title: Hybrid pulmonary surfactant-coated nanogels mediate efficient in vivo delivery of siRNA to murine alveolar macrophages.
abstract: The local delivery of small interfering RNA (siRNA) to the lungs may provide a therapeutic solution to a range of pulmonary disorders. Resident alveolar macrophages (rAM) in the bronchoalveolar lumen play a critical role in lung inflammatory responses and therefore constitute a particularly attractive target for siRNA therapeutics. However, achieving efficient gene silencing in the lung while avoiding pulmonary toxicity requires appropriate formulation of siRNA in functional nanocarriers. In this study, we evaluated pulmonary surfactant-coated dextran nanogels for the delivery of siRNA to rAM upon pharyngeal aspiration in BALB/c mice. Both the surfactant-coated and uncoated nanogels achieved high levels of siRNA uptake in rAM, yet only the surfactant-coated formulation could significantly reduce gene expression on the protein level. Surfactant-coated nanogels induced a profound downregulation of target mRNA levels, reaching 70% knockdown with ~1mgkg(-1) siRNA dose. In addition, only mild acute pro-inflammatory cytokine and chemokine responses were detected one day after nanoparticle aspiration, accompanied by a moderate neutrophil infiltration in the bronchoalveolar lumen. The latter could be substantially reduced by removal of excess surfactant from the formulation. Overall, our hybrid core-shell nanoparticles have demonstrated safe and effective siRNA delivery to rAM, providing a new therapeutic approach for treatment of inflammatory pathologies in the lung.
authors: Laboratory of General Biochemistry and Physical Pharmacy, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, Ghent 9000, Belgium. Electronic address: lynn.debacker@ugent.be.
authors: Lynn
authors: L
authors: De Backer
authors: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde 9052, Belgium. Electronic address: Thomas.Naessens@astrazeneca.com.
authors: Thomas
authors: T
authors: Naessens
authors: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde 9052, Belgium. Electronic address: stefaan.dekoker@irc.ugent.be.
authors: Stefaan
authors: S
authors: De Koker
authors: Laboratory of General Biochemistry and Physical Pharmacy, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, Ghent 9000, Belgium. Electronic address: elzagato.zagato@ugent.be.
authors: Elisa
authors: E
authors: Zagato
authors: Laboratory of General Biochemistry and Physical Pharmacy, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, Ghent 9000, Belgium. Electronic address: jo.demeester@ugent.be.
authors: Jo
authors: J
authors: Demeester
authors: Laboratory of Molecular Immunology, Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde 9052, Belgium. Electronic address: Johan.Grooten@irc.ugent.be.
authors: Johan
authors: J
authors: Grooten
authors: Laboratory of General Biochemistry and Physical Pharmacy, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, Ghent 9000, Belgium. Electronic address: stefaan.desmedt@ugent.be.
authors: Stefaan C
authors: SC
authors: De Smedt
authors: Laboratory of General Biochemistry and Physical Pharmacy, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, Ghent 9000, Belgium. Electronic address: koen.raemdonck@ugent.be.
authors: Koen
authors: K
authors: Raemdonck
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry; D005260:Female; D005782:Gels; D020868:Gene Silencing; D017493:Leukocyte Common Antigens / Q000235:genetics* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011663:Pulmonary Surfactants / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D016207:Cytokines; D003911:Dextrans; D005782:Gels; D011663:Pulmonary Surfactants; D034741:RNA, Small Interfering; D017493:Leukocyte Common Antigens
keywords: Dextran nanogel; In vivo test; Macrophage; Pulmonary delivery; Pulmonary surfactant; siRNA