We investigated a renal tubule-targeting carbohydrate (RENTAC) that can selectively deliver small-molecule and nucleic acid analogs to the proximal convoluted tubules of the kidney following systemic delivery in mice. We comprehensively evaluated anti-miR-21-peptide nucleic acid-RENTAC, and fluorophore-RENTAC conjugates in cell culture and in vivo. We established that RENTAC conjugates showed megalin- and cubilin-dependent endocytic uptake in the immortalized kidney cell line. In vivo biodistribution studies confirmed the retention of RENTAC conjugates in the kidneys for several days compared with other organs. Immunofluorescence staining confirmed the selective distribution of the RENTAC conjugates in proximal convoluted tubules. We further demonstrated proximal convoluted tubule targeting features of RENTAC conjugates in a folic acid-induced kidney fibrosis mouse model. As a biological readout, we targeted miR-33 using antisense peptide nucleic acid (PNA) 33-RENTAC conjugates in the fibrotic kidney disease model. The targeted delivery of PNA 33-RENTAC resulted in slower fibrosis progression and decreased collagen deposition. We also confirmed that the RENTAC ligand did not exert any adverse reactions. Thus, we established that the RENTAC ligand can be used for broad clinical applications targeting the kidneys selectively.

中文翻译：

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通过化学改性碳水化合物偶联物进行高效和选择性的肾脏靶向


我们研究了一种靶向肾小管的碳水化合物 （RENTAC），它可以在小鼠全身递送后选择性地将小分子和核酸类似物递送到肾脏的近端曲小管。我们在细胞培养和 体内全面评估了抗 miR-21 肽核酸-RENTAC 和荧光团-RENTAC 偶联物。我们确定 RENTAC 偶联物在永生化肾细胞系中显示出巨蛋白和肘蛋白依赖性内吞摄取。体内 生物分布研究证实，与其他器官相比，RENTAC 偶联物在肾脏中的保留时间长达数天。免疫荧光染色证实了 RENTAC 偶联物在近端曲小管中的选择性分布。我们进一步证明了叶酸诱导的肾纤维化小鼠模型中 RENTAC 偶联物的近端曲曲小管靶向特征。作为生物学读数，我们在纤维化肾病模型中使用反义肽核酸 （PNA） 33-RENTAC 偶联物靶向 miR-33。PNA 33-RENTAC 的靶向递送导致纤维化进展缓慢并减少胶原蛋白沉积。我们还证实 RENTAC 配体没有产生任何不良反应。因此，我们确定 RENTAC 配体可用于选择性靶向肾脏的广泛临床应用。