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Original

Delivery of rSLPI in a liposomal carrier for inhalation provides protection against cathepsin L degradation

, , &
Pages 513-522 | Published online: 21 Aug 2009
 

Abstract

Secretory leukocyte protease inhibitor (SLPI) is an endogenous serine protease inhibitor that protects the lungs from excessive tissue damage caused by leukocyte proteases released during inflammation. Recombinant SLPI (rSLPI) has shown potential as a treatment for inflammatory lung conditions. To date, its clinical application has been limited by rapid enzymatic cleavage by cathepsins and rapid clearance from the lungs after inhalation. In this study, rSLPI was encapsulated in 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine] : Cholesterol (DOPS : Chol) liposomes for inhalation. Incubation of rSLPI with cathepsin L leads to complete loss of activity while encapsulation of rSLPI in DOPS : Chol liposomes retained 92.6% of its activity after challenge with cathepsin L. rSLPI-loaded liposomes were aerosolized efficiently using a standard nebulizer with a minimal loss of activity and stability. This formulation was biocompatible and encapsulation did not appear to diminish access to intracellular sites of action in in vitro cell culture studies. Liposome encapsulation of rSLPI therefore improves stability and potentially reduces the level and frequency of dosing required for therapeutic effect after inhalation.

Abbreviations
Anti-NE=

Anti-neutrophil elastase

BAL=

Bronchoalveolar lavage

Cat L=

Cathepsin L

Chol=

Cholesterol

DMEM=

Dulbecco's modified eagle's medium

DOPC=

1,2-Dioleoyl-sn-Glycero-3-Phosphocholine

DOPC-rSLPI=

rSLPI encapsulated in DOPC : Chol liposomes

DOPS=

1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]

DOPS-rSLPI=

rSLPI encapsulated in DOPS : Chol liposomes

ED=

Emitted dose

ELF=

Epithelial lining fluid

FCS=

Foetal calf serum

LUVs=

Large unilamellar vesicles

NE=

Neutrophil elastase

NF-κB=

Nuclear factor-κB

NRF=

Non-respirable fraction

RF=

Respirable fraction

rSLPI=

Recombinant secretory leukocyte protease inhibitor

SLPI=

Secretory leukocyte protease inhibitor

TEM=

Transmission Electron Microscopy

TSI=

Twin stage impinger.

Abbreviations
Anti-NE=

Anti-neutrophil elastase

BAL=

Bronchoalveolar lavage

Cat L=

Cathepsin L

Chol=

Cholesterol

DMEM=

Dulbecco's modified eagle's medium

DOPC=

1,2-Dioleoyl-sn-Glycero-3-Phosphocholine

DOPC-rSLPI=

rSLPI encapsulated in DOPC : Chol liposomes

DOPS=

1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]

DOPS-rSLPI=

rSLPI encapsulated in DOPS : Chol liposomes

ED=

Emitted dose

ELF=

Epithelial lining fluid

FCS=

Foetal calf serum

LUVs=

Large unilamellar vesicles

NE=

Neutrophil elastase

NF-κB=

Nuclear factor-κB

NRF=

Non-respirable fraction

RF=

Respirable fraction

rSLPI=

Recombinant secretory leukocyte protease inhibitor

SLPI=

Secretory leukocyte protease inhibitor

TEM=

Transmission Electron Microscopy

TSI=

Twin stage impinger.

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