Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA.
Small. 2020 Nov;16(44):e2002578. doi: 10.1002/smll.202002578. Epub 2020 Oct 7.
Engineered DNA frameworks have been extensively exploited as affinity scaffolds for drug delivery. However, few studies focus on the rational design to comprehensively improve their stability, internalization kinetics, and drug loading efficiency. Herein, DNA framework-based hybrid nanomaterials are rationally engineered by using a molecular docking tool, where the framework acts as a template to support conjugated polymers. The hybrid materials exhibit high stability in biofluids owning to the multiple interactions between DNA and cationic conjugated polymer. Through molecular docking, it is found that a specific structure of the conjugated polymer at major grooves of DNA gives rise to a unique pocket for small-molecular drug doxorubicin (DOX) yielding lower binding energy than conventional DOX binding sites. This increases the binding affinity of DOX, allowing for high drug loading content and efficiency, and preventing drug leakage under physiological condition. As a proof of concept, the hybrid nanomaterials equipped with aptamer are used to carry DOX and antisense oligonucleotide G3139, which effectively inhibits solid tumor growth and shows negligible side effects on mice. It is anticipated that this approach would find broad applications in hybrid materials design and precise medicine.
DNA 框架已被广泛用作药物输送的亲和支架。然而，很少有研究关注合理设计来全面提高其稳定性、内化动力学和药物装载效率。在此，通过使用分子对接工具，合理设计了基于 DNA 框架的杂化纳米材料，其中框架作为支持共轭聚合物的模板。该杂化材料在生物流体中表现出高稳定性，这是由于 DNA 和阳离子共轭聚合物之间的多种相互作用。通过分子对接，发现共轭聚合物在 DNA 大沟中的特定结构会产生一个用于小分子药物阿霉素（DOX）的独特口袋，其结合能低于传统 DOX 结合位点。这增加了 DOX 的结合亲和力，允许高药物装载含量和效率，并在生理条件下防止药物泄漏。作为概念验证，用适配体装备的杂化纳米材料用于携带 DOX 和反义寡核苷酸 G3139，有效抑制实体瘤生长，对小鼠几乎没有副作用。预计这种方法将在杂化材料设计和精准医学中得到广泛应用。
