些缺点。通过聚乙二醇聚（谷氨酸）嵌段共聚物与CDDP（NC - 6004）之间形成聚合物 - 金属络合物，将顺铂掺入聚合物胶束中。在大鼠或小鼠中进行了CDDP和NC - 6004的药代动力学、药效学及毒性研究。NC - 6004的粒径约为30nm，粒径分布较窄。在大鼠中，NC - 6004的曲线下面积和全身清除率值分别是CDDP的65倍和十九分之一（分别为P < 0.001和0.01）。在植入MKN - 45的小鼠中，NC - 6004倾向于表现出抗肿瘤活性，与CDDP相当或更强。组织病理学和生化研究表明，NC - 6004显著抑制了CDDP的肾毒性。另一方面，血液生化显示在给予NC - 6004后第7天出现短暂的肝毒性。此外，与给予NC - 6004的大鼠相比，给予CDDP的大鼠后爪感觉神经传导速度显著延迟（P < 0.05）。给予CDDP的大鼠的电子显微镜检查表明坐骨神经发生变性，但在给予NC - 6004的大鼠中未观察到这些发现。这些结果可能归因于给予NC - 6004时铂在神经组织中的积累显著减少（P < 0.05）。NC - 6004保留了CDDP的抗肿瘤活性并降低了其肾毒性和神经毒性，因此这似乎表明在必须注意肝功能障碍的情况下，NC - 6004可以允许长期给予CDDP。
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