Antitumour activity of NK012, SN-38-incorporating polymeric micelles, in hypovascular orthotopic pancreatic tumour.
Antitumour activity of NK012, SN-38-incorporating polymeric micelles, in hypovascular orthotopic pancreatic tumour.
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DOI：
10.1016/j.ejca.2009.11.014
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发表时间：
2010-02
影响因子：
8.4
通讯作者：
Yohei Saito;M. Yasunaga;J. Kuroda;Y. Koga;Y. Matsumura
中科院分区：
文献类型：
--
作者：
Yohei Saito;M. Yasunaga;J. Kuroda;Y. Koga;Y. Matsumura
人胰腺癌化疗难治的部分原因是抗癌药物的渗透受阻。这个问题必须考虑到，特别是药物输送系统（DDS）。本研究的目的是研究与吉西他滨和盐酸伊立替康（CPT-11）（7-乙基-10-羟基喜树碱（SN-38）的低分子量前药）相比，NK 012（SN-38掺入聚合物胶束）归类为DDS如何在原位胰腺肿瘤模型中发挥其抗肿瘤作用。将NK 012（30 mg/kg/d）、CPT-11（66.7mg/kg/d）和吉西他滨（16.5mg/kg/d）的最大耐受剂量（MTD）给予原位植入的携带人胰腺癌细胞（SUIT-2）异种移植物的小鼠。评价了这些化合物的抗肿瘤作用。通过荧光显微镜和高效液相色谱法（HPLC）检查肿瘤内的药物分布。与CPT-11和吉西他滨相比，NK 012具有强效的抗肿瘤作用。直至192 h，观察到高浓度的NK 012和从NK 012释放的SN-38。另一方面，仅在注射后1小时检测到CPT-11转化的SN-38。NK 012的荧光在注射后48小时内仍能检测到，而CPT-11的荧光在注射后24小时几乎消失。NK 012似乎对难治性富含基质的原位胰腺肿瘤异种移植物具有强效抗肿瘤活性，因为其充分蓄积，随后SN-38从NK 012中有效缓释。
Human pancreatic cancer is refractory to chemotherapy partly because of blockage to penetration of anticancer agents. This issue must be taken into account particularly for the drug delivery system (DDS). The aim of the present study is to investigate how NK012 (SN-38-incorporating polymeric micelles) categorised as DDS exerts its antitumour effect in an orthotopic pancreatic tumour model compared with gemcitabine and irinotecan hydrochloride (CPT-11), a low-molecular-weight prodrug of a 7-ethyl-10-hydroxy-camptothecin (SN-38). The maximum tolerated doses (MTDs) of NK012 (30mg/kg/d), CPT-11 (66.7mg/kg/d) and gemcitabine (16.5mg/kg/d) were administered to mice bearing human pancreatic cancer cell (SUIT-2) xenografts implanted orthotopically. Antitumour effects of these compounds were evaluated. Drug distribution within the tumour was examined by fluorescence microscopy and high performance liquid chromatography (HPLC). NK012 exerted potent antitumour effects compared with CPT-11 and gemcitabine. A high concentration of NK012 and SN-38 released from NK012 had been observed until 192h. On the other hand, SN-38 converted from CPT-11 was detected only 1h postinjection. Fluorescence from NK012 was detected up to 48h, whereas that from CPT-11 almost disappeared by 24h postinjection. NK012 appeared to exert potent antitumour activity against intractable stroma-rich orthotopic pancreatic tumour xenografts due to its sufficient accumulation followed by the effective sustained release of SN-38 from NK012.