title: Synthesis, characterization, and evaluation of mPEG-SN38 and mPEG-PLA-SN38 micelles for cancer therapy.
abstract: 7-Ethyl-10-hydroxy camptothecin (SN38) is a potent topoisomerase inhibitor and a metabolite of irinotecan. Its clinical development has been hampered by its poor solubility. To address this problem, methoxy poly(ethylene glycol)-2000 (mPEG2K)-SN38 and mPEG2K-poly(lactide) (PLA1.5K)-SN38 conjugates were prepared and then dispersed into an aqueous medium to form micelles. Physicochemical characteristics of SN38-polymer conjugate micelles, for example, micelle diameter, zeta potential, morphology, and drug content, were then evaluated. The results showed that the mean diameters of mPEG2K-SN38 and mPEG2K-PLA1.5K-SN38 micelles were ~130 and 20 nm, respectively. These two micelles had similar drug contents. mPEG2K-PLA1.5K-SN38 micelles were more homogeneous than mPEG2K-SN38 micelles. Moreover, in vitro drug release behavior of the micelles was studied by high performance liquid chromatography. SN38 release from mPEG2K-SN38 micelles was much faster than from mPEG2K-PLA1.5K-SN38 micelles. In vitro cytotoxicity, cellular uptake, and apoptosis assays of the SN38-polymer conjugate micelles were carried out on BEL-7402 human liver cancer cells. In vivo biodistribution and antitumor tumor efficacy studies were carried out in a nude mouse xenograft model derived from BEL-7402 cells. The results showed that mPEG2K-PLA1.5K-SN38 micelles were significantly more effective than mPEG2K-SN38 micelles in tumor inhibition, and the inhibitory effect of mPEG2K-PLA1.5K-SN38 micelles on tumor growth was significantly greater than that of mPEG2K-SN38 micelles (1,042 vs 1,837 mm) at 30 days. In conclusion, mPEG-PLA-SN38 is a promising anticancer agent that warrants further investigation.
authors.affiliation: College of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Hangzhou PushiKang Biotechnology Co., Ltd, Hangzhou, People's Republic of China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Teng
authors.affiliation: Hangzhou PushiKang Biotechnology Co., Ltd, Hangzhou, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: College of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Jilin University, Changchun, People's Republic of China; Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: College of Life Sciences, Jilin University, Changchun, People's Republic of China.
authors.forename: Lesheng
authors.initials: L
authors.lastname: Teng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy*; D011091:Polyesters / Q000138:chemical synthesis* / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry*; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011091:Polyesters; C492425:methoxy poly(ethylene glycol)-poly(lactide); D011092:Polyethylene Glycols; D000077146:Irinotecan; D016650:Fluorescein-5-isothiocyanate; D002166:Camptothecin
keywords: SN38; chemotherapy; liver cancer; micelles; polymer conjugate