AS1411 is a G-rich DNA oligonucleotide that functions as an aptamer of the protein nucleolin, found at high levels on the surface of cancer cells but not on the surface of normal cells. Herein, we have studied AS1411 as a supramolecular carrier for the delivery of an acridine-based G-quadruplex ligand, C8, to HeLa cancer cells. Two AS1411 derivatives, LNA-AS1411 and U-AS1411, were also tested, in an attempt to compare AS1411 pharmacological properties. The results showed that AS1411-C8 complexation was made with great binding strength and that it lowered the ligand's cytotoxicity towards non-malignant cells. This effect was suggested to be due to a decreased internalization of the complexed versus free C8 as shown by flow cytometry. The AS1411 derivatives, despite forming a stable complex with C8, lacked the necessary tumour-selective behaviour. The binding of C8 to AS1411 G-quadruplex structure did not negatively affect the recognition of nucleolin by the aptamer. The AS1411-C8 repressed c-MYC expression at the transcriptional level, possibly due to C8 ability to stabilize the c-MYC promoter G-quadruplexes. Overall, this study demonstrates the usefulness of AS1411 as a supramolecular carrier of the G-quadruplex binder C8 and the potential of using its tumour-selective properties for the delivery of ligands for cancer therapy.

Centro de Ciências e Tecnologias Nucleares Instituto Superior Técnico Universidade de Lisboa Estrada Nacional 10 2695 066 Bobadela LRS Portugal

CICS UBI Centro de Investigação em Ciências da Saúde Universidade da Beira Interior Av Infante D Henrique 6200 506 Covilhã Portugal

Unidade de Gestão Operacional em Citometria Centro Hospitalar e Universitário de Coimbra Coimbra Portugal CIMAGO iCBR CIBB Faculdade de Medicina da Universidade de Coimbra Coimbra Portugal Instituto Politécnico de Coimbra ESTESC Coimbra Health School Ciências Biomédicas Laboratoriais Coimbra Portugal

Univ Bordeaux ARNA laboratory INSERM U1212 CNRS UMR 5320 IECB F 33600 Pessac France

Univ Bordeaux ARNA laboratory INSERM U1212 CNRS UMR 5320 IECB F 33600 Pessac France Institute of Biophysics AS CR v v i Kralovopolska 135 612 65 Brno Czech Republic

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