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


METHODS
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.


CONCLUSIONS
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.
Takahashi
Amane
A
Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Ohkohchi
Nobuhiro
N
Yasunaga
Masahiro
M
Kuroda
Jun-Ichiro
J
Koga
Yoshikatsu
Y
Kenmotsu
Hirotsugu
H
Kinoshita
Taira
T
Matsumura
Yasuhiro
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D008823:Micelles; D000077146:Irinotecan; D002166:Camptothecin