Abstract P742: Nanoparticles Targeting the Inflammatory Network in Acute Neurovascular Inflammation: Lungs to Brain Axis

After acute ischemic stroke, the cerebral vasculature is known to become more permeable to circulating leukocytes (WBC). Several laboratories attempted to use this for co-opting WBC do deliver into the central nervous system drugs and nanoparticle (NP) loaded into WBC ex vivo or in the peritoneal cavity. In theory, intravascular loading WBC may provide an interesting alternative. We hypothesize: i) direct in vivo targeting of WBC accessible to NP in the bloodstream (mainly pulmonary intravascular monocytes and marginated neutrophils in lungs), followed by carrier WBC migration to the brain will allow NP delivery to the brain and, ii) that targeted NP against WBC would be a relevant in treatment of acute brain inflammation. In fact, intravenous injection of ICAM-targeted NP 2h after the injection of tumor necrosis factor (TNF) in the brain initially showed a low uptake of the carrier in the brain that increased with time, as shown by radiotracing (5 times increase) and intravital microscopy of the brain. However, ICAM targeted NP were rapidly accumulated in the lungs and declined with time. Complete blood counts and flow cytometry revealed: i) an increase in circulating WBC counts following injury, ii) >60% of the ICAM-targeted NP were uptaken by WBC in the lungs, iii) ICAM targeted NP were almost exclusively in WBC in the brain (>98%; panel A shows the cellular distribution). Finally, we observed that the anti-inflammatory drug dexamethasone reduces brain edema only when encapsulated in ICAM-targeted nanoparticles (panel B). In conclusion, ICAM targeted NP: i) can be taken up by WBC, ii) migrate to the inflamed brain and iii) can reduce brain edema when encapsulating dexamethasone.