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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：三阴性乳腺癌（TNBC）是一种复发性乳腺癌，异质，和浸润性乳腺癌。以顺序方式用紫杉醇和氟尿嘧啶治疗TNBC患者已显示出有希望的结果。然而,将这些化学治疗剂依次递送至TNBC肿瘤具有挑战性.我们旨在通过紫杉醇和氟尿嘧啶的序贯给药探索TNBC的精确治疗策略。
方法：我们开发了一种双重化学负载的适体，该适体具有对氧化还原敏感的笼式紫杉醇，用于快速释放，而不可裂解的笼式氟尿嘧啶用于缓慢释放。使用酶连接的寡核苷酸测定和表面等离子体共振测定验证对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进入肿瘤的靶向和内化能力。通过体外和体内药理学研究评估了对TNBC进展的抑制作用。
结果:合成了各种氧化还原响应性适体-紫杉醇缀合物。其中,具有硫醚接头（ASP）的AS1411-紫杉醇缀合物对TNBC细胞具有较高的抗增殖能力，并通过氟尿嘧啶修饰进一步提高了其靶向能力。具有硫醚接头(FASP)的氟尿嘧啶修饰的AS1411-紫杉醇缀合物表现出对TNBC细胞的有效靶向,并且在体外和体内显著改善对TNBC进展的抑制作用。
结论：本研究成功开发了具有硫醚接头的氟尿嘧啶修饰的AS1411-紫杉醇偶联物，用于TNBC的靶向联合化疗。这些缀合物证明了对TNBC细胞的有效识别，实现紫杉醇和氟尿嘧啶的靶向递送和控释。这种方法导致协同抗肿瘤作用和降低的体内毒性。然而,与稳定有关的挑战，免疫原性,和可扩展性需要进一步研究未来的翻译应用程序。
方法：我们开发了一种双重化学负载的适体，该适体具有对氧化还原敏感的笼式紫杉醇，用于快速释放，而不可裂解的笼式氟尿嘧啶用于缓慢释放。使用酶连接的寡核苷酸测定和表面等离子体共振测定验证对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进入肿瘤的靶向和内化能力。通过体外和体内药理学研究评估了对TNBC进展的抑制作用。
结果:合成了各种氧化还原响应性适体-紫杉醇缀合物。其中,具有硫醚接头（ASP）的AS1411-紫杉醇缀合物对TNBC细胞具有较高的抗增殖能力，并通过氟尿嘧啶修饰进一步提高了其靶向能力。具有硫醚接头(FASP)的氟尿嘧啶修饰的AS1411-紫杉醇缀合物表现出对TNBC细胞的有效靶向,并且在体外和体内显著改善对TNBC进展的抑制作用。
结论：本研究成功开发了具有硫醚接头的氟尿嘧啶修饰的AS1411-紫杉醇偶联物，用于TNBC的靶向联合化疗。这些缀合物证明了对TNBC细胞的有效识别，实现紫杉醇和氟尿嘧啶的靶向递送和控释。这种方法导致协同抗肿瘤作用和降低的体内毒性。然而,与稳定有关的挑战，免疫原性,和可扩展性需要进一步研究未来的翻译应用程序。
