Enhancing the Pharmacokinetics of Aptamers: Targeting AXL In Vivo Using a Bottlebrush Polymer-Conjugated Aptamer.

Abstract

The overexpression of receptor tyrosine kinase AXL receptor tyrosine kinase (AXL) is linked to acquired drug resistance in cancer treatments. Aptamers, acting as antibody surrogates, have been envisioned as potential inhibitors for AXL. However, aptamers face difficult pharmacological challenges including rapid degradation and clearance. Herein, a phosphodiester-backboned bottlebrush polymer is reported as a carrier for conjugated aptamers. Termed polymer-augmented conjugates of DNA (pacDNA), the conjugate improves aptamer specificity in vivo, prolongs blood retention, and enhances overall aptamer bioactivity. Treatment with pacDNA in AXL-overexpressing cell lines significantly inhibits AXL phosphorylation, resulting in reduced cancer cell migration and invasion. In a non-small cell lung cancer xenograft model (NCI-H1299), pacDNA treatment leads to single-agent reduction in tumor growth. These results highlight the potential of bottlebrush polymers in the field of aptamer therapeutics.