Article In: orcid, cienciavitae

AS1411 derivatives as carriers of G-quadruplex ligands for cervical cancer cells

International Journal of Pharmaceutics

Joana Figueiredo; Jéssica Lopes-Nunes; et al — 2019 — Elsevier

Key information

Authors:

Joana Figueiredo; Jéssica Lopes-Nunes; Josué Carvalho; Francisca Antunes; Márcia Ribeiro; Maria Paula Cabral Campello (Maria Paula Cordeiro Crespo Cabral Campello Aboim de Barros); António Paulo (António Manuel Rocha Paulo); et al

Published in

September 2019

Abstract

Nucleic acid aptamers can specifically bind to target molecules on the cell membrane that mediate their entrance into the cells. Their small size, high binding affinity, specificity, good biocompatibility, stability and low immunogenicity make them ideal drug delivery systems for cancer therapy. These biopharmaceuticals have potential for the delivery of anticancer compounds to diseased tissues, increasing their effectiveness while mitigating the off-target toxicity towards healthy cells. Herein, we have studied two quadruplex-forming DNA sequences derived from the nucleolin-targeted aptamer AS1411 as supramolecular carriers for the cancer-selective delivery of acridine orange derivatives (C3, C5 and C8) in cervical cancer cells. The devised delivery strategy relied on the non-covalent association of the acridine derivatives and the G-quadruplex (G4) structures. This association is done with a high binding strength, as suggested by the obtained KD values in the 10−6–10−7 M range, leading to the thermal stabilization of the G4 structures, particularly for C8. The stability of the resulting supramolecular conjugates was evaluated in fetal bovine serum, which proved their resistance against serum nucleases up to 48 h. Previous studies showed that the tested acridine orange derivatives were cytotoxic towards cervical cancer cells (HeLa) and non-malignant cells. However, when conjugated to AS1411 derivatives, the cytotoxicity of the free ligands towards non-malignant cells was restrained. Furthermore, conjugated C3 showed an enhanced cytotoxicity against HeLa cancer cells. Confocal microscopy indicated that both G4 sequences appear to colocalize with nucleolin, suggesting their ability to recognize and bind nucleolin on the cell surface. Additionally, the results confirmed the internalization of these delivery systems into HeLa cancer cells and their sustained cell trafficking, although being able to dissociate intracellularly to deliver C8 to the nucleoli. Overall, we showed that AS1411-derived G4s can be used as a potential cancer drug delivery system for cervical cancer.

Publication details

Authors in the community:

Publication version

AO - Author's Original

Publisher

Elsevier

Link to the publisher's version

https://www.sciencedirect.com/journal/international-journal-of-pharmaceutics

Title of the publication container

International Journal of Pharmaceutics

First page or article number

118511

Volume

568

ISSN

0378-5173

DOI

10.1016/j.ijpharm.2019.118511

WoS (Web of Science)

WOS:000482624300007

Fields of Science and Technology (FOS)

basic-medicine - Basic medicine

Keywords

  • G-quadruplex aptamers
  • Drug delivery
  • AS1411 derivatives
  • Acridine orange ligands
  • Cervical cancer,

Publication language (ISO code)

eng - English

Alternative identifier (URI)

http://dx.doi.org/10.1016/j.ijpharm.2019.118511

Rights type:

Only metadata available