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Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy.

ABSTRACT: Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer-drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the therapeutic potential of aptamer-DOX conjugates, we synthesized trifurcated Newkome-type monomer (TNM) structures with three DOX molecules bound through pH-sensitive hydrazone bonds to formulate TNM-DOX. The aptamer-TNM-DOX conjugate (Apt-TNM-DOX) was produced through a simple self-loading process. Chemical validation revealed that Apt-TNM-DOX stably carried high drug payloads of 15 DOX molecules per aptamer sequence. Functional characterization showed that DOX payload release from Apt-TNM-DOX was pH-dependent and occurred at pH 5.0, which reflects the microenvironment of tumor cell lysosomes. Further, Apt-TNM-DOX specifically targeted lymphoma cells without affecting off-target control cells. Aptamer-mediated cell binding resulted in the uptake of Apt-TNM-DOX into targeted cells and the release of DOX payload within cell lysosomes to inhibit growth of targeted lymphoma cells. The Apt-TNM-DOX provides a simple, non-toxic approach to develop aptamer-based targeted therapeutics and may reduce the non-specific side effects associated with traditional chemotherapy.

SUBMITTER: Zeng Z

PROVIDER: S-EPMC8398837 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy.

Zeng Zihua Z Qi Jianjun J Wan Quanyuan Q Zu Youli Y

Pharmaceutics 20210807 8

Doxorubicin (DOX) is a common anti-tumor drug that binds to DNA or RNA via non-covalent intercalation between G-C sequences. As a therapeutic agent, DOX has been used to form aptamer-drug conjugates for targeted cancer therapy in vitro and in vivo. To improve the therapeutic potential of aptamer-DOX conjugates, we synthesized trifurcated Newkome-type monomer (TNM) structures with three DOX molecules bound through pH-sensitive hydrazone bonds to formulate TNM-DOX. The aptamer-TNM-DOX conjugate (A ...[more]

PMID: 34452182

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Project description:BackgroundTriple-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.MethodsWe 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.ResultsVarious 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.ConclusionsThis 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.

Dataset Information

Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy.

Publications

Aptamers with Self-Loading Drug Payload and pH-Controlled Drug Release for Targeted Chemotherapy.

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