G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 5; pp. 1414 - 1428
• Main Authors: Bates, Paula J., Reyes-Reyes, Elsa M., Malik, Mohammad T., Murphy, Emily M., O'Toole, Martin G., Trent, John O.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2017
• Subjects: animal models; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Aptamer; Aptamers, Nucleotide; AS1411; Binding Sites; Cancer; Cell Proliferation - drug effects; Cell Survival - drug effects; Contrast agent; Contrast Media - chemistry; Contrast Media - metabolism; Diagnostic Imaging - methods; DNA; Drug Carriers; Drug delivery; endocytosis; G-Quadruplexes; Guanosine - chemistry; Guanosine - metabolism; Humans; image analysis; Imaging; Ligands; Nanoparticles; neoplasm cells; neoplasms; Neoplasms - diagnostic imaging; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Nucleolin; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - metabolism; Oligodeoxyribonucleotides - therapeutic use; oligonucleotides; patients; Phosphoproteins - metabolism; Quadruplex; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiosensitizer; RNA-Binding Proteins - metabolism; Structure-Activity Relationship; therapeutics; Nanoparticles; AS1411; Imaging; Contrast agent; Radiosensitizer; Aptamer; Drug delivery; Quadruplex; Nucleolin; Cancer
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.12.015

AS1411 is a 26-mer G-rich DNA oligonucleotide that forms a variety of G-quadruplex structures. It was identified based on its cancer-selective antiproliferative activity and subsequently determined to be an aptamer to nucleolin, a multifunctional protein that preferentially binds quadruplex nucleic acids and which is present at high levels on the surface of cancer cells. AS1411 has exceptionally efficient cellular internalization compared to non-quadruplex DNA sequences. Recent developments related to AS1411 will be examined, with a focus on its use for targeted delivery of therapeutic and imaging agents. Numerous research groups have used AS1411 as a targeting agent to deliver nanoparticles, oligonucleotides, and small molecules into cancer cells. Studies in animal models have demonstrated that AS1411-linked materials can accumulate selectively in tumors following systemic administration. The mechanism underlying the cancer-targeting ability of AS1411 is not completely understood, but recent studies suggest a model that involves: (1) initial uptake by macropinocytosis, a form of endocytosis prevalent in cancer cells; (2) stimulation of macropinocytosis by a nucleolin-dependent mechanism resulting in further uptake; and (3) disruption of nucleolin-mediated trafficking and efflux leading to cargoes becoming trapped inside cancer cells. Human trials have indicated that AS1411 is safe and can induce durable remissions in a few patients, but new strategies are needed to maximize its clinical impact. A better understanding of the mechanisms by which AS1411 targets and kills cancer cells may hasten the development of promising technologies using AS1411-linked nanoparticles or conjugates for cancer-targeted therapy and imaging. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. •AS1411 is a G-quadruplex DNA oligonucleotide that is also a nucleolin aptamer.•This review covers the structure, clinical status, uses, and mechanism of AS1411.•AS1411 is being widely used to deliver therapeutic and imaging agents to cancer cells.•Its cancer-targeting activity has been demonstrated in at least 30 animal studies.•Its targeting mechanism is not fully understood but may involve macropinocytosis.