Intervention in growth factor activated signaling pathways by renally targeted kinase inhibitors

Marjan M. Fretz, M. E.(Emmy) M. Dolman, Marie Lacombe, Jai Prakash, Tri Q. Nguyen, Roel Goldschmeding, Janos Pato, Gert Storm, Wim E. Hennink, Robbert J. Kok*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    22 Citations (Scopus)

    Abstract

    Cell-specific targeting to renal tubular cells is an interesting approach to enhance the accumulation of drugs in the kidney. Low molecular weight proteins are rapidly filtered and extensively accumulate in proximal tubular cells. We therefore have used lysozyme (LZM, 14 kDa) as a tubular cell-specific carrier for the delivery of kinase inhibitors. Two different kinase inhibitors (LY364947 and erlotinib, directed to either the TGF-β receptor kinase or the EGF receptor) were individually conjugated to LZM via a novel platinum-based linker (Universal Linkage System; ULS). The cellular handling and pharmacological efficacy of the conjugates were evaluated in cultured proximal tubular cells (HK-2 cells). Both conjugates were efficiently internalized via endocytosis. TGF-β or EGF activated HK-2 cells showed a strong activation of the studied kinases and the conjugates inhibited these events, as was demonstrated by Western blotting of phosphorylated downstream mediators and quantitative gene expression analysis. In conclusion, we have developed tubular cell-specific kinase inhibitor-LZM conjugates via a novel linker strategy, which both showed to be effective in vitro. Future in vivo studies should show their potential for the treatment of renal diseases.

    Original languageEnglish
    Pages (from-to)200-207
    Number of pages8
    JournalJournal of controlled release
    Volume132
    Issue number3
    DOIs
    Publication statusPublished - 18 Dec 2008

    Keywords

    • Drug targeting
    • Fibrosis
    • Kidney
    • Kinase inhibitors
    • Linker technology

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