Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia

Ranran Li; Piotr S Kowalski; Henriëtte W M Morselt; Ilona Schepel; Rianne M Jongman; Adnan Aslan; Marcel H J Ruiters; Jan G Zijlstra; Grietje Molema; Matijs van Meurs; Jan A A M Kamps

doi:10.1371/journal.pone.0196976

Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia

PLoS One. 2018 May 15;13(5):e0196976. doi: 10.1371/journal.pone.0196976. eCollection 2018.

Authors

Ranran Li¹, Piotr S Kowalski¹, Henriëtte W M Morselt¹, Ilona Schepel¹, Rianne M Jongman^{1

2

3}, Adnan Aslan^{1

2}, Marcel H J Ruiters¹, Jan G Zijlstra², Grietje Molema¹, Matijs van Meurs^{1

2}, Jan A A M Kamps¹

Affiliations

¹ Dept. of Pathology & Medical Biology, Medical Biology Section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
² Dept. of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³ Dept. of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Abstract

Microvascular endothelial cells play a pivotal role in the pathogenesis of sepsis-induced inflammatory responses and multiple organ failure. Therefore, they represent an important target for pharmacological intervention in the treatment of sepsis. Glucocorticosteroids were widely used in the treatment of sepsis but vast evidence to support their systemic use is lacking. The limited effects of glucocorticoids in the treatment of sepsis may be explained by differential effects of drug initiated NF-κB inhibition in different cell types and insufficient drug delivery in target cells. The current study aimed therefore to investigate the effects of an endothelial targeted delivery of dexamethasone in a mouse model of endotoxemia induced by two consecutive i.p. injections of lipopolysaccharide (LPS). To achieve endothelial cell specific delivery of dexamethasone, we modified SAINT-O-Somes, a new generation of liposomes that contain the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl-pyridinium chloride, with antibodies against vascular cell adhesion molecule-1 (VCAM-1). In LPS challenged mice, the systemic administration of free dexamethasone had negligible effects on the microvascular inflammatory endothelial responses. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically localized at VCAM-1 expressing endothelial cells in the microvasculature of inflamed organs. This was associated with a marginal attenuation of the expression of a few pro-inflammatory genes in kidney and liver, while no effects in the lung were observed. This study reveals that, although local accumulation of the targeted drug was achieved, endothelial targeted dexamethasone containing anti-VCAM-1 SAINT-O-Somes exhibited marginal effects on inflammatory endothelial cell activation in a model of endotoxemia. Studies with more potent drugs encapsulated into anti-VCAM-1 SAINT-O-Somes will in the future reveal whether this delivery system can be further developed for efficacious endothelial directed delivery of drugs in the treatment of sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / pharmacology*
Dexamethasone / pharmacology*
Disease Models, Animal
Drug Delivery Systems / methods*
Endothelium, Vascular / metabolism*
Endothelium, Vascular / pathology
Endotoxemia* / chemically induced
Endotoxemia* / drug therapy
Endotoxemia* / metabolism
Endotoxemia* / pathology
Human Umbilical Vein Endothelial Cells
Humans
Lipopolysaccharides / toxicity
Male
Mice
Vascular Cell Adhesion Molecule-1 / metabolism*

Substances

Antibodies
Lipopolysaccharides
Vascular Cell Adhesion Molecule-1
Dexamethasone

Grants and funding

This work was funded by the Top Institute Pharma (TI Pharma project D5-301, The Netherlands) and the University Medical Center Groningen, The Netherlands.