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

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. Coupling of a novel multitargeted sunitinib analogue to NH2‐PAMAM‐G3 dendrimers via the platinum (II)‐based ULS yields a conjugate with retained pharmacological activity. It accumulates rapidly in the kidneys and provides high intrarenal drug levels that last for several days, making such conjugates promising for the development of novel therapeutics for the treatment of renal diseases.