Drug-selective modulation of chemotherapeutic cytotoxicity by nucleolin-targeting G-quadruplex aptamers in primary lymphoma cells

초록

Functional heterogeneity in therapeutic response remains a major challenge in lymphoma management, and genomic classification alone does not fully predict drug sensitivity. Ex vivo drug sensitivity testing (DST) provides a functional platform to evaluate pharmacologic responses directly in patient-derived tumor cells. Although nucleolin-targeting G-quadruplex aptamers such as AS1411 and AT11 have demonstrated anti-cancer activity, whether they modulate the efficacy of conventional chemotherapeutic agents in primary tumor cells remains largely unexplored. In this study, we integrated ex vivo DST, flow cytometric assessment of target engagement, and in silico docking analysis to investigate drug–aptamer interactions in primary lymphoma samples. Across four chemotherapeutic agents, doxorubicin exhibited the most consistent aptamer-associated modulation. Specifically, AT11 potentiated doxorubicin-induced cytotoxicity, whereas AS1411 produced neutral or attenuating effects under comparable conditions. Docking analysis supported structurally plausible interaction between doxorubicin and the G-quadruplex scaffold of AT11. Notably, AT11 binding positivity strongly correlated with the degree of doxorubicin potentiation, whereas lineage-defining immunophenotypic markers showed minimal association. These findings demonstrate that G-quadruplex aptamers can selectively modulate chemotherapeutic efficacy in primary lymphoma cells and highlight the importance of functional profiling to capture interaction-specific pharmacologic effects. © The Author(s), under exclusive licence to The Korean Society for Biotechnology and Bioengineering 2026.

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