Efficient and selective kidney targeting by chemically modified carbohydrate conjugates

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.