LOCAL DELIVERY OF FLAVOPIRIDOL IN POLY(LACTIC-CO-GLYCOLIC ACID) NANOPARTICLES REGULATES INFLAMMATION AND REPAIRS SPINAL CORD INJURY
Hao Ren, Min Han, Jing Zhou, Ze-Feng Zheng, Ping Lu, Jun-Juan Wang, Jia-Qiu Wang, Qi-Jiang Mao, Jian-Qing Gao, Hong-Wei Ouyang
Zhejiang University, China
Spinal cord injury (SCI) results in neuronal death, reactive astrogliosis, and extensive inflammation. The cell-cycle inhibitor flavopiridol has been shown to improve recovery from SCI in animal models. However, the systemic dose of flavopiridol has sideeffects 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 righthemisectioned 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 in astrocytes. For the first time we showed the different changes of diverse inflammatory cytokines systemically after SCI at protein level, using multiplex immunoassay. Flavopiridol NPs alleviated the reduction of the cytokines beneficial for SCI repair, such as GM-CSF, and the increase of the cytokines detrimental for SCI repair, such as IP-10. In-vivo study also 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 functional recovery of injured animals. These findings demonstrated that local delivery of flavopiridol in PLGA NPs improves recovery from SCI by systemic regulation of inflammatory cytokines, and inhibition of astrocyte proliferation, migration and inflammatory factor synthesis.