Aptamers in cancer research: Focus on leukemia

ABSTRACT: Aptamers are single-stranded DNA or RNA molecules that fold into unique 3-dimensional structures and are selected through systematic evolution of ligands by exponential enrichment (SELEX) and its advanced variants. They provide high target specificity, low immunogenicity, easy synthesis and modification, reversible denaturation, and superior tissue penetration compared with monoclonal antibodies. The approvals by the Food and Drug Administration of pegaptanib in 2004 and avacincaptad pegol in 2023 established aptamers as clinically viable therapeutic platforms. Leukemia is a hematological malignancy characterized by the uncontrolled proliferation of abnormal white blood cells. Its genetic and molecular heterogeneity poses diagnostic and therapeutic challenges. Although the rapid development of novel therapies has improved outcomes for patients with leukemia, challenges such as high relapse rates (particularly in acute myeloid leukemia [AML]), tyrosine kinase inhibitor resistance in chronic myeloid leukemia (CML), and treatment toxicity persist. Diagnostically, aptamer-based biosensors are sensitive detectors of leukemia cells and minimal residual disease. Therapeutically, aptamer-drug conjugates and standalone aptamers enable targeted delivery of cytotoxic agents (methotrexate and doxorubicin) or modulate oncogenic pathways (nucleolin, protein tyrosine kinase 7, and C-X-C motif chemokine 12). This review details the clinical milestones (AS1411 in AML and NOX-A12 in chronic lymphocytic leukemia [CLL]) and preclinical successes across AML, ALL, CML, and CLL, additionally spotlighting the challenges in stability, scalability, and tumor penetration. Future research should focus on enhancing stability, advanced delivery systems, and synergistic immunotherapy combinations.