Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats.
Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats.
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DOI：
10.1038/sj.bjc.6602772
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发表时间：
2005-09-19
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
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尽管顺铂（CDDP）的临床有用性，但由于其肾毒性和神经毒性，在许多情况下难以继续施用CDDP。我们研究了将CDDP掺入聚合物胶束中，以观察这是否允许解决这些缺点。顺铂通过聚乙二醇聚谷氨酸嵌段共聚物和CDDP（NC-6004）之间形成聚合物-金属络合物而被掺入聚合物胶束中。在大鼠或小鼠中进行了CDDP和NC-6004的药代动力学、药效学和毒性研究。NC-6004的粒径约为30 nm，具有窄的粒径分布。在大鼠中，NC-6004的曲线下面积和全身清除率值是CDDP值的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倾向于显示出抗肿瘤活性，其与CDDP相当或更高。组织学和生物化学研究表明，NC-6004可显著抑制顺铂的肾毒性。另一方面，血液生化显示在NC-6004给药后第7天出现一过性肝毒性。此外，与给予NC-6004的大鼠相比，给予CDDP的大鼠在其后爪中显示出感觉神经传导速度的显著延迟（P<0.05）。给予CDDP的大鼠的电子显微镜检查显示坐骨神经变性，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当给予NC-6004时，铂在神经组织中的蓄积显著减少（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，因此似乎表明NC-6004可以允许长期给予CDDP，其中必须注意肝功能障碍。
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.
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影响因子：
8.8
作者：
通讯作者：
--
影响因子：
45.3
作者：
GREGG, RW;MOLEPO, JM;STEWART, DJ
通讯作者：
STEWART, DJ
影响因子：
10.3
作者：
du Bois, A;Lück, HJ;Pfisterer, J
通讯作者：
Pfisterer, J
影响因子：
8.8
作者：
Screnci D;McKeage MJ;Galettis P;Hambley TW;Palmer BD;Baguley BC
通讯作者：
Baguley BC
DOI：
10.1016/0277-5379(82)90116-x
发表时间：
1982-01-01
期刊：
EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY
影响因子：
--
作者：
LEVI, FA;HRUSHESKY, WJM;KENNEDY, BJ
通讯作者：
KENNEDY, BJ