Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1861, Issue 5, Pages 1414-1428Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2016.12.015
Keywords
AS1411; Quadruplex; Aptamer; Nucleolin; Cancer; Nanoparticles; Radiosensitizer; Drug delivery; Imaging; Contrast agent
Categories
Funding
- NIH [R01 CA122383]
- US National Institutes of Health [R01 CA122383, R01 CA113735, R21 CA104230]
- US Department of Defense [DAMD17-98-1-8583, PC030134, PC073700, BC087587]
- Kentucky Science and Engineering Foundation [COMMFUND-1453-RFP-015]
- Kentucky Lung Cancer Program
- Komen Foundation
- University of Louisville Coulter Translational Partnership
- Jewish Heritage Fund for Excellence
- Antisoma PLC
- Kosair Charities
- Evan Dunbar Neuroblastoma Foundation
- University of Louisville
- Brown Cancer Center
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Background: 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. Scope of review: Recent developments related to AS1411 will be examined, with a focus on its use for targeted delivery of therapeutic and imaging agents. Major conclusions: Numerous research groups have used AS1411 as a targeting agent to deliver nanoparticles, oligonudeotides, 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. Significance: 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. (C) 2016 Published by Elsevier B.V.
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