Cell-specific Delivery of a Transforming Growth Factor-beta Type I Receptor Kinase Inhibitor to Proximal Tubular Cells for the Treatment of Renal Fibrosis.

@article{citeulike:2268908, abstract = {PURPOSE: Activation of tubular epithelial cells by transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-beta type-I receptor kinase inhibitor (TKI) and evaluated its efficacy in vitro and in vivo. METHODS: TKI was conjugated to the protein Lysozyme (LZM) via a platinum-based linker. TKI-LZM was evaluated in human tubular cells (HK-2) for its anti-fibrotic activity. Plasma, kidney and urine drug levels after a single intravenous dose of TKI-LZM in rats were determined by HPLC or immunodetection. Anti-fibrotic effects of TKI-LZM were examined in the unilateral ureteral obstruction (UUO) model. RESULTS: TKI-LZM conjugate was successfully synthesized at an 1:1 drug/carrier ratio, and inhibited TGF-beta1-induced procollagen-1alpha1 gene expression in HK-2 cells. In vivo, TKI-LZM accumulated rapidly in tubular cells and provided a local depot for 3 days. Interestingly, a single dose of TKI-LZM inhibited the activation of tubular cells and fibroblasts in UUO rats and reduced renal inflammation. In contrast, free TKI at an equimolar (low) dosage exhibited little effects. CONCLUSIONS: Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important role of tubular activation in renal fibrosis.}, address = {Department of Pharmacokinetics and Drug Delivery, Groningen Research Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands, J.Prakash@rug.nl.}, author = {Prakash, Jai and de Borst, Martin H. and van Loenen-Weemaes, Annemiek M. and Lacombe, Marie and Opdam, Frank and van Goor, Harry and Meijer, Dirk K. and Moolenaar, Frits and Poelstra, Klaas and Kok, Robbert J. }, citeulike-article-id = {2268908}, doi = {10.1007/s11095-007-9515-x}, issn = {0724-8741}, journal = {Pharm Res}, keywords = {delivery, hk2, inhibitor, pt, tgfb, uuo}, month = {January}, posted-at = {2008-01-21 14:23:09}, priority = {2}, title = {Cell-specific Delivery of a Transforming Growth Factor-beta Type I Receptor Kinase Inhibitor to Proximal Tubular Cells for the Treatment of Renal Fibrosis.}, url = {http://dx.doi.org/10.1007/s11095-007-9515-x}, year = {2008} }

TY - JOUR ID - citeulike:2268908 L3 - citeulike-article-id:2268908 TI - Cell-specific Delivery of a Transforming Growth Factor-beta Type I Receptor Kinase Inhibitor to Proximal Tubular Cells for the Treatment of Renal Fibrosis. JF - Pharm Res AD - Department of Pharmacokinetics and Drug Delivery, Groningen Research Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands, J.Prakash@rug.nl. SN - 0724-8741 N2 - PURPOSE: Activation of tubular epithelial cells by transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-beta type-I receptor kinase inhibitor (TKI) and evaluated its efficacy in vitro and in vivo. METHODS: TKI was conjugated to the protein Lysozyme (LZM) via a platinum-based linker. TKI-LZM was evaluated in human tubular cells (HK-2) for its anti-fibrotic activity. Plasma, kidney and urine drug levels after a single intravenous dose of TKI-LZM in rats were determined by HPLC or immunodetection. Anti-fibrotic effects of TKI-LZM were examined in the unilateral ureteral obstruction (UUO) model. RESULTS: TKI-LZM conjugate was successfully synthesized at an 1:1 drug/carrier ratio, and inhibited TGF-beta1-induced procollagen-1alpha1 gene expression in HK-2 cells. In vivo, TKI-LZM accumulated rapidly in tubular cells and provided a local depot for 3 days. Interestingly, a single dose of TKI-LZM inhibited the activation of tubular cells and fibroblasts in UUO rats and reduced renal inflammation. In contrast, free TKI at an equimolar (low) dosage exhibited little effects. CONCLUSIONS: Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important role of tubular activation in renal fibrosis. KW - delivery KW - hk2 KW - inhibitor KW - pt KW - tgfb KW - uuo AU - Prakash, Jai AU - de Borst, Martin AU - van Loenen-Weemaes, Annemiek AU - Lacombe, Marie AU - Opdam, Frank AU - van Goor, Harry AU - Meijer, Dirk AU - Moolenaar, Frits AU - Poelstra, Klaas AU - Kok, Robbert PY - 2008/01/09/ UR - http://dx.doi.org/10.1007/s11095-007-9515-x ER -