Cabral Horacio, Nishiyama Nobuhiro, Kataoka Kazunori
Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
J Control Release. 2007 Aug 28;121(3):146-55. doi: 10.1016/j.jconrel.2007.05.024. Epub 2007 May 29.
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.
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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