三种癌症药物在DNA折纸上的共价附着在纳米摩尔浓度下增加细胞毒性。

IF 4.2 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Nanomedicine : nanotechnology, biology, and medicine Pub Date : 2023-11-24 DOI:10.1016/j.nano.2023.102722
Natalia Navarro MSc , Anna Aviñó PhD , Òscar Domènech PhD , Jordi H. Borrell PhD , Ramon Eritja PhD , Carme Fàbrega PhD
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引用次数: 0

摘要

DNA纳米结构作为癌症治疗的药物传递载体引起了人们的极大兴趣。尽管该领域进展迅速,但一些障碍,如低细胞摄取、低组织特异性或不明确的药物负荷,仍未得到解决。在本研究中,众所周知的抗肿瘤药物(阿霉素、奥斯特丁和氟尿定)被位点特异性地结合到DNA纳米结构中,证明了通过结构钉共价连接药物分子而不是通过非共价结合相互作用结合药物的潜在优势。共价策略避免了诸如未知数量的药物- dna结合事件和药物过早释放等关键问题。此外,共价修饰的折纸提供了将几种协同抗肿瘤药物以预定的摩尔比精确地结合到DNA纳米结构中的可能性,并控制药物进入DNA折纸的精确空间方向。此外,据报道,基于dna的纳米支架具有较低的细胞内摄取。因此,研究了两种细胞摄取增强机制:引入与DNA折纸共价连接的叶酸单位和用Lipofectamine转染DNA折纸。重要的是,这两种方法都增加了DNA折纸在HTB38和HCC2998结肠直肠癌细胞中的内化,并且当DNA折纸加入抗增殖药物时,产生了更大的细胞毒活性。该研究结果为开发基于dna的纳米结构作为药物递送载体提供了一种成功的、概念上独特的方法,这可以被认为是开发高精度纳米药物的重要一步。
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Defined covalent attachment of three cancer drugs to DNA origami increases cytotoxicity at nanomolar concentration

DNA nanostructures have captured great interest as drug delivery vehicles for cancer therapy. Despite rapid progress in the field, some hurdles, such as low cellular uptake, low tissue specificity or ambiguous drug loading, remain unsolved. Herein, well-known antitumor drugs (doxorubicin, auristatin, and floxuridine) were site-specifically incorporated into DNA nanostructures, demonstrating the potential advantages of covalently linking drug molecules via structural staples instead of incorporating the drugs by noncovalent binding interactions. The covalent strategy avoids critical issues such as an unknown number of drug-DNA binding events and premature drug release. Moreover, covalently modified origami offers the possibility of precisely incorporating several synergetic antitumor drugs into the DNA nanostructure at a predefined molar ratio and to control the exact spatial orientation of drugs into DNA origami. Additionally, DNA-based nanoscaffolds have been reported to have a low intracellular uptake. Thus, two cellular uptake enhancing mechanisms were studied: the introduction of folate units covalently linked to DNA origami and the transfection of DNA origami with Lipofectamine. Importantly, both methods increased the internalization of DNA origami into HTB38 and HCC2998 colorectal cancer cells and produced greater cytotoxic activity when the DNA origami incorporated antiproliferative drugs. The results here present a successful and conceptually distinct approach for the development of DNA-based nanostructures as drug delivery vehicles, which can be considered an important step towards the development of highly precise nanomedicines.

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来源期刊
CiteScore
11.10
自引率
0.00%
发文量
133
审稿时长
42 days
期刊介绍: The mission of Nanomedicine: Nanotechnology, Biology, and Medicine (Nanomedicine: NBM) is to promote the emerging interdisciplinary field of nanomedicine. Nanomedicine: NBM is an international, peer-reviewed journal presenting novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the life and health sciences. Content includes basic, translational, and clinical research addressing diagnosis, treatment, monitoring, prediction, and prevention of diseases.
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