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bioRxiv · 10.1101/2024.11.21.624647

Nanoparticles loaded with a CSF1R antagonist selectively depletes microglial cells and modulates inflammation in spinal cord injury

Yang, J.·Ucakar, B.·Vnavarenberg, K.·Malfanti, A.·des Rieux, A.
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Abstract

Neuroinflammation is a principal event occurring after spinal cord injury (SCI). M1-like microglia are key players in the inflammatory response after injury. We hypothesize that the depletion of this microglia subtype would result in a more pro-resolutive environment, favorable to SCI repair. The colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 has been used to deplete microglia in the central nervous system. Although PLX5622 can freely cross the blood-brain barrier after systemic administration, the low drug concentration within the SCI site hampers its effectiveness. Additionally, systemic administration of PLX5622 in the scope of SCI treatment can induce side effects due to off-target accumulation. In this study, we specifically depleted M1- like microglia by designing polymeric nanoparticles loaded with PLX5622 (PLX NPs) to locally treat spinal cord contusion. PLX NP was prepared using a microfluidic-assisted approach showing high encapsulation efficiency (approx. 84%), nanosized dimensions (100 nm), and batch-to-batch reproducibility. PLX NP displayed selective activity in depleting M1-like microglial cells in both resting and lipopolysaccharide (LPS)-activated mixed microglial cell models compared with the free drug counterparts while preserving non-targeted glial cells. Furthermore, locally administered PLX NP downregulated proinflammatory cytokines (e.g., TNF-, IL-6, and IL-1{beta}), increasing the M2/M1-like microglia ratio, thus reducing inflammation in a SCI contusion model. Our data support the hypothesis that local treatment with PLX NPs, a formulation with a high translational value, reduces neuroinflammation, with potential applications in SCI and central nervous system inflammatory diseases. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/624647v1_ufig1.gif" ALT="Figure 1000"> View larger version (55K): org.highwire.dtl.DTLVardef@1bfd912org.highwire.dtl.DTLVardef@446923org.highwire.dtl.DTLVardef@1527c0borg.highwire.dtl.DTLVardef@4df259_HPS_FORMAT_FIGEXP M_FIG The colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 loaded in polymeric nanoparticles (PLX NP) is delivered for the treatment of neuroinflammation in spinal cord injury. C_FIG

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Yang, J., Ucakar, B., Vnavarenberg, K., Malfanti, A., des Rieux, A.. 2024-11-21. Nanoparticles loaded with a CSF1R antagonist selectively depletes microglial cells and modulates inflammation in spinal cord injury. https://doi.org/10.1101/2024.11.21.624647

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