Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Department of Biological Science & Technology, China Medical University, Taichung 40402, Taiwan.
Mol Pharm. 2024 Nov 4;21(11):5690-5702. doi: 10.1021/acs.molpharmaceut.4c00674. Epub 2024 Oct 10.
Nucleoside analogs are potent inhibitors for cancer treatment, but the main obstacles to their application in humans are their toxicity, nonspecificity, and lack of targeted delivery tools. Here, we report the use of RNA four-way junctions (4WJs) to deliver two nucleoside analogs, floxuridine (FUDR) and gemcitabine (GEM), with high payloads through routine and simple solid-state RNA synthesis and nanoparticle assembly. The design of RNA nanotechnology for the co-delivery of nucleoside analogs and the chemotherapeutic drug paclitaxel (PTX) resulted in synergistic effects and high efficacy in the treatment of Triple-Negative Breast Cancer (TNBC). The 4WJ-drug complexes were confirmed to have efficient tumor spontaneous targeting and no toxicity because the motility of RNA nanoparticles has been previously shown to enable these RNA-drug complexes to spontaneously accumulate in tumor blood vessels. The negative charge of RNA enables those RNA complexes that are not targeted to tumor vasculature to circulate in the blood and enter the urine through the kidney glomerulus, without accumulating in organs, therefore being nontoxic. Drug incorporation into RNA 4WJ can be precisely controlled with a defined loading amount, location, and ratio. The incorporation of nucleoside analogs into 4WJ only requires one step using nucleoside analogue phosphoramidites during solid-phase RNA synthesis, without the need for additional conjugation and purification processes.
核苷类似物是治疗癌症的有效抑制剂，但将其应用于人体的主要障碍是其毒性、非特异性和缺乏靶向递药工具。在这里，我们报告了使用 RNA 四链结（4WJ）通过常规和简单的固态 RNA 合成和纳米颗粒组装来高载量递送两种核苷类似物，氟尿嘧啶（FUDR）和吉西他滨（GEM）。为了实现核苷类似物和化疗药物紫杉醇（PTX）的共递药，设计了 RNA 纳米技术，这导致了协同作用和对三阴性乳腺癌（TNBC）的高效治疗。4WJ-药物复合物被证实具有有效的肿瘤自发性靶向作用，而且没有毒性，因为 RNA 纳米颗粒的迁移性以前已经表明这些 RNA-药物复合物能够自发地在肿瘤血管中积累。RNA 的负电荷使那些未靶向肿瘤血管的 RNA 复合物能够在血液中循环并通过肾脏肾小球进入尿液，而不会在器官中积累，因此没有毒性。药物可以通过在固相 RNA 合成过程中使用核苷类似物的磷酰胺来精确控制 4WJ 中的药物掺入量、位置和比例。将核苷类似物掺入 4WJ 只需要在固相 RNA 合成过程中使用核苷类似物的磷酰胺进行一步反应，而不需要额外的偶联和纯化过程。
