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Novel SN-38–Incorporating Polymeric Micelles, NK012, Eradicate Vascular Endothelial Growth Factor–Secreting Bulky Tumors

¹ Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; ² Pharmaceutical Research Laboratories, Research and Development Group, Nippon Kayaku Co., Ltd, Kita-ku, Tokyo, Japan; and ³ Department of Medicine, National Cancer Center Hospital, Tyuo-ku, Tokyo, Japan

Requests for reprints: Yasuhiro Matsumura, Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. Phone: 81-4-7134-6857; Fax: 81-4-7134-6857; E-mail: yhmatsum{at}east.ncc.go.jp.

7-Ethyl-10-hydroxy-camptothecin (SN-38), a biological active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity but has not been used clinically because it is a water-insoluble drug. For delivery by i.v. injection, we have successfully developed NK012, a SN-38-releasing nanodevice. The purpose of this study is to investigate the pharmacologic character of NK012 as an anticancer agent, especially in a vascular endothelial growth factor (VEGF)–secreting tumor model. The particle size of NK012 was 20 nm with a narrow size distribution. NK012 exhibited a much higher cytotoxic effect against lung and colon cancer cell lines as compared with CPT-11. NK012 showed significantly potent antitumor activity against a human colorectal cancer HT-29 xenograft as compared with CPT-11. Enhanced and prolonged distribution of free SN-38 in the tumor was observed after the injection of NK012. NK012 also had significant antitumor activity against bulky SBC-3/Neo (1,533.1 ± 1,204.7 mm³) and SBC-3/VEGF tumors (1,620.7 ± 834.0 mm³) compared with CPT-11. Furthermore, NK012 eradicated bulky SBC-3/VEGF tumors in all mice but did not eradicate SBC-3/Neo tumors. In the drug distribution analysis, an increased accumulation of SN-38 in SBC-3/VEGF tumors was observed as compared with that in SBC-3/Neo tumors. NK012 markedly enhanced the antitumor activity of SN-38, especially in highly VEGF-secreting tumors, and could be a promising SN-38-based formulation. (Cancer Res 2006; 66(20): 10048-56)

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