title: PEG-b-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53-dependent apoptosis in zebrafish.
abstract: Micro/nanoparticles could cause adverse effects on cardiovascular system and increase the risk for cardiovascular disease-related events. Nanoparticles prepared from poly(ethylene glycol) (PEG)-b-poly(ε-caprolactone) (PCL), namely PEG-b-PCL, a widely studied biodegradable copolymer, are promising carriers for the drug delivery systems. However, it is unknown whether polymeric PEG-b-PCL nano-micelles give rise to potential complications of the cardiovascular system. Zebrafish were used as an in vivo model to evaluate the effects of PEG-b-PCL nano-micelle on cardiovascular development. The results showed that PEG-b-PCL nano-micelle caused embryo mortality as well as embryonic and larval malformations in a dose-dependent manner. To determine PEG-b-PCL nano-micelle effects on embryonic angiogenesis, a critical process in zebrafish cardiovascular development, growth of intersegmental vessels (ISVs) and caudal vessels (CVs) in flk1-GFP transgenic zebrafish embryos using fluorescent stereomicroscopy were examined. The expression of fetal liver kinase 1 (flk1), an angiogenic factor, by real-time quantitative polymerase chain reaction (qPCR) and in situ whole-mount hybridization were also analyzed. PEG-b-PCL nano-micelle decreased growth of ISVs and CVs, as well as reduced flk1 expression in a concentration-dependent manner. Parallel to the inhibitory effects on angiogenesis, PEG-b-PCL nano-micelle exposure upregulated p53 pro-apoptotic pathway and induced cellular apoptosis in angiogenic regions by qPCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay. This study further showed that inhibiting p53 activity, either by pharmacological inhibitor or RNA interference, could abrogate the apoptosis and angiogenic defects caused by PEG-b-PCL nano-micelles, indicating that PEG-b-PCL nano-micelle inhibits angiogenesis by activating p53-mediated apoptosis. This study indicates that polymeric PEG-b-PCL nano-micelle could pose potential hazards to cardiovascular development.
authors.affiliation: Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing.
authors.forename: Haide
authors.initials: H
authors.lastname: Wu
authors.affiliation: College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Chongqing Key Laboratory of Nano/Micro Composite Materials and Devices, School of Metallury and Materials Engineering, Chongqing University of Science and Technology, Chongqing, People's Republic of China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liao
authors.affiliation: Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing.
authors.forename: Guixue
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002208:Caproates / Q000737:chemistry*; D004337:Drug Carriers / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007783:Lactones / Q000737:chemistry*; D008823:Micelles; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D009389:Neovascularization, Pathologic; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish
chemical_list: D002208:Caproates; D004337:Drug Carriers; D007783:Lactones; D008823:Micelles; D011091:Polyesters; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; C121056:caprolactone
keywords: PEG-b-PCL; angiogenesis; apoptosis; cardiovascular diseases; nanoparticles; zebrafish