Renal targeting of kinase inhibitors.
Activation of proximal tubular cells by fibrotic and inflammatory mediators is an important hallmark of chronic kidney disease. We have developed a novel strategy to intervene in renal fibrosis, by means of locally delivered kinase inhibitors. Such compounds will display enhanced activity within tubular cells and reduced unwanted systemic effects. In our approach kinase inhibitors are linked to the renal carrier lysozyme using a platinum-based linker that binds drugs via a coordinative linkage. Many kinase inhibitors contain aromatic nitrogen atoms able to bind to this linker without the need of prior derivatization. The resulting drug-lysozyme conjugates are rapidly filtered in the glomerulus into the tubular lumen and subsequently reabsorbed via the endocytic pathway for clearance of low-molecular weight proteins. An important property of the formed conjugates is their in vivo stability and the sustained drug release profile within target cells. This review summarizes the state-of-the-art of drug targeting to the kidney. Furthermore, we will highlight recent results obtained with kinase inhibitor-lysozyme conjugates targeted to different kinases, i.e. the transforming growth factor (TGF)-beta-receptor kinase, p38 MAPkinase and Rho-associated kinase. Both in vitro and in vivo results demonstrated their efficient tubular uptake and beneficial therapeutic effects, superior to treatment with free kinase inhibitors. These proof-of-concept studies clearly indicate the feasibility of drug targeting for improving the renal specificity of kinase inhibitors.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.
M E M
ME
Dolman
M M
MM
Fretz
G J W
GJ
Segers
M
M
Lacombe
J
J
Prakash
G
G
Storm
W E
WE
Hennink
R J
RJ
Kok
D000818:Animals; D016503:Drug Delivery Systems; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy* / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism; D009113:Muramidase / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D009113:Muramidase