title: Enhanced pulmonary delivery of fluticasone propionate in rodents by mucus-penetrating nanoparticles.
abstract: Most attempts to achieve sustained drug delivery to pulmonary tissues using nanoparticles have focused on mucoadhesive particles (MAP). However, MAP become trapped in the luminal mucus layer and, as a result, are largely eliminated from the respiratory tract by mucociliary escalator and expiratory clearance, which undermines their sustained release potential. Recent studies have shown that mucus-penetrating particles (MPP) engineered to diffuse through mucus can avoid rapid mucociliary clearance in vivo and persist in the lung longer. Nonetheless, it has not been confirmed that MPP encapsulating small molecules can sustain drug release in the lung longer than MAP of similar size and core composition. As a proof of concept, we encapsulated fluticasone propionate (FP) into poly(lactide)-based MPP and MAP (both ∼ 200 nm diameter, ∼ 30-35% drug loading) and evaluated their pulmonary residence by measuring FP levels in mouse lungs over 24h following intratracheal instillation. Furthermore, we evaluated the duration of action of FP MPP in a rat lung inflammation model compared to that of a non-encapsulated FP control. In rodents, pulmonary delivery of FP formulated as MPP provided a 60% higher local exposure compared to MAP and extended the single dose efficacy by at least 16 h compared to non-encapsulated FP.
authors.affiliation: Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, MA 02453, USA, USA. Electronic address: alexey.popov@kalarx.com.
authors.forename: Alexey
authors.initials: A
authors.lastname: Popov
authors.affiliation: Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, MA 02453, USA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schopf
authors.affiliation: Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, MA 02453, USA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bourassa
authors.affiliation: Kala Pharmaceuticals, Inc., 100 Beaver Street, Suite 201, Waltham, MA 02453, USA, USA.
authors.forename: Hongming
authors.initials: H
authors.lastname: Chen
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D000068298:Fluticasone / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases; D008297:Male; D051379:Mice; D009093:Mucus / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011917:Rats, Inbred Lew
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D008070:Lipopolysaccharides; D011091:Polyesters; C033616:poly(lactide); D000068298:Fluticasone
keywords: Drug delivery; Fluticasone; Inflammation; Mucoadhesive; Mucus-penetrating particles; Nanoparticles; Pulmonary