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
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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.
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.
Apparent permeability (Papp) of free-rSLPI was significantly higher at 4.9 × 10−6 cm/s than for DOPS-rSLPI, Papp of 2.05 × 10−7 cm/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.
Encapsulation of rSLPI in DOPS:Chol liposomes improves stability, reduces clearance and increases residence time in the lungs after local delivery.
KEY WORDSasthma guinea pig intratracheal instillation liposome lung rSLPI
air interface culture
bronchoalveolar lavage fluid
- Cat L
rSLPI encapsulated in DOPS:Chol liposomes
early allergic response
late allergic response
apparent permeability coefficient
recombinant secretory leukocyte protease inhibitor
secretory leukocyte protease inhibitor
trans-epithelial electrical resistance
This project was supported by the Irish Research Council for Science, Engineering and Technology (contract: SC/2004/B0419), the Health Research Board (Grant No. PHD/2007/11), and the Department for Employment and Learning (Northern Ireland) through its “Strengthening the All-Island Research Base” initiative (CT). The authors gratefully acknowledge the supply of rSLPI from Amgen®.
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