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: Qinjie Wu, Guoyou Li, Senyi Deng, Liang Ouyang, Ling Li, Lei Liu, Na Luo, Xiangrong Song, Gu He, Changyang Gong, Yuquan Wei
• Journal: Nanoscale (Nanoscale) Vol. 6 Issue 20 Pg. 11940-52 (Oct 21 2014) ISSN: 2040-3372 [Electronic] England
• PMID: 25175172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biocompatible Materials
• Disulfides
• Hydrogels
• Indole Alkaloids
• Micelles
• Polymers
• Reactive Oxygen Species
• chetomin
• Polyethylene Glycols
• Glutathione

Topics

• Animals
• Animals, Genetically Modified
• Antineoplastic Agents (chemistry)
• Apoptosis
• Biocompatible Materials (chemistry)
• Disease Models, Animal
• Disulfides (chemistry)
• Fermentation
• Glutathione (chemistry)
• Hydrogels (chemistry)
• Indole Alkaloids (chemistry)
• Mice
• Micelles
• Microcirculation
• Models, Molecular
• Molecular Dynamics Simulation
• Neoplasm Metastasis
• Neoplasms (drug therapy)
• Particle Size
• Polyethylene Glycols (chemistry)
• Polymers (chemistry)
• Reactive Oxygen Species (chemistry)
• Temperature
• Zebrafish