Journal
EUROPEAN JOURNAL OF CANCER
Volume 46, Issue 3, Pages 650-658Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2009.11.014
Keywords
Pancreatic cancer; DDS (drug delivery system); Polymer micelles; NK012
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Funding
- Third Term Comprehensive Control Research for Cancer, the Ministry of Health, Labour and Welfare [H19-025]
- Ministry of Education, Culture, Sports, Science and Technology [17016087]
- Japanese Foundation for Multidisciplinary Treatment of Cancer
- Princess Takamatsu Cancer Research Fund [07-23908]
- Grants-in-Aid for Scientific Research [17016087] Funding Source: KAKEN
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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 (30 mg/kg/d), CPT-11 (66.7 mg/kg/d) and gemcitabine (16.5 mg/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 192 h. On the other hand, SN-38 converted from CPT-11 was detected only 1 h postinjection. Fluorescence from NK012 was detected up to 48 h, whereas that from CPT-11 almost disappeared by 24 h 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. (C) 2009 Elsevier Ltd. All rights reserved.
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