Local Delivery of Flavopiridol in PLGA Nanoparticles Improves the Repair of Spinal Cord Injury by Inhibiting
Astrocyte Growth and Inflammatory Factor Synthesis
REN Hao1, HAN Min2, ZHOU Jing1, ZHENG Zefeng3, LU Ping1, WANG Junjuan1, WANG Jiaqiu3, MAO Qijiang3, GAO Jianqing2, OUYANG Hongwei1
(1. Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University;2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058;3. School of Medicine, Zhejiang University, Hangzhou 310058)
Foundations: NSFC grants (81330041, 81125014, J1103603, 81101356，31200739), the National Key Scientific Program (2012CB966604), the National High Technology Research and Development Program of China (863Program) (No. 2012AA020503), the Doctoral Fund of Ministry of Education of China (20120101120003), the Science and Technology Department Program of Zhejiang Province (2012C3112, 2013C33156)
Abstract: The cell cycle inhibitor flavopiridol was previously shown in animal models to improve SCI recovery. However, the systematic dosage of flavopiridol is with side effects and the mechanism is not clear. This study aims to develop a strategy for local delivery of flavopiridol and investigate its mechanisms of function as well. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) was used for the sustained delivery of flavopiridol. The spinal cords were right-hemisectioned and NPs were  administered into the injury site. Transparent spinal cord technology was applied for the three-dimensional observation of the anterograde tracing. The results showed that flavopiridol NPs had a susteined release of up to 3 days in vitro. Flavopiridol NPs significantly decreased inflammatory
factor synthesis of astrocytes, including tnf-alpha, il-1beta, and il-6, while the il-10 expression was
elevated. In-vivo study demonstrated that flavopiridol NPs decreased inflammatory expression and glial scarring, and facilitated neuronal survival and neural transmitting. Cavitation volume was decreased by proximately 90%. Administration of flavopiridol NPs also improved the motor recovery f injured animals. These findings illustrated that local delivery of flavopiridol in PLGA NPs improved SCI recovery through inhibiting astrocyte growth and inflammatory factor synthesis.
Key words: spinal surgery; cell activation; nanoparticle; astrocyte; inflammation; drug release