Department of Medicine, University of Louisville, USA; James Graham Brown Cancer Center, University of Louisville, USA.
Department of Medicine, University of Arizona, USA.
Biochim Biophys Acta Gen Subj. 2017 May;1861(5 Pt B):1414-1428. doi: 10.1016/j.bbagen.2016.12.015. Epub 2016 Dec 20.
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 是一种 26 个碱基对富含 G 的 DNA 寡核苷酸，可形成多种 G-四链体结构。它是基于其选择性的抗肿瘤增殖活性而被鉴定出来的，随后被确定为核仁素的适体，核仁素是一种多功能蛋白，优先结合四链体核酸，并且在癌细胞表面高水平表达。与非四链体 DNA 序列相比，AS1411 具有非常高效的细胞内化作用。
将检查与 AS1411 相关的最新进展，重点关注其用于靶向递送达药物和成像剂。
许多研究小组已将 AS1411 用作靶向剂，将纳米颗粒、寡核苷酸和小分子递送到癌细胞中。动物模型研究表明，AS1411 连接的材料在系统给药后可以选择性地在肿瘤中积累。AS1411 具有肿瘤靶向能力的机制尚不完全清楚，但最近的研究提出了一种模型，该模型涉及：（1）最初通过巨胞饮作用摄取，巨胞饮作用是癌细胞中普遍存在的一种内吞作用形式；（2）通过核仁素依赖性机制刺激巨胞饮作用，导致进一步摄取；（3）破坏核仁素介导的运输和外排，导致货物被困在癌细胞内。
人体试验表明，AS1411 是安全的，可以使少数患者产生持久缓解，但需要新的策略来最大程度地发挥其临床影响。更好地了解 AS1411 靶向和杀死癌细胞的机制可能会加速使用 AS1411 连接的纳米颗粒或缀合物进行癌症靶向治疗和成像的有前途的技术的发展。本文是题为“G-四链体”的特刊的一部分，客座编辑：Concetta Giancola 博士和 Daniela Montesarchio 博士。
