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

## TL;DR

A new polymer-based delivery system improves aptamer stability and effectiveness in targeting AXL, a protein linked to cancer drug resistance.

## Contribution

A phosphodiester-backboned bottlebrush polymer (pacDNA) is introduced to enhance aptamer pharmacokinetics and bioactivity in vivo.

## Key findings

- pacDNA conjugates significantly inhibit AXL phosphorylation in cancer cell lines.
- pacDNA treatment reduces tumor growth in a non-small cell lung cancer xenograft model.
- The polymer improves aptamer specificity, blood retention, and bioactivity in vivo.

## 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.

A phosphodiester‐backboned bottlebrush polymer (pacDNA) engineered for aptamer delivery is presented. This design enhances aptamer stability, plasma pharmacokinetics, and target engagement in vivo. In AXL‐driven cancer models, pacDNA inhibits AXL signaling and reduces tumor growth, highlighting the promise of precision polymer scaffolds in aptamer‐based cancer therapeutics.