Selection of Aptamers for Hydrophobic Drug Docetaxel To Improve Its Solubility

Abstract

With the development of combinatorial chemistry and high-throughput screening, the number of hydrophobic drug candidates continues to increase. However, the low solubility of hydrophobic drugs could induce erratic absorption patterns and affect the drug efficacy. Aptamers are artificially selected highly water-soluble oligonucleotides that bind to ions, small molecules, proteins, living cells, and even tissues. Herein, to increase the solubility of hydrophobic drug, we screened the aptamer by exploiting DNA library immobilization selection strategy and microfluidic technology. The highly water-soluble aptamer might influence the dissolving capacity of its target. To demonstrate the concept, docetaxel (DOC), a second-generation taxoid cytotoxic with significant antitumor agent activity, was chosen as the model. It is generally known that the clinical application of docetaxel is limited greatly owing to its poor water solubility and serious side effects. After seven rounds of selection, two docetaxel-specific aptamers DOC6–5 and DOC7–38, were successfully obtained, and their apparent dissociation constants (<i>K</i>_d) were at nanomolar level. Then these two 100 mer ssDNA aptamers against docetaxel were truncated to 22 mer ones by utilizing the recognition domain. Moreover, the shorter aptamer exhibited higher binding affinity than 100 mer ssDNA aptamers. By adding the optimized aptamer, the solubility of docetaxel was increased from ∼14 μM to ∼145 μM, and the cytotoxicity of docetaxel did not reduce in the presence of aptamer. Therefore, the aptamer was used as a solubilizer to improve the solubility of hydrophobic drug (docetaxel) in aqueous phase. This strategy may also be extended to other hydrophobic drugs. Meanwhile, this work could also provide a useful tool for tumor targeting therapy by combining with cell target ligands