Dendrimer-Based Macromolecular Conjugate for the Kidney-Directed Delivery of a Multitargeted Sunitinib Analogue

Authors

  • M. E. (Emmy) M. Dolman,

    1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Kim M. A. van Dorenmalen,

    1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Ebel H. E. Pieters,

    1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Rolf W. Sparidans,

    1. Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Marie Lacombe,

    1. Kreatech Biotechnology BV, Vlierweg 20, 1032 LG Amsterdam, The Netherlands
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  • Bálint Szokol,

    1. Vichem Chemie Ltd., Herman Ottó u. 15, Budapest 1022, Hungary
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  • László Őrfi,

    1. Vichem Chemie Ltd., Herman Ottó u. 15, Budapest 1022, Hungary
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  • György Kéri,

    1. Vichem Chemie Ltd., Herman Ottó u. 15, Budapest 1022, Hungary
    2. Pathobiochemistry Research Group of Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
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  • Niels Bovenschen,

    1. Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
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  • Gert Storm,

    1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Wim E. Hennink,

    1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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  • Robbert J. Kok

    Corresponding author
    1. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
    • Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
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Abstract

The development of a macromolecular conjugate of a multitargeted tyrosine kinase inhibitor is described that can be used for renal-specific delivery into proximal tubular cells. A novel sunitinib analogue, that is, 17864, is conjugated to a NH2-PAMAM-G3 dendrimer via the platinum (II)-based Universal Linkage System (ULS™). The activity of 17864 is retained after coordination to the ULS linker alone or when coupled to NH2-PAMAM-G3. 17864-UlS-NH2-PAMAM-G3 is non-toxic to proximal tubular cells in vitro. After intravenous administration to mice, 17864-UlS-NH2-PAMAM-G3 rapidly and efficiently accumulates in the kidneys. These results are encouraging for future studies focusing on the development of novel therapeutics for the treatment of renal diseases.

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