|Title / Titel||Immunotargeting of Liposomes and Virosomes to Mesangial Cells: A New Strategy for Directed Drug Delivery to Treat Mesangial Proliferative Glomerulonephritis|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||BACKGROUND: New strategies of drug delivery to glomerular mesangial cells are clinically relevant. The most common glomerulonephritis worldwide, IgA nephropathy, occurs histologically mostly as mesangial prolifera-tive glomerulonephritis and frequently leads to progressive renal failure despite any treatment attempts.
In glomeruli of rat kidneys, mesangial cells are characterized by the presence of Thy1.1 antigen on their surface. Therefore, virosomes and liposomes conjugated with Fab’-fragments derived from anti-Thy1.1 IgG are expected to serve as vehicles for directed drug delivery to these cells. Cellular access of virosomes and liposomes is favored by the glomerular anatomy, since the mesangium is separated from the glomerular capillary lumina only by the fenestrated endothelial cells without an intervening glomerular basement membrane.
HYPOTHESIS: Selective targeting of mesangial cells in the kidney can be achieved by the use of anti-Thy1.1 antibody derived Fab’-virosomes or Fab’-liposomes. These immunovirosomes or immunoliposomes allow directed drug delivery to targeted mesangial cells in the kidney of healthy rats.
SPECIFIC AIM: The principle aim of this grant proposal is the proof of principle of immunotargeting of liposomes or virosomes to glomerular mesangial cells. Thereby, we will develop a new strategy for the treatment of experimental mesangial proliferative glomerulonephritis and of related glomerulopathies.
EXPERIMENTAL DESIGN: Studies are performed in three parts, including in vitro and in vivo investigations:
Part 1 consists mainly of the production of various formulations of Fab’-virosomes/liposomes.
In Part 2, the binding of FITC-Fab’-virosomes/liposomes to cultured mesangial cells will be analyzed by flow cytometry. Cellular internalization of FITC-Fab’-virosomes/liposomes will be visualized by confocal laser scanning microscopy. Thereafter, we will investigate the effect of Fab’-virosomes/liposomes loaded with clodronate, matrix metalloproteinase (MMP) inhibitors, MMP-2 antisense oligonucleotides, or MMP-2 antisense peptide nucleic acids (PNA) on mesangial cells. We expect internalized clodronate to induce apoptotic cell death, and the remaining agents to inhibit cell proliferation and MMP activity/expression.
In Part 3, we will analyze the effect of Fab’-virosomes/liposomes in healthy rats. Mesangial deposition of 3H-labeled Fab’-virosomes/liposomes will be shown by autoradiography. Cellular uptake of virosomes/liposomes will be investigated by Fab’-virosomes/liposomes expressing luciferase. Finally, we will analyze effects of en-capsulated clodronate, MMP inhibitors or MMP-2 antisense oligonucleotides/PNA on mesangial cells in vivo.
|Publications / Publikationen||Tuffin G, Wälti E, Hammer C, Huwyler J, Marti HP. Immunotargeting of liposomes to mesangial cells: A New Strategy for Directed Drug Delivery in the kidney. Submitted for publication.|
|Keywords / Suchbegriffe||immunoliposomes, drug targeting, glomerulonephritis, liposomes|
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
|SNF (Personen- und Projektförderung)
|In collaboration with /
In Zusammenarbeit mit
|Duration of Project / Projektdauer||Sep 2003 to Sep 2006|