title: G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms.
abstract: 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.
authors.affiliation: Department of Medicine, University of Louisville, USA; James Graham Brown Cancer Center, University of Louisville, USA. Electronic address: paula.bates@louisville.edu.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Bates
authors.affiliation: Department of Medicine, University of Arizona, USA.
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Reyes-Reyes
authors.affiliation: Department of Medicine, University of Louisville, USA; James Graham Brown Cancer Center, University of Louisville, USA.
authors.forename: Mohammad T
authors.initials: MT
authors.lastname: Malik
authors.affiliation: Department of Biomedical Engineering, University of Louisville, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Murphy
authors.affiliation: Department of Biomedical Engineering, University of Louisville, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: O'Toole
authors.affiliation: Department of Medicine, University of Louisville, USA; James Graham Brown Cancer Center, University of Louisville, USA.
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods*; D004337:Drug Carriers; D054856:G-Quadruplexes; D006151:Guanosine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097796:Nucleolin
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D003287:Contrast Media; D004337:Drug Carriers; D006151:Guanosine; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D019275:Radiopharmaceuticals; D000097796:Nucleolin; C513936:AGRO 100
keywords: AS1411; Aptamer; Cancer; Contrast agent; Drug delivery; Imaging; Nanoparticles; Nucleolin; Quadruplex; Radiosensitizer