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Pharmacokinetic Properties of DNA Aptamers with Base Modifications

2017; Mary Ann Liebert, Inc.; Volume: 27; Issue: 6 Linguagem: Inglês

10.1089/nat.2017.0683

2159-3345

Shashi Kumar Gupta, Daniel W. Drolet, Steven K. Wolk, Sheela Waugh, John C. Rohloff, Jeffery D. Carter, Wesley S. Mayfield, Matthew R. Otis, Catherine R. Fowler, Tomoki Suzuki, Masao Hirota, Yuichi Ishikawa, Daniel J. Schneider, Nebojša Janjić,

DNA and Nucleic Acid Chemistry

The addition of novel side chains at the 5-position of uracil is an effective means to increase chemical diversity of aptamers and hence the success rate for discovery of high-affinity ligands to protein targets. Such modifications also increase nuclease resistance, which is useful in a range of applications, especially for therapeutics. In this study, we assess the impact of these side chains on plasma pharmacokinetics of modified aptamers conjugated to a 40 kDa polyethylene glycol. We show that clearance from plasma depends on relative hydrophobicity: side chains with a negative cLogP (more hydrophilic) result in slower plasma clearance compared with side chains with a positive cLogP (more hydrophobic). We show that clearance increases with the number of side chains in sequences of ≥28 synthons, but this effect is dramatically diminished in shorter sequences. These results serve as a guide for the design of new therapeutic aptamers with diversity-enhancing side chains.