TY - JOUR

T1 - Integrin Targeting and Toxicological Assessment of Peptide-Conjugated Liposome Delivery Systems to Activated Endothelial Cells

AU - Kermanizadeh, Ali

AU - Villadsen, Klaus

AU - Østrem, Ragnhild G

AU - Jensen, Knud J

AU - Møller, Peter

AU - Loft, Steffen

N1 - © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2017/4

Y1 - 2017/4

N2 - Utilization of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines after exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells.

AB - Utilization of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines after exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells.

KW - Binding Sites

KW - Cell Survival/drug effects

KW - Coculture Techniques

KW - Cytokines/immunology

KW - Dose-Response Relationship, Drug

KW - Drug Delivery Systems

KW - Endocytosis

KW - Endothelial Cells/drug effects

KW - Flow Cytometry

KW - Human Umbilical Vein Endothelial Cells

KW - Integrin alpha5beta1/metabolism

KW - Integrin alphaVbeta3/metabolism

KW - Integrins/metabolism

KW - Lipopolysaccharides/pharmacology

KW - Liposomes

KW - Macrophages/drug effects

KW - Microscopy, Fluorescence

KW - Molecular Targeted Therapy

KW - Monocytes/drug effects

KW - Oligopeptides/chemistry

KW - Particle Size

KW - Surface Properties

U2 - 10.1111/bcpt.12692

DO - 10.1111/bcpt.12692

M3 - Article

C2 - 27767251

VL - 120

SP - 380

EP - 389

JO - Basic & clinical pharmacology & toxicology

JF - Basic & clinical pharmacology & toxicology

SN - 1742-7835

IS - 4

ER -