title: Nano-inside-micro: Disease-responsive microgels with encapsulated nanoparticles for intracellular drug delivery to the deep lung.
abstract: It is well appreciated that delivery of therapeutic agents through the pulmonary route could provide significant improvement in patient compliance and reduce systemic toxicity for a variety of diseases. Many inhalable drug formulations suffer from low respirable fractions, rapid clearance by alveolar macrophages, target non-specificity, and difficulty in combining aerodynamic properties with efficient cellular uptake. To overcome these challenges, we developed an enzyme-responsive, nanoparticle-in-microgel delivery system. This system is designed to provide optimal aerodynamic carrier size for deep lung delivery, improved residence time of carriers in the lungs by avoiding rapid clearance by macrophages, and reduction of side effects and toxicity by releasing encapsulated therapeutics in response to disease-specific stimuli. This unique carrier system is fabricated using a new Michael addition during (water-in-oil) emulsion (MADE) method, especially suitable for biologic drugs due to its gentle fabrication conditions. The resulting microgels have a highly porous internal structure and an optimal aerodynamic diameter for effective deep lung delivery. They also exhibit triggered release of various nanoparticles and biologics in the presence of physiological levels of enzyme. In addition, the nanoparticle-carrying microgels showed little uptake by macrophages, indicating potential for increased lung residence time and minimal clearance by alveolar macrophages. Collectively, this system introduces a rationally designed, disease-specific, multi-tiered delivery system for use as an improved pulmonary carrier for biologic drugs.
authors: Department of Biomedical Engineering, The University of Texas at Austin, 107 West Dean Keeton Street, Stop C0800, Austin, TX 78712‐1801, USA.
authors: Prinda
authors: P
authors: Wanakule
authors: Gary W
authors: GW
authors: Liu
authors: Asha T
authors: AT
authors: Fleury
authors: Krishnendu
authors: K
authors: Roy
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods*; D005782:Gels; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D014357:Trypsin / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D005782:Gels; D007074:Immunoglobulin G; D009842:Oligopeptides; C521883:poly(ethylene glycol) tetra-acrylate; D011092:Polyethylene Glycols; D004247:DNA; D014357:Trypsin