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

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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.

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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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Authors and Affiliations

  1. Intera Healthcare, IKP Knowledge Park, Genome Valley, Shameerpet, Hyderabad, TS, 500101, India

    Hari R. Desu

  2. Plough Center for Sterile Drug Delivery Systems, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Laura A. Thoma

  3. Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee, USA

    George C. Wood

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Correspondence to Hari R. Desu.

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Desu, H.R., Thoma, L.A. & Wood, G.C. Nebulization of Cyclic Arginine-Glycine-(D)-Aspartic Acid-Peptide Grafted and Drug Encapsulated Liposomes for Inhibition of Acute Lung Injury. Pharm Res 35, 94 (2018). https://doi.org/10.1007/s11095-018-2366-9

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  • DOI: https://doi.org/10.1007/s11095-018-2366-9

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