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
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.