title: Analysis of the murine immune response to pulmonary delivery of precisely fabricated nano- and microscale particles.
abstract: Nanomedicine has the potential to transform clinical care in the 21(st) century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Reid A
authors.initials: RA
authors.lastname: Roberts
authors.forename: Tammy
authors.initials: T
authors.lastname: Shen
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Warefta
authors.initials: W
authors.lastname: Hasan
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology; D007109:Immunity / Q000187:drug effects; D019344:Lactic Acid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000648:ultrastructure; D036103:Nanotechnology; D010316:Particle Size; D011014:Pneumonia / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols