Detailed distribution of NK012, an SN-38-incorporating micelle, in the liver and its potent antitumor effects in mice bearing liver metastases.

Abstract

PURPOSE:

To clarify and compare the antitumor effects and specific biodistribution of NK012, an SN-38-incorporating polymeric micelle, in mice bearing multiple liver metastases of human colon cancer HT-29 cells with irinotecan hydrochloride (CPT-11).

EXPERIMENTAL DESIGN:

The maximum tolerable dose of NK012 (30 mg/kg) or CPT-11 (66.7 mg/kg) was i.v. administered three times every 4 days to mice bearing metastases to the liver colonized 7 days after the portal administration of HT-29 cells (n = 6). In vivo antitumor effects were evaluated by bioluminescence imaging and histopathologic examination. Drug biodistribution was analyzed by high-performance liquid chromatography and fluorescence microscopy (n = 3).

RESULTS:

NK012 eradicated the liver metastases and produced a significant longer survival rate than CPT-11 (P = 0.0006). High-performance liquid chromatography showed the prolonged distribution of NK012 and free SN-38 released from NK012 in the tumors, liver, and spleen for weeks after NK012 administration. On the other hand, the accumulation levels of CPT-11 and free SN-38 converted from CPT-11 rapidly decreased within 1 day after CPT-11 administration. In the liver metastases, fluorescence microscopy and immunohistochemistry showed that administered NK012 was distributed mainly adjacent to tumor vessels after 1 day. As for the normal liver, NK012 was distributed in Kupffer cells instead of hepatocytes for at least 7 days after administration.

CONCLUSION:

This study suggests that NK012 is strongly effective against liver metastases and does not damage the liver despite the long retention time of NK012 in Kupffer cells.

• Authors: Amane Takahashi, Nobuhiro Ohkohchi, Masahiro Yasunaga, Jun-Ichiro Kuroda, Yoshikatsu Koga, Hirotsugu Kenmotsu, Taira Kinoshita, Yasuhiro Matsumura
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 19 Pg. 4822-31 (Oct 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20807756 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Antineoplastic Agents
• Micelles
• Irinotecan
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology)
• Cell Proliferation (drug effects)
• Chromatography, High Pressure Liquid
• Colonic Neoplasms (pathology)
• Disease Models, Animal
• Humans
• Irinotecan
• Kaplan-Meier Estimate
• Liver (drug effects, metabolism, pathology)
• Liver Neoplasms, Experimental (drug therapy, metabolism, pathology, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Micelles
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays