Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis

Pharmaceutical Research
Jai PrakashRobbert J Kok

Abstract

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. 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. 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. Inhibition of TGF-beta signaling by local drug delivery is a promis...Continue Reading

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Citations

Jul 4, 2008·Pharmaceutical Research·R J Kok
Mar 9, 2011·Nephrology·Jakub ZiegKarel Matousovic
Jul 25, 2008·Journal of the American Society of Nephrology : JASN·Jai PrakashRobbert J Kok
Feb 16, 2012·International Journal of Nanomedicine·M E M DolmanRobbert J Kok
Nov 25, 2011·Expert Opinion on Drug Delivery·Marike Marjolijn van BeugeJai Prakash
Aug 4, 2012·Journal of Diabetes and Its Complications·Tsung-Jen HungYu-Lin Yang
Jul 28, 2012·Seminars in Nephrology·Leslie Gewin, Roy Zent
Sep 14, 2011·Journal of Controlled Release : Official Journal of the Controlled Release Society·M E M DolmanR J Kok
Sep 17, 2008·Journal of Controlled Release : Official Journal of the Controlled Release Society·Marjan M FretzRobbert J Kok
Jun 14, 2008·International Journal of Pharmaceutics·M E M DolmanR J Kok
Sep 2, 2010·International Journal of Experimental Pathology·Amélie DendoovenJaap A Joles
Feb 19, 2015·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·P Boor, J Floege
Aug 27, 2013·International Journal of Pharmaceutics·Xiaohong WangZhirong Zhang
Jun 29, 2015·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Zhi-xiang YuanLee Yong Lim
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Mar 21, 2019·Current Opinion in Nephrology and Hypertension·Leslie Gewin
Dec 15, 2019·Seminars in Nephrology·Marieta TheodorakopoulouPantelis Sarafidis
Feb 19, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Fatemeh OroojalianMichael R Hamblin
Jun 5, 2021·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Daniel Fleischmann, Achim Goepferich

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