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

Purpose. Activation of tubular epithelial cells by transforming growth factor-beta (TGF-β) plays an important role in the pathogenesis of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-β 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-β1-induced procollagen-1α1 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.