Molecular Science and Biomedicine Laboratory , State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Life Sciences, and Aptamer Engineering Center of Hunan Province, Hunan University , Changsha , Hunan 410082 , China.
Institute of Molecular Medicine (IMM) , Renji Hospital, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University , Shanghai , China.
J Am Chem Soc. 2019 Mar 13;141(10):4282-4290. doi: 10.1021/jacs.8b10795. Epub 2019 Mar 5.
In this article, we used an artificial DNA base to manipulate the formation of DNA nanoflowers (NFs) to easily control their sizes and functionalities. Nanoflowers have been reported as the noncanonical self-assembly of multifunctional DNA nanostructures, assembled from long DNA building blocks generated by rolling circle replication (RCR). They could be incorporated with myriad functional moieties. However, the efficacy of these DNA NFs as potential nanocarriers delivering cargo in biomedicine is limited by the bioavailability and therapeutic efficacy of their cargo. Here we report the incorporation of metal-containing artificial analogues into DNA strands to control the size and the functions of NFs. We have engineered bioinspired, size-controllable, self-degradable cancer-targeting DNA nanoflowers (Sgc8-NFs-Fc) via the incorporation of an artificial sandwich base. More specifically, the introduction of a ferrocene base not only resulted in the size controllability of Sgc8-NFs-Fc from 1000 to 50 nm but also endowed Sgc8-NFs-Fc with self-degradability in the presence of HO via Fenton's reaction. In vitro experiments confirmed that Sgc8-NFs-Fc/Dox could be selectively taken up by protein tyrosine kinase 7 (PTK7)-positive cancer cells and subsequently cleaved via Fenton's reaction, resulting in rapid release kinetics, nuclear accumulation, and enhanced cytotoxicity of their cargo. In vivo experiments further confirmed that Sgc8-NFs-Fc has good tumor-targeting ability and could significantly improve the therapeutic efficacy of doxorubicin in a xenograft tumor model. On the basis of their tunable size and on-demand drug release kinetics upon HO stimulation, the Sgc8-NFs-Fc nanocarriers possess promising potential in drug delivery.
在本文中，我们使用人工 DNA 碱基来操纵 DNA 纳米花（NFs）的形成，从而轻松控制其大小和功能。纳米花已被报道为多功能 DNA 纳米结构的非经典自组装，这些结构由通过滚环复制（RCR）产生的长 DNA 构建块组装而成。它们可以与无数功能部分结合。然而，这些 DNA NFs 作为在生物医学中输送 cargo 的潜在纳米载体的功效受到其 cargo 的生物利用度和治疗效果的限制。在这里，我们报告了将含金属的人工类似物掺入 DNA 链中以控制 NFs 的大小和功能。我们通过掺入仿生、尺寸可控、自降解的靶向癌症 DNA 纳米花（Sgc8-NFs-Fc）来控制尺寸和功能。更具体地说，引入二茂铁碱基不仅导致 Sgc8-NFs-Fc 的尺寸可控性从 1000 到 50nm，而且还使 Sgc8-NFs-Fc 在存在 HO 的情况下通过 Fenton 反应具有自降解性。体外实验证实，Sgc8-NFs-Fc/Dox 可以被蛋白酪氨酸激酶 7（PTK7）阳性癌细胞选择性摄取，随后通过 Fenton 反应迅速释放其 cargo，导致其快速释放动力学、核积累和增强的细胞毒性。体内实验进一步证实，Sgc8-NFs-Fc 具有良好的肿瘤靶向能力，并能显著提高阿霉素在异种移植肿瘤模型中的治疗效果。基于其可调的尺寸和对 HO 刺激的按需药物释放动力学，Sgc8-NFs-Fc 纳米载体在药物输送方面具有很大的潜力。
