RNA纳米技术用于与癌症的高付核苷类似物，具有协同作用
RNA Nanotechnology for Codelivering High-Payload Nucleoside Analogs to Cancer with a Synergetic Effect
影响因子:4.50000
分区:医学2区 / 药学2区 医学：研究与实验3区
发表日期:2024 Nov 04
作者:
Xin Li, Kai Jin, You-Cheng Liao, Wen-Jui Lee, Li-Ching Chen, Tzu-Chun Cheng, Yuan-Soon Ho, Peixuan Guo
摘要
核苷类似物是对癌症治疗的有效抑制剂，但是其在人类中应用的主要障碍是它们的毒性，非特异性和缺乏目标递送工具。在这里，我们报告了RNA四方连接（4WJ）的使用来传递两个核苷类似物，氟耐酸（FUDR）和吉西他滨（GEM），并通过常规和简单的固态RNA合成和纳米颗粒组件具有高有效载荷。 RNA纳米技术的设计用于核苷类似物和化学治疗药物紫杉醇（PTX）的共传递，从而导致协同作用和高效率在治疗三层乳腺癌（TNBC）方面。 4WJ-Crug复合物已被证实具有有效的肿瘤自发靶向，并且无毒性，因为先前已经证明RNA纳米颗粒的运动能够使这些RNA-drug复合物能够自发地积累在肿瘤血管中。 RNA的负电荷使那些不针对肿瘤脉管系统的RNA复合物可以在血液中循环并通过肾脏肾小球进入尿液，而无需在器官中积聚，因此是无毒的。可以通过定义的加载量，位置和比率精确控制RNA 4WJ的药物。在固相RNA合成过程中，将核苷类似物掺入4WJ仅需要使用核苷类似物磷光素的一步，而无需进行额外的共轭和纯化过程。
Abstract
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.