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Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy.

ABSTRACT: Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies.

SUBMITTER: De La Fuente A

PROVIDER: S-EPMC9281582 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAptamers have been widely used as targeted therapeutic agents due to its relatively small physical size, flexible structure, high specificity, and selectivity. Aptamers functionalized nanomaterials, not only enhance the targeting of nanomaterials, but can also improve the stability of the aptamers. We developed aptamer C2NP (Apt) conjugated straight DNA nanotubes (S-DNT-Apt) and twisted DNA nanotubes (T-DNT-Apt) as nanocarriers for doxorubicin (DOX).MethodsThe twisted DNA nanotubes (T-DNT) and straight DNA nanotubes (S-DNT) were assembled with a scaffold and hundreds of staples. Apt was site-specifically anchored on DNA nanotubes with either different spatial distribution (3 or 6 nm) or varied stoichiometry (15Apt or 30Apt). The developed nanocarriers were characterized with agarose gel electrophoresis and transmission electron microscopy. The drug loading and release in vitro were evaluated by measuring the fluorescence intensity of DOX using a microplate reader. The stability of DNT in cell culture medium plus 10% of FBS was evaluated by agarose gel electrophoresis. The cytotoxicity of DNA nanostructures against K299 cells was tested with a standard CCK8 method. Cellular uptake, cell apoptosis, cell cycle and reactive oxygen species level were investigated by flow cytometry. The expression of p53 was examined by Western Blot.ResultsT-DNT-30Apt-6 exhibited the highest cytotoxicity when the concentration of Apt was 120 nM. After intercalation of DOX, the cytotoxicity of DOX@T-DNT-30Apt-6 was further enhanced due to the combination of chemotherapy of DOX and biotherapy of Apt. The enhanced cytotoxicity of DOX@T-DNT-30Apt-6 can be explained by the increase in the cellular uptake, cell apoptosis and intracellular ROS levels. Additionally, the interaction between Apt and its receptor CD30 could upregulate the expression of p53.ConclusionThese results demonstrate that both stoichiometry and spatial arrangement of Apt on T-DNT-Apt influence the anticancer activity. The developed twisted DNA nanotubes may be a solution for the synergistic treatment of cancer.

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Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy.

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