title: Targeting Rapamycin to Podocytes Using a Vascular Cell Adhesion Molecule-1 (VCAM-1)-Harnessed SAINT-Based Lipid Carrier System.
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.
authors.affiliation: Department of Pathology & Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Ganesh Ram R
authors.initials: GR
authors.lastname: Visweswaran
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Shima
authors.initials: S
authors.lastname: Gholizadeh
authors.affiliation: Department of Pathology & Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Marcel H J
authors.initials: MH
authors.lastname: Ruiters
authors.affiliation: Department of Pathology & Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
authors.affiliation: Department of Pathology & Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jan A A M
authors.initials: JA
authors.lastname: Kamps
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D002454:Cell Differentiation; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007249:Inflammation / Q000378:metabolism; D008055:Lipids; D008297:Male; D051379:Mice; D058726:Nanoconjugates; D050199:Podocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D008055:Lipids; D058726:Nanoconjugates; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D020123:Sirolimus