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负载(1,2-二氨基环己烷)铂(II)的聚合物胶束的优化,旨在改善肿瘤靶向性并增强抗肿瘤活性。

Optimization of (1,2-diamino-cyclohexane)platinum(II)-loaded polymeric micelles directed to improved tumor targeting and enhanced antitumor activity.

作者信息

Cabral Horacio, Nishiyama Nobuhiro, Kataoka Kazunori

机构信息

Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

出版信息

J Control Release. 2007 Aug 28;121(3):146-55. doi: 10.1016/j.jconrel.2007.05.024. Epub 2007 May 29.


DOI:10.1016/j.jconrel.2007.05.024
PMID:17628162
Abstract

Polymeric micelles are promising nanocarriers, which might enhance the efficacy of antitumor drugs. Herein, polymeric micelles incorporating dichloro(1,2-diamino-cyclohexane)platinum(II) (DACHPt), the oxaliplatin parent complex, were prepared through the polymer-metal complex formation of DACHPt with poly(ethylene glycol)-b-poly(glutamic acid) [PEG-b-P(Glu)] block copolymer having different lengths of the poly(glutamic acid) block [p(Glu): 20, 40, and 70 U]. The resulting micelles were studied with the aim of optimizing the system's biological performance. DACHPt-loaded micelles (DACHPt/m) were approximately 40 nm in diameter and had a narrow size distribution. In vivo biodistribution and antitumor activity experiments (CDF1 mice bearing the murine colon adenocarcinoma C-26 inoculated subcutaneously) showed 20-fold greater accumulation of DACHPt/m at the tumor site than free oxaliplatin to achieve substantially higher antitumor efficacy. Moreover, the micelles prepared from PEG-b-P(Glu) with 20 U of P(Glu) exhibited the lowest non-specific accumulation in the liver and spleen to critically reduce non-specific accumulation, resulting in higher specificity to solid tumors. The antitumor effect of DACHPt/m was also evaluated on multiple metastases generated from intraperitoneally injected bioluminescent HeLa (HeLa-Luc) cells. The in vivo bioluminescent data indicated that DACHPt/m decreased the signal 10-to 50-fold compared to the control indicating a very strong antitumor activity. These results suggest that DACHPt/m could be an outstanding drug delivery system for oxaliplatin in the treatment of solid tumors.

摘要

聚合物胶束是很有前景的纳米载体,可能会提高抗肿瘤药物的疗效。在此,通过二氯(1,2 - 二氨基环己烷)铂(II)(DACHPt),即奥沙利铂的母体配合物,与具有不同聚谷氨酸嵌段长度(聚谷氨酸:20、40和70个单元)的聚(乙二醇)-b-聚(谷氨酸)[PEG-b-P(Glu)]嵌段共聚物形成聚合物 - 金属配合物,制备了包含DACHPt的聚合物胶束。对所得胶束进行了研究,目的是优化该系统的生物学性能。负载DACHPt的胶束(DACHPt/m)直径约为40 nm,粒径分布窄。体内生物分布和抗肿瘤活性实验(对皮下接种小鼠结肠腺癌C - 26的CDF1小鼠)表明,DACHPt/m在肿瘤部位的蓄积量比游离奥沙利铂高20倍,从而实现了显著更高 的抗肿瘤疗效。此外,由具有20个单元聚谷氨酸的PEG-b-P(Glu)制备的胶束在肝脏和脾脏中的非特异性蓄积最低,从而显著降低了非特异性蓄积,提高了对实体瘤的特异性。还对腹腔注射生物发光的HeLa(HeLa-Luc)细胞产生的多处转移灶评估了DACHPt/m的抗肿瘤作用。体内生物发光数据表明,与对照组相比,DACHPt/m使信号降低了10至50倍,表明其具有非常强的抗肿瘤活性。这些结果表明,DACHPt/m可能是用于治疗实体瘤的奥沙利铂的出色药物递送系统。

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