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  • br Introduction br Conventional chemotherapeutics su er from a


    1. Introduction
    Conventional chemotherapeutics suffer from a narrow therapeutic window due to their poor specificity towards tumor/healthy cells, leading to the so called “off-target” side effects (Zhou and Rossi, 2017). There is a need of developing targeted delivery systems to improve drug selective accumulation in cancer cells while increasing its effectiveness.
    Corresponding author.
    E-mail address: [email protected] (C. Cruz). 1 These authors contributed equally to this work. 
    One approach to tackle such need is the use of cell-specific carriers that guide the delivery of the drug to the cancer cell. Nucleic 4-Hydroxytamoxifen aptamers have emerged as an attractive class of drug delivery systems due to their ability to bind with high affinity to specific ligands, their high chemical flexibility as well as tissue penetration capability (Zhou and Rossi, 2017). They have several advantages such as a relatively small size, flexible structure, inexpensive and reproducible chemical production
    J. Figueiredo, et al.
    when compared to antibodies, ease of chemical modification, high stability and lack of immunogenicity (Zhou and Rossi, 2017). Taking advantage of such properties, nucleic acid aptamers have been used to selectively convey ligands with therapeutic or imaging purposes into cancer cells (Alshaer et al., 2018; Vandghanooni et al., 2018).
    Several aptamers have already been developed against a wide array of therapeutically relevant targets (Alshaer et al., 2018; Vandghanooni et al., 2018; Zhu et al., 2015). Among these, DNA aptamer AS1411 that targets the nucleolin protein has been extensively used as a cancer-targeting agent (Bates et al., 2017; Vandghanooni et al., 2018c). Nu-cleolin is considered a tumor biomarker as it is overexpressed in the surface of cancer cells, while in non-malignant cells it is found primarily in the nuclei and cytoplasm (Mongelard and Bouvet, 2007). In vivo studies showed that AS1411-linked ligands selectively accumulate in cancer cells following systemic administration, emphasizing the po-tential of using this aptamer as a drug delivery system (Bates et al., 2017). Due to its G-rich nature, AS1411 is able to fold into a G4 structure (Bates et al., 2017). The aptamer structure is however highly polymorphic with at least eight different folding patterns detected by size exclusion chromatography (Dailey et al., 2010), complicating the identification of the structure(s) relevant for its biological behavior. More recently, Phan and colleagues reported the NMR structures of a series of AS1411 aptamer derivatives that adopted a single G4 structure in solution with identical antiproliferative activity (Chung et al., 2015; Do et al., 2017). These AS1411 derivatives, namely AT11 and AT11-B0 (a more thermally stable version of AT11) (Do et al., 2017), are po-tentially promising for the development of cancer-targeted systems for the delivery of anticancer ligands.
    Herein, using AT11 and AT11-B0 derivatives, we studied aptamer-guided approaches for the delivery of ligands with anticancer potential into HeLa cervical cancer cells. The ligands used were acridine orange (AO) derivatives (C3, C5 and C8) that showed potent inhibitory effect towards HeLa cells (low micromolar IC50 values at 24 h incubation) (Carvalho et al., 2018; Pereira et al., 2017). However, the ligands had a similar antiproliferative effect on non-malignant human fibroblasts (NHDF) and their application in further in vitro or in vivo assays would benefit from a cancer-selective drug delivery system. The ligands were also shown to bind and stabilize a variety of G4 structures such as telomeric and oncogene promoter G4s (Carvalho et al., 2018). Using a supramolecular strategy relying on the G4-binding ability of the AO derivatives, lacking any chemical modifications of both sequences and ligands, the ability of AT11 and AT11-B0 to selectively convey C3, C5 and C8 to HeLa human cervical cancer cells was assessed using an array of spectroscopic and biochemical techniques.