title: Biodegradable polymeric micelles encapsulated JK184 suppress tumor growth through inhibiting Hedgehog signaling pathway.
abstract: JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China. chygong14@163.com xieym@scu.edu.cn.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.forename: Shichang
authors.initials: S
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Senyi
authors.initials: S
authors.lastname: Deng
authors.forename: Linjiang
authors.initials: L
authors.lastname: Song
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Weijun
authors.initials: W
authors.lastname: Su
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xie
authors.forename: Changyang
authors.initials: C
authors.lastname: Gong
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D050997:Nanomedicine / Q000379:methods; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011108:Polymers / Q000737:chemistry; D015398:Signal Transduction; D013844:Thiazoles / Q000008:administration & dosage*; D019076:Transgenes; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D001672:Biocompatible Materials; D053823:Hedgehog Proteins; D006574:Heterocyclic Compounds, 2-Ring; C525593:JK184; D008823:Micelles; D011108:Polymers; D013844:Thiazoles