三阴性乳腺癌（TNBC）是一种复发性、异质性和侵袭性乳腺癌。紫杉醇和氟尿嘧啶序贯治疗 TNBC 患者已显示出有希望的结果。然而，将这些化疗药物依次递送至 TNBC 肿瘤具有挑战性。我们的目标是通过紫杉醇和氟尿嘧啶的顺序递送来探索TNBC的精准治疗策略。我们开发了一种双化疗负载适配体，其中氧化还原敏感的笼状紫杉醇用于快速释放，不可裂解的笼状氟尿嘧啶用于缓慢释放。使用酶联寡核苷酸测定和表面等离子共振测定验证与靶蛋白的结合亲和力。使用流式细胞术测定和共聚焦显微镜测定证实了肿瘤的靶向和内化能力。通过体外和体内药理学研究评估其对TNBC进展的抑制作用。合成了各种氧化还原响应的适配体-紫杉醇缀合物。其中，带有硫醚连接体（ASP）的AS1411-紫杉醇缀合物对TNBC细胞表现出较高的抗增殖能力，并且通过氟尿嘧啶修饰进一步提高了其靶向能力。氟尿嘧啶修饰的带有硫醚连接体的AS1411-紫杉醇偶联物（FASP）表现出对TNBC细胞的有效靶向性，并显着提高了体外和体内对TNBC进展的抑制作用。本研究成功开发了氟尿嘧啶修饰的带有硫醚连接体的AS1411-紫杉醇偶联物用于 TNBC 的靶向联合化疗。这些缀合物能够有效识别 TNBC 细胞，从而实现紫杉醇和氟尿嘧啶的靶向递送和控释。这种方法产生了协同抗肿瘤作用并降低了体内毒性。然而，未来的转化应用需要进一步研究与稳定性、免疫原性和可扩展性相关的挑战。© 2024。作者。

Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil.We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo.Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo.This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.© 2024. The Author(s).