Design and Characterization of Integrin α4β1-Specific DNA Aptamer Conjugates for Cancer Targeting Applications

Abstract

Cancer can exert a burdensome toll on all in its grasp, causing physical as well as psychological distress. Therapies currently in use to treat cancer either carry a variety of unpleasant side-effects or are prohibitively expensive. Therapies using active antigen targeting strategies present one solution. While antibody intermediates have been used in this strategy, DNA aptamers surprisingly have yet to see this application. Owing to their many advantages as safe, low cost, high-affinity targeting ligands, we hypothesize that cancer-specific DNA aptamers can serve as powerful, cost-effective, and safe tools for a variety of cancer targeting applications. Despite their favorable properties on paper however, aptamers experience three major challenges in vivo. Aptamers are readily degraded by nucleases in blood serum, assume different conformations at body temperature compared to 4C, and are subject to rapid renal filtration due to their small size. Fortunately, there are various strategies that can be employed to mitigate the aforementioned issues. Through rational chemical modification and conjugation of aptamers to various moieties, it is possible to improve the in vivo pharmacokinetics of aptamers. Thus, this project explores the characterization, modification, and potential application of HR7A1, a cancer selective integrin α4β1-specific aptamer. The results of this project will better inform the development of more aptamer-based targeted therapies to expand the accessibility of precision medicine to all patients.