title: Repair of spinal cord injury by inhibition of astrocyte growth and inflammatory factor synthesis through local delivery of flavopiridol in PLGA nanoparticles.
abstract: The cell-cycle inhibitor flavopiridol has been shown to improve recovery from spinal cord injury in animal models. However, the systemic dose of flavopiridol has side-effects and the mechanism of action is not clear. This study aimed to develop a strategy for the local delivery of flavopiridol and investigate its mechanisms of action. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used for the sustained delivery of flavopiridol. The spinal cord was right-hemisectioned and NPs were delivered into the injury site. Transparent spinal cord technology was used for the three-dimensional observation of anterograde tracing. The results showed that flavopiridol NPs had a sustained release of up to 3 days in vitro. Flavopiridol NPs significantly decreased inflammatory factor synthesis by astrocytes, including TNF-α, IL-1β, and IL-6, while the IL-10 expression was elevated. In vivo study demonstrated that flavopiridol NPs decreased cell-cycle activation, inflammatory expression and glial scarring, and facilitated neuronal survival and regeneration. The cavitation volume was decreased by ~90%. Administration of flavopiridol NPs also improved the motor recovery of injured animals. These findings demonstrated that local delivery of flavopiridol in PLGA NPs improves recovery from spinal cord injury by inhibiting astrocyte growth and inflammatory factor synthesis.
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Ze-Feng
authors.initials: ZF
authors.lastname: Zheng
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Jun-Juan
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jia-Qiu
authors.initials: JQ
authors.lastname: Wang
authors.affiliation: School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Qi-Jiang
authors.initials: QJ
authors.lastname: Mao
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address: gaojianqing@zju.edu.cn.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Gao
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China. Electronic address: hwoy@zju.edu.cn.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D019344:Lactic Acid / Q000737:chemistry*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D018797:Cell Cycle Proteins; D005419:Flavonoids; D005904:Glial Fibrillary Acidic Protein; D018836:Inflammation Mediators; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D010880:Piperidines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C077990:alvocidib
keywords: Astrocyte; Cell activation; Drug release; Inflammation; Nanoparticle; Spinal surgery