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Pharmaceutical Research

, Volume 28, Issue 9, pp 2233–2245 | Cite as

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
Research Paper

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 × 10−6 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.

Conclusion

Encapsulation of rSLPI in DOPS:Chol liposomes improves stability, reduces clearance and increases residence time in the lungs after local delivery.

KEY WORDS

asthma guinea pig intratracheal instillation liposome lung rSLPI 

ABBREVIATIONS

AHR

allergic hyperresponsiveness

AIC

air interface culture

AMs

alveolar macrophages

Anti-NE

anti-neutrophil elastase

BAL

bronchoalveolar lavage

BALF

bronchoalveolar lavage fluid

Cat L

bathepsin L

Chol

cholesterol

DOPS

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

DOPS-rSLPI

rSLPI encapsulated in DOPS:Chol liposomes

EAR

early allergic response

Free-rSLPI

rSLPI alone

i.t.

intratracheal instillation

LAR

late allergic response

NE

neutrophil elastase

Ova

ovalbumin

Papp

apparent permeability coefficient

rSLPI

recombinant secretory leukocyte protease inhibitor

SLPI

secretory leukocyte protease inhibitor

TEER

trans-epithelial electrical resistance

Notes

ACKNOWLEDGMENTS

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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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Aileen Gibbons
    • 1
  • Danielle Padilla-Carlin
    • 2
  • Ciara Kelly
    • 1
  • Anthony J. Hickey
    • 2
  • Clifford Taggart
    • 3
  • Noel G. McElvaney
    • 4
  • Sally-Ann Cryan
    • 1
  1. 1.School of Pharmacy, Royal College of Surgeons in IrelandDublinIreland
  2. 2.Department of Molecular Pharmaceutics, School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.School of Medicine and DentistryQueen’s University BelfastBelfastNorthern Ireland
  4. 4.Department of MedicineBeaumont Hospital, R.C.S.I.DublinIreland

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