Marked antitumor activity of NK012, 7-ethyl-10-hydroxycamptothecin-incorporating micellar nanoparticle, in liver metastatic tumor model of colorectal cancer Free

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Background: NK012 is a micellar-forming nanoparticle of 7-ethyl-10-hydroxycamptothecin (EHC or SN-38), an active metabolite of irinotecan hydrochloride (CPT-11), and gradually releases EHC in enzyme-independent manner at physiological pH. We reported that NK012 maintained high EHC concentrations in tumor tissue for more than 7 days after intravenous administration and exerted superior antitumor activity to CPT-11 against various subcutaneously transplanted solid tumors in rodents (2006 AACR Annual Meeting, #3062). Here, we further evaluated the efficacy of NK012 in liver metastatic model of mouse colon cancer. In addition, the difference of the distribution of NK012 and CPT-11 in metastatic liver tissue was visually demonstrated.

Methods: A suspension of 10⁵ cells of Colon 26-L5 (a liver metastatic variant of mouse colon adenocarcinoma Colon 26) was injected via portal vein of anesthetized BALB/c female mice at Day 0. When the metastases were established (Day 5), maximal tolerated dose of NK012 (30 mg/kg/day) or CPT-11 (66.7 mg/kg/day) was administered intravenously by the optimal schedule (q4dx3). On the eighteenth day, liver weight of each mouse was recorded, and growth inhibition of metastatic tumor was estimated. Cell proliferation of liver metastatic tumor was microscopically evaluated by immunohistochemical staining of Ki-67.

Results: NK012 exhibited marked inhibition (96%) of liver metastatic weight of Colon 26-L5, whereas CPT-11 showed moderate growth inhibition (39%). Cell proliferation index of remained region of tumor estimated by Ki-67 immunostaining was much lower in NK012-treated group (26%) than CPT-11-treated (52%) or control group (43%). Distribution of NK012 and CPT-11 in tumor tissue was compared by observing fluorescence of each drug with a fluorescence microscope. Micellar NK012 clearly distributed in tumor tissue and retained for a long period (> 2 days). On the contrary, CPT-11 disappeared rapidly from tumor tissue and could not be detected after 24 hours of administration.

Conclusion: NK012 showed superior antitumor activity to CPT-11 in the liver metastatic tumor model of colon cancer. The improvement of efficacy was accounted for by the sustained exposure time and concentration of EHC released from the micellar NK012, which specifically accumulated in tumor tissue due to leakiness of tumor blood vessel to nano-size molecules. NK012 has potential usefulness for treating patients with liver metastasis of colon cancer. The phase I study of NK012 starts soon in the United States.