caa a22 4500 445312025 CHVBK 20180317142633.0 cr unu---uuuuu 170323e20110901xx s 000 0 eng 10.1007/s11095-011-0454-1 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0454-1 The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model [Elektronische Daten] [Aileen Gibbons, Danielle Padilla-Carlin, Ciara Kelly, Anthony Hickey, Clifford Taggart, Noel McElvaney, Sally-Ann Cryan] ABSTRACT: Purpose: Inhaled recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) has shown potential for treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs have limited clinical efficacy. Encapsulation of rSLPI within 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]:Cholesterol liposomes (DOPS-rSLPI) protects rSLPI against Cat L inactivation in vitro. We aimed to determine the effect of liposomes on rSLPI pharmacokinetics and activity in vitro and after local delivery to the airways in vivo. Methods: Transport of DOPS-rSLPI and free-rSLPI across a polarised air-liquid epithelial monolayer was measured. An asthma guinea pig model was administered either DOPS-rSLPI liposomes or free-rSLPI by intratracheal instillation. Results: Apparent permeability (Papp) of free-rSLPI was significantly higher at 4.9 × 10−6cm/s than for DOPS-rSLPI, Papp of 2.05 × 10−7cm/s, confirmed by in vivo studies. Plasma rSLPI concentrations were highest in free-rSLPI-treated animals compared with those treated with DOPS-rSLPI; there also appeared to be a trend for higher intracellular rSLPI content in animals dosed with DOPS-rSLPI compared to free-rSLPI. Eosinophil influx was recorded as a measure of inflammation. Pre-dosing with either free-rSLPI or DOPS-rSLPI prevented inflammatory response to antigen challenge to levels comparable to control animals. Conclusion: Encapsulation of rSLPI in DOPS:Chol liposomes improves stability, reduces clearance and increases residence time in the lungs after local delivery. Springer Science+Business Media, LLC, 2011 asthma nationallicence guinea pig nationallicence intratracheal instillation nationallicence liposome nationallicence lung nationallicence rSLPI nationallicence AHR : allergic hyperresponsiveness nationallicence AIC : air interface culture nationallicence AMs : alveolar macrophages nationallicence Anti-NE : anti-neutrophil elastase nationallicence BAL : bronchoalveolar lavage nationallicence BALF : bronchoalveolar lavage fluid nationallicence Cat L : bathepsin L nationallicence Chol : cholesterol nationallicence DOPS : 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine] nationallicence DOPS-rSLPI : rSLPI encapsulated in DOPS:Chol liposomes nationallicence EAR : early allergic response nationallicence Free-rSLPI : rSLPI alone nationallicence i.t. : intratracheal instillation nationallicence LAR : late allergic response nationallicence NE : neutrophil elastase nationallicence Ova : ovalbumin nationallicence Papp : apparent permeability coefficient nationallicence rSLPI : recombinant secretory leukocyte protease inhibitor nationallicence SLPI : secretory leukocyte protease inhibitor nationallicence TEER : trans-epithelial electrical resistance nationallicence Gibbons Aileen School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland aut Padilla-Carlin Danielle Department of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, 27599, Chapel Hill, North Carolina, USA aut Kelly Ciara School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland aut Hickey Anthony Department of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, 27599, Chapel Hill, North Carolina, USA aut Taggart Clifford School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland aut McElvaney Noel Department of Medicine, Beaumont Hospital, R.C.S.I., Dublin, Ireland aut Cryan Sally-Ann School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/9(2011-09-01), 2233-2245 0724-8741 28:9<2233 2011 28 11095 https://doi.org/10.1007/s11095-011-0454-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0454-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gibbons Aileen School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland aut NATIONALLICENCE 700 1- Padilla-Carlin Danielle Department of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, 27599, Chapel Hill, North Carolina, USA aut NATIONALLICENCE 700 1- Kelly Ciara School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland aut NATIONALLICENCE 700 1- Hickey Anthony Department of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, 27599, Chapel Hill, North Carolina, USA aut NATIONALLICENCE 700 1- Taggart Clifford School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland aut NATIONALLICENCE 700 1- McElvaney Noel Department of Medicine, Beaumont Hospital, R.C.S.I., Dublin, Ireland aut NATIONALLICENCE 700 1- Cryan Sally-Ann School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/9(2011-09-01), 2233-2245 0724-8741 28:9<2233 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer