RNA纳米技术用于高载量核苷类似物的协同递送及抗癌效果

RNA Nanotechnology for Codelivering High-Payload Nucleoside Analogs to Cancer with a Synergetic Effect

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MOLECULAR PHARMACEUTICS

影响因子:4.5

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

DOI: 10.1021/acs.molpharmaceut.4c00674

摘要

核苷类似物是癌症治疗的有效抑制剂，但其在人体应用中的主要障碍包括毒性、非特异性和缺乏靶向递送工具。本文报道利用RNA四叉交叉（4WJs）实现高载量递送两种核苷类似物——氟尿嘧啶（FUDR）和吉西他滨（GEM），通过常规且简单的固相RNA合成和纳米粒子组装。基于RNA纳米技术的核苷类似物及化疗药物紫杉醇（PTX）协同递送设计，获得了协同效应并在三阴性乳腺癌（TNBC）治疗中表现出高效。验证结果显示，4WJ-药物复合物具有高效的肿瘤自发靶向能力，无毒性，因为RNA纳米粒子的运动性已被证明能使这些RNA-药物复合物自发积累在肿瘤血管中。RNA的负电荷使未靶向肿瘤血管的RNA复合物在血液中循环，通过肾小球进入尿液，避免在器官中积累，从而无毒性。核苷类似物的包封入RNA 4WJ中，可精确控制载荷数量、位置和比例。利用核苷类似物的磷酰胺试剂在固相RNA合成过程中一步实现包封，无需额外的连接和纯化步骤。

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.