Nebulization of Cyclic Arginine-Glycine-(D)-Aspartic Acid-Peptide Grafted and Drug Encapsulated Liposomes for Inhibition of Acute Lung Injury

Research Paper
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Abstract

Purpose

Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo.

Methods

In vivo ALI model was simulated through intra-tracheal instillation of IL-1β solution (100 μg/mL in PBS, pH 7.2, 200 μL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (LcRGD) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-LcRGD). Formulations were nebulized in vivo in rats using micro-pump nebulizer.

Results

Liposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-LcRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels.

Conclusion

From the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.

Key words

drug delivery formulation inflammation liposome nebulization 

Abbreviations

ALI

Acute lung injury

BALF

Broncho-alveolar lavage fluid

CHOL

Cholesterol

DSPE-PEG2000-Mal

Distearoyl phosphatidylethanolamine-PEG2000-maleimide

GSD

Geometric size distribution

HEPES

(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid])

HSPC

Hydrogenated stearoyl phosphatidylcholine

i.t.

Intra-tracheal

i.v.

Intra-venous

IACUC

Institution animal care and use committee

MCP-1

Monocyte chemokine protein-1

MIP-1α

Macrophage inhibitory protein-1 alpha

MLV

Multi-lamellar vesicles

MMAD

Mass median aerodynamic diameter

MPO

Myeloperoxidase

MP

Methylprednisolone

MPS

Methylprednisolone sodium succinate

MTT

Methyl thioazolyl tetrazolium

PBS

Phosphate buffer saline

RGD

Arginine-glycine-(D)-aspartic acid

rhIL-1β

Recombinant human interleukin-1beta

SUV

Small unilamellar vesicles

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hari R. Desu
    • 1
  • Laura A. Thoma
    • 2
  • George C. Wood
    • 3
  1. 1.Intera Healthcare, IKP Knowledge ParkHyderabadIndia
  2. 2.Plough Center for Sterile Drug Delivery Systems, College of PharmacyThe University of Tennessee Health Science CenterMemphisUSA
  3. 3.Department of Pharmaceutical SciencesThe University of Tennessee Health Science CenterMemphisUSA

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