Targeting Rapamycin to Podocytes Using a Vascular Cell Adhesion Molecule-1 (VCAM-1)-Harnessed SAINT-Based Lipid Carrier System

PLoS One. 2015 Sep 25;10(9):e0138870. doi: 10.1371/journal.pone.0138870. eCollection 2015.

Abstract

Together with mesangial cells, glomerular endothelial cells and the basement membrane, podocytes constitute the glomerular filtration barrier (GFB) of the kidney. Podocytes play a pivotal role in the progression of various kidney-related diseases such as glomerular sclerosis and glomerulonephritis that finally lead to chronic end-stage renal disease. During podocytopathies, the slit-diaphragm connecting the adjacent podocytes are detached leading to severe loss of proteins in the urine. The pathophysiology of podocytopathies makes podocytes a potential and challenging target for nanomedicine development, though there is a lack of known molecular targets for cell selective drug delivery. To identify VCAM-1 as a cell-surface receptor that is suitable for binding and internalization of nanomedicine carrier systems by podocytes, we investigated its expression in the immortalized podocyte cell lines AB8/13 and MPC-5, and in primary podocytes. Gene and protein expression analyses revealed that VCAM-1 expression is increased by podocytes upon TNFα-activation for up to 24 h. This was paralleled by anti-VCAM-1 antibody binding to the TNFα-activated cells, which can be employed as a ligand to facilitate the uptake of nanocarriers under inflammatory conditions. Hence, we next explored the possibilities of using VCAM-1 as a cell-surface receptor to deliver the potent immunosuppressant rapamycin to TNFα-activated podocytes using the lipid-based nanocarrier system Saint-O-Somes. Anti-VCAM-1-rapamycin-SAINT-O-Somes more effectively inhibited the cell migration of AB8/13 cells than free rapamycin and non-targeted rapamycin-SAINT-O-Somes indicating the potential of VCAM-1 targeted drug delivery to podocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Cell Differentiation
  • Cell Line
  • Gene Expression
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Inflammation / metabolism
  • Lipids*
  • Male
  • Mice
  • Nanoconjugates*
  • Podocytes / cytology
  • Podocytes / drug effects*
  • Podocytes / metabolism*
  • Sirolimus / administration & dosage*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism*

Substances

  • Antibodies, Monoclonal
  • Immunosuppressive Agents
  • Lipids
  • Nanoconjugates
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Sirolimus

Grant support

This work is supported by NanoNextNL, a micro and nanotechnology consortium of the Government of the Netherlands and 130 partners (Grant number: project 03D.07), http://www.nanonextnl.nl/.