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.
Aileen Gibbons
Danielle Padilla-Carlin
Ciara Kelly
Anthony J. Hickey
Clifford Taggart
Noel G. McElvaney
Sally-Ann Cryan
10779/rcsi.10797989.v1
https://repository.rcsi.com/articles/journal_contribution/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_/10797989
<p>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.</p>
<p>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.</p>
<p>RESULTS: Apparent permeability (P(app)) of free-rSLPI was significantly higher at 4.9 x 10⁻⁶ cm/s than for DOPS-rSLPI, P(app) of 2.05 x 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.</p>
<p>CONCLUSION: Encapsulation of rSLPI in DOPS:Chol liposomes improves stability, reduces clearance and increases residence time in the lungs after local delivery.</p>
2019-11-22 17:21:48
Administration
Inhalation
Animals
Anti-Asthmatic Agents
Asthma
Biological Transport
Cell Line
Cell Membrane Permeability
Disease Models
Animal
Drug Compounding
Drug Delivery Systems
Drug Stability
Electric Impedance
Enzyme-Linked Immunosorbent Assay
Guinea Pigs
Humans
Liposomes
Male
Respiratory Mucosa
Secretory Leukocyte Peptidase Inhibitor
Pharmaceutical Sciences