title: Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity.
abstract: 7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0-24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0-24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Piao
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Food Science, Shenyang Normal University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Jinwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D048271:Chitosan / Q000737:chemistry; D000077146:Irinotecan; D046911:Macromolecular Substances / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010316:Particle Size; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D046911:Macromolecular Substances; D008823:Micelles; D011355:Prodrugs; D000077146:Irinotecan; D048271:Chitosan; D002166:Camptothecin
keywords: in vitro cytotoxicity; in vivo antitumor activity; pharmacokinetics; self-assembled prodrug micelles
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