title: Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors.
abstract: 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.
authors.affiliation: Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Takahito
authors.initials: T
authors.lastname: Negishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Onda
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011897:Random Allocation; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D008823:Micelles; D042461:Vascular Endothelial Growth Factor A; D011099:Polyglutamic Acid; D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin