title: Cyclopamine disrupts tumor extracellular matrix and improves the distribution and efficacy of nanotherapeutics in pancreatic cancer.
abstract: The dense extracellular matrix in pancreatic ductal adenocarcinoma dramatically reduces the penetration and efficacy of nanotherapeutics. Disruption of the tumor extracellular matrix may help improve the distribution and efficacy of nanotherapeutics in pancreatic cancer. In this study, we tested whether cyclopamine, a special inhibitor of the hedgehog signaling pathway with powerful anti-fibrotic activity, could promote the penetration and efficacy of nanotherapeutics in pancreatic cancer. It was shown that cyclopamine disrupted tumor extracellular fibronectins, decompressed tumor blood vessels, and improved tumor perfusion. Furthermore, cyclopamine improved the accumulation and intratumoral distribution of i.v.-administered fluorescence indicator-labeled nanoparticles. Finally, cyclopamine also significantly improved the tumor growth inhibition effect of i.v.-injected nanotherapeutics in pancreatic tumor xenograft mouse models. Thus, cyclopamine may have great potential to improve the therapeutic effects of nanomedicine in patients with pancreatic cancer.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Shen
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: She
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Tuo
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, China. Electronic address: dr_huyu@126.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: zqpang@fudan.edu.cn.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution; D016896:Treatment Outcome; D014704:Veratrum Alkaloids / Q000008:administration & dosage*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014704:Veratrum Alkaloids; D017239:Paclitaxel; C000541:cyclopamine
keywords: Cyclopamine; Hedgehog signaling pathway; Nanotherapeutics; Pancreatic cancer; Tumor extracellular matrix