Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 20; pp. 10048 - 10056
• Main Authors: Koizumi, Fumiaki, Kitagawa, Masayuki, Negishi, Takahito, Onda, Takeshi, Matsumoto, Shin-Ichi, Hamaguchi, Tetsuya, Matsumura, Yasuhiro
• Format: Journal Article
• Language: English
• Published: United States 15.10.2006
• Subjects: Animals; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacokinetics; Camptothecin - pharmacology; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - secretion; Colonic Neoplasms - blood; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - secretion; Female; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secretion; Mice; Mice, Inbred BALB C; Micelles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polyglutamic Acid - administration & dosage; Polyglutamic Acid - chemistry; Polyglutamic Acid - pharmacokinetics; Random Allocation; Tissue Distribution; Vascular Endothelial Growth Factor A - secretion; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-1605

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 approximately 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 mm(3)) and SBC-3/VEGF tumors (1,620.7 +/- 834.0 mm(3)) 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.