title: Delivering nanoparticles to lungs while avoiding liver and spleen through adsorption on red blood cells.
abstract: Nanoparticulate drug delivery systems are one of the most widely investigated approaches for developing novel therapies for a variety of diseases. However, rapid clearance and poor targeting limit their clinical utility. Here, we describe an approach to harness the flexibility, circulation, and vascular mobility of red blood cells (RBCs) to simultaneously overcome these limitations (cellular hitchhiking). A noncovalent attachment of nanoparticles to RBCs simultaneously increases their level in blood over a 24 h period and allows transient accumulation in the lungs, while reducing their uptake by liver and spleen. RBC-adsorbed nanoparticles exhibited ∼3-fold increase in blood persistence and ∼7-fold higher accumulation in lungs. RBC-adsorbed nanoparticles improved lung/liver and lung/spleen nanoparticle accumulation by over 15-fold and 10-fold, respectively. Accumulation in lungs is attributed to mechanical transfer of particles from the RBC surface to lung endothelium. Independent tracing of both nanoparticles and RBCs in vivo confirmed that RBCs themselves do not accumulate in lungs. Attachment of anti-ICAM-1 antibody to the exposed surface of NPs that were attached to RBCs led to further increase in lung targeting and retention over 24 h. Cellular hitchhiking onto RBCs provides a new platform for improving the blood pharmacokinetics and vascular delivery of nanoparticles while simultaneously avoiding uptake by liver and spleen, thus opening the door for new applications.
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering University of California , Santa Barbara, California 93106, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Anselmo
authors.forename: Vivek
authors.initials: V
authors.lastname: Gupta
authors.forename: Blaine J
authors.initials: BJ
authors.lastname: Zern
authors.forename: Daniel
authors.initials: D
authors.lastname: Pan
authors.forename: Michael
authors.initials: M
authors.lastname: Zakrewsky
authors.forename: Vladimir
authors.initials: V
authors.lastname: Muzykantov
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
mesh_terms: D000327:Adsorption; D000818:Animals; D002469:Cell Separation; D016503:Drug Delivery Systems; D004727:Endothelium / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry; D008099:Liver / Q000187:drug effects*; D008168:Lung / Q000098:blood supply / Q000187:drug effects*; D008171:Lung Diseases / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D036103:Nanotechnology; D011137:Polystyrenes / Q000737:chemistry; D013154:Spleen / Q000187:drug effects*; D013314:Stress, Mechanical; D014018:Tissue Distribution
chemical_list: D011137:Polystyrenes; D018799:Intercellular Adhesion Molecule-1