Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain

Ex vivo-loaded white blood cells (WBC)can transfercargo to pathological foci in the central nervous system (CNS). Herewe tested affinity ligand driven in vivo loadingof WBC in order to bypass the need for ex vivo WBCmanipulation. We used a mouse model of acute brain inflammation causedby local injection of tumor necrosis factor alpha (TNF-& alpha;). Weintravenously injected nanoparticles targeted to intercellular adhesionmolecule 1 (anti-ICAM/NP). We found that (A) at 2 h, >20% of anti-ICAM/NPwere localized to the lungs; (B) of the anti-ICAM/NP in the lungs>90% were associated with leukocytes; (C) at 6 and 22 h, anti-ICAM/NPpulmonary uptake decreased; (D) anti-ICAM/NP uptake in brain increasedup to 5-fold in this time interval, concomitantly with migration ofWBCs into the injured brain. Intravital microscopy confirmed transportof anti-ICAM/NP beyond the blood-brain barrier and flow cytometrydemonstrated complete association of NP with WBC in the brain (98%).Dexamethasone-loaded anti-ICAM/liposomes abrogated brain edema inthis model and promoted anti-inflammatory M2 polarization of macrophagesin the brain. In vivo targeted loading of WBC inthe intravascular pool may provide advantages of coopting WBC predisposedto natural rapid mobilization from the lungs to the brain, connecteddirectly via conduit vessels.