Advancing Targeted Combination Chemotherapy in Triple Negative Breast Cancer: Nucleolin Aptamer-mediated Controlled Drug Release

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Jul 2

PMID 38951906

Authors

Yuan Ma

Duoli Xie

Zefeng Chen

Xinyang Shen

Xiaoqiu Wu

Feng Ding

Shijian Ding

Yufei Pan

Fangfei Li

Aiping Lu

Ge Zhang

Affiliations

Soon will be listed here.

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.

Citing Articles

Peptide Aptamer-Paclitaxel Conjugates for Tumor Targeted Therapy.

Shen X, Ma Y, Luo H, Abdullah R, Pan Y, Zhang Y Pharmaceutics. 2025; 17(1).

PMID: 39861688 PMC: 11768741. DOI: 10.3390/pharmaceutics17010040.

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