Li Wei, Wang Zhongliang, Su Qing, Chen Jie, Wu Qian, Sun Xue, Zhu Shuhan, Li Xiaodie, Wei Hao, Zeng Jialin, Guo Linlang, Zhang Chao, He Jian
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China.
Department of Endocrinology and Metabolism, 481 Center for Diabetes and Metabolism Research, West China 482 Hospital, Sichuan University, Chengdu 610041, China.
JACS Au. 2024 Mar 29;4(4):1345-1355. doi: 10.1021/jacsau.3c00661. eCollection 2024 Apr 22.
A major limitation of tumor antiangiogenic therapy is the pronounced off-target effect, which can lead to unavoidable injury in multiple organs. Ensuring sufficient delivery and controlled release of these antiangiogenic agents at tumor sites is crucial for realizing their clinical application. Here, we develop a smart DNA-based nanodrug, termed Endo-rDFN, by precisely assembling the antiangiogenic agent, endostar (Endo), into a reconfigurable DNA framework nanotube (rDFN) that could recognize tumor-overexpressed nucleolin to achieve the targeted delivery and controllable release of Endo. Endo-rDFN can not only effectively enhance the tumor-targeting capability of Endo and maintain its efficient accumulation in tumor tissues but also achieve on-demand release of Endo at tumor sites via the specific DNA aptamer for tumor-overexpressed nucleolin, named AS1411. We also found that Endo-rDFN exhibited significant inhibition of angiogenesis and tumor growth, while also providing effective protection against multiorgan injury (heart, liver, spleen, kidney, lung, etc.) to some extent, without compromising the function of these organs. Our study demonstrates that rDFN represents a promising vector for reducing antiangiogenic therapy-induced multiorgan injury, highlighting its potential for promoting the clinical application of antiangiogenic agents.
肿瘤抗血管生成疗法的一个主要局限性是明显的脱靶效应，这可能导致多个器官不可避免的损伤。确保这些抗血管生成药物在肿瘤部位的充分递送和控释对于实现其临床应用至关重要。在此，我们通过将抗血管生成药物内皮抑素（Endo）精确组装到可重构的DNA框架纳米管（rDFN）中，开发了一种基于DNA的智能纳米药物，称为Endo-rDFN，该纳米管可以识别肿瘤过表达的核仁素，以实现Endo的靶向递送和可控释放。Endo-rDFN不仅可以有效增强Endo的肿瘤靶向能力并维持其在肿瘤组织中的高效积累，还可以通过针对肿瘤过表达核仁素的特异性DNA适配体AS1411在肿瘤部位实现Endo的按需释放。我们还发现，Endo-rDFN在一定程度上对血管生成和肿瘤生长具有显著抑制作用，同时还能有效保护多器官（心脏、肝脏、脾脏、肾脏、肺等）免受损伤，且不影响这些器官的功能。我们的研究表明，rDFN是一种有前途的载体，可减少抗血管生成疗法引起的多器官损伤，突出了其在促进抗血管生成药物临床应用方面的潜力。
