Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, Utrecht, The Netherlands.
Macromol Biosci. 2012 Jan;12(1):93-103. doi: 10.1002/mabi.201100277. Epub 2011 Oct 13.
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 NH(2) -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 NH(2) -PAMAM-G3. 17864-UlS-NH(2) -PAMAM-G3 is non-toxic to proximal tubular cells in vitro. After intravenous administration to mice, 17864-UlS-NH(2) -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.
一种多靶点酪氨酸激酶抑制剂的大分子缀合物的开发，可用于肾特异性递送至近端肾小管细胞。一种新型舒尼替尼类似物，即 17864，通过基于铂 (II) 的通用连接系统 (ULS™) 与 NH(2) -PAMAM-G3 树枝状大分子偶联。17864 在单独与 ULS 接头配位或与 NH(2) -PAMAM-G3 偶联后，其活性得以保留。17864-UlS-NH(2) -PAMAM-G3 在体外对近端肾小管细胞无毒性。在给小鼠静脉注射后，17864-UlS-NH(2) -PAMAM-G3 可快速高效地积聚在肾脏中。这些结果为未来专注于开发治疗肾脏疾病的新型疗法的研究提供了希望。
