Advancing targeted combination chemotherapy in triple negative breast cancer: nucleolin aptamer-mediated controlled drug release

Yuan Ma*, Duoli Xie, Zefeng Chen, Xinyang Shen, Xiaoqiu Wu, Feng Ding, Shijian Ding, Yufei Pan, Fangfei Li, Aiping Lu*, Ge Zhang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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.
Original languageEnglish
Article number604
Number of pages13
JournalJournal of Translational Medicine
Volume22
Issue number1
DOIs
Publication statusPublished - 1 Jul 2024

Scopus Subject Areas

  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • AS1411
  • Fluorouracil
  • Paclitaxel
  • Redox-responsive linker
  • Scheduled drug release
  • Triple negative breast cancer

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