Sun Tingyu, Lin Jiachen, Xue Chenyang, Wang Yuyan, Chen Peiru, Wei Yun, Xu Guobin, Sidonia Anais, Nenopoulos Chris, Tashkandi Hossam, Shen Caroline, Wang Allison, Wang Alex, Zhang Ke
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA.
Department of Biochemistry, Northeastern University, Boston, Massachusetts, 02115, USA.
Adv Healthc Mater. 2025 Jun 26:e2405083. doi: 10.1002/adhm.202405083.
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.
受体酪氨酸激酶AXL（AXL受体酪氨酸激酶）的过表达与癌症治疗中获得性耐药有关。适体作为抗体替代物，被视为AXL的潜在抑制剂。然而，适体面临着包括快速降解和清除在内的艰巨药理学挑战。在此，报道了一种磷酸二酯主链的刷状聚合物作为共轭适体的载体。这种共轭物被称为聚合物增强DNA共轭物（pacDNA），它提高了适体在体内的特异性，延长了血液滞留时间，并增强了整体适体生物活性。在AXL过表达细胞系中用pacDNA处理可显著抑制AXL磷酸化，从而减少癌细胞的迁移和侵袭。在非小细胞肺癌异种移植模型（NCI-H1299）中，pacDNA处理导致肿瘤生长单药减少。这些结果突出了刷状聚合物在适体治疗领域的潜力。
