Preparation of a minocycline polymer micelle thermosensitive gel and its application in spinal cord injury

Abstract

Neuroprotection is an important approach for the treatment of spinal cord injury (SCI). Minocycline (MC), a known neuroprotective agent, has been utilized for SCI treatment, but its therapeutic effect is limited by instability and low bioavailability. Herein, we developed an innovative micellar thermosensitive hydrogel (MCPP-M-gel) that encapsulates MC in polyethylene glycol (PEG)–poly(lactide-co-glycolic acid) (PLGA) micelles to enhance its therapeutic efficacy in a rat model of SCI. The micelles were synthesized via the thin-film hydration method and characterized for encapsulation efficiency, particle size, zeta potential, and polydispersity index (PDI). MCPP-M-gel demonstrated favorable physico-mechanical properties and extended MC release over 72 hours in vitro without cytotoxic effects on neural crest-derived ectoderm mesenchymal stem cells (EMSCs). Thereafter, MC, MCPP-M, MCPP-M-gel and a blank micellar thermosensitive gel were injected into the injured site of SCI rats. Histopathological evaluation demonstrated that MCPP-M-gel could promote neuronal regeneration at the injured site of the SC after 28 days. Immunofluorescence techniques revealed that MCPP-M-gel increased the expression of neuronal class III β-tubulin (Tuj1), myelin basic protein (MBP), growth-associated protein 43 (GAP43), neurofilament protein-200 (NF-200) and nestin as well as reduced glial-fibrillary acidic protein (GFAP) expression in damaged areas of the SC. In conclusion, this study innovatively developed MCPP-M-gel based on a PEG–PLGA copolymer as a biomaterial, laying a solid foundation for further research and application of MCPP-M-gel in SCI models or other neurodegenerative diseases.