title: Enhanced antitumor activity and mechanism of biodegradable polymeric micelles-encapsulated chetomin in both transgenic zebrafish and mouse models.
abstract: Chetomin is a promising molecule with anti-tumor activities in the epipolythiodioxopiperazine family of fungal secondary metabolites; however, strong hydrophobicity has limited its further applications. In this work, chetomin was encapsulated into polymeric micelles to obtain an aqueous formulation, and the chetomin loaded micelles (Che-M) exhibited small particle size and high encapsulation efficiency. When the concentration of copolymer was higher than the critical gelation concentration, the Che-M could form a thermosensitive hydrogel (Che-H), which was free-flowing sol at ambient temperature and converted into a non-flowing gel at body temperature. The molecular modeling study has indicated that chetomin interacted with PCL as a core, which was embraced by PEG as a shell. Che-M showed equal cytotoxicity with free chetomin, but the apoptosis inducing effects of Che-M were more significant. Besides, Che-M could increase the GSSG level, decrease the GSH level, and increase the ROS in CT26 cells. Furthermore, stronger inhibitory effects of Che-M were observed on embryonic angiogenesis, tumor-induced angiogenesis and tumor growth in transgenic zebrafish models. In addition, Che-M was effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT26 tumor model. In a colorectal peritoneal carcinomatosis model, both Che-M and Che-H showed excellent therapeutic effects, but Che-H was more effective. In conclusion, Che-M and Che-H may serve as candidates for cancer therapy.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. chygong14@163.com heguscu@163.com.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Wu
authors.forename: Guoyou
authors.initials: G
authors.lastname: Li
authors.forename: Senyi
authors.initials: S
authors.lastname: Deng
authors.forename: Liang
authors.initials: L
authors.lastname: Ouyang
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Song
authors.forename: Gu
authors.initials: G
authors.lastname: He
authors.forename: Changyang
authors.initials: C
authors.lastname: Gong
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry*; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry*; D005285:Fermentation; D005978:Glutathione / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry; D026121:Indole Alkaloids / Q000737:chemistry*; D051379:Mice; D008823:Micelles; D008833:Microcirculation; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000737:chemistry; D013696:Temperature; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004220:Disulfides; D020100:Hydrogels; D026121:Indole Alkaloids; D008823:Micelles; D011108:Polymers; D017382:Reactive Oxygen Species; C001598:chetomin; D011092:Polyethylene Glycols; D005978:Glutathione