Résumé :
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Nanosized particles have various innovative medical applications in fields such as imaging contrast fluids, topic antimicrobials, surgery tools, drug and gene delivery and vaccine adjuvant (Alum). Biodistribution of particles injected into muscle is unknown. To examine if and how particles translocate to distant sites, we injected 20?L suspension of two types of particles: exploratory polychromatic fluorescent latex beads (FLBs), and a confirmatory Alum-relevant nanohybrid (Al-rho) in which Al(OH)3 is coupled with rhodamine. After i.m. injection, both particles massively reached draining lymph nodes (dLNs), peaking at d4 and decreasing at d21; dLN emptying was associated with increase of particle-loaded phagocytes in blood and spleen peaking at d21; slow but relentless accumulation occurred in brain from d21 to the d180 endpoint. Neurodelivery increased by 2-fold in mdx mice who have chronically altered blood-brain barrier occurring in combination with neoangiogenesis and marked microglial activation. Compared to the i.m. route, intravenous injection resulted in virtually no neurodelivery. In contrast dLN ablation prior to i.m. injection reduced particle-loaded cells by 60-80% in blood, spleen and brain. Intracerebral (i.c.) particle injection showed lack of recirculation unique to brain, likely contributing to progressive cerebral particle accumulation.In mice deficient in CCL2/MCP-1 (the master inflammatory MO chemoattractan), the amount of particle-loaded cells after i.m. injection markedly decreased at d21, in blood (-85%) and brain (-82%). Conversely, i.m. co-injection of Al-rho and CCL2 was associated with dramatic increase of the number of particle-loaded cells in blood (+274%) and brain (+414%). Brain delivery was even stronger in case of combination of i.m. and i.c. infusion of CCL2 (+700%). Rhodamine remained coated with Aluminium after brain entry, as assessed by Morin stain.In conclusion, following i.m. injection of inert particles, a MCP-1-driven Trojan horse mechanism is involved in particle systemic biodistribution and neurodelivery. This general mechanism, which also applies to viral particles (HIV, HCV), may underlie beneficial/adverse effects of nanosized particles (e.g. desired neurodelivery of therapeutic agents in DMD vs. Alum particle neurotoxicity in susceptible individuals with constitutionally high MCP-1 tissue levels).
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