Aptamer-guided acridine derivatives for cervical cancer

18/02/2019

DNA aptamers represent a way to target cancer cells at a molecular level and continue to be developed with a view to improve treatment and imaging in cancer medicine. AT11-L0, derived from the DNA sequence AT11, forms a single major parallel G-quadruplex (G4) conformation and exhibits an anti-proliferative activity similar to that of AT11 and AS1411 aptamers. On the other side, acridine orange derivatives represent a valuable class of G4 ligands. Herein, we evaluate AT11-L0 G4 as a supramolecular carrier for the delivery of acridine ligands C3, C5 and C8 to HeLa cancer cells. The CD titrations suggest no changes in the chiroptical signal upon addition of an excess of ligands maintaining the parallel G4 topology and C8 stabilizes the structure for more than 20 °C. All the ligands exhibit high affinity (micromolar range) towards AT11-L0 G4, and the respective complexes against nucleolin (nanomolar range) suggesting that the ligands do not negatively affect the recognition of the nucleolin by AT11-L0 G4. NMR studies showed that AT11-L0 forms a G4 containing four G-tetrad layers. Ligand C8 binds AT11-L0 G4 through π–π stacking of the acridine moiety onto the top-tetrad with the involvement of additional interactions with the ligand's side chain and iodobenzene ring. In vitro, the complexes lowered the ligand's cytotoxicity towards non-malignant cells but have a weak inhibitory effect in HeLa cancer cells, except for the AT11-L0-C5 complex. All complexes are efficiently internalized into nucleolin-positive HeLa cells. Overall, these results suggest that AT11-L0 can act as an aptamer by targeting nucleolin and a delivery system of cytotoxic ligands for cervical cancer.

Autores da comunidade :

• 

  M

  Maria Paula Cordeiro Crespo Cabral Campello Aboim de Barros

  ist25375

  Afiliações e fontes

  IST > DECN

  Departamento de Engenharia e Ciências Nucleares

  IST > C2TN

  Centro de Ciências e Tecnologias Nucleares

  De: orcid

  ID: 56320085

  De: cienciavitae

  ID: 616695

• 

  A

  António Manuel Rocha Paulo

  ist126677

  Afiliações e fontes

  IST > DECN

  Departamento de Engenharia e Ciências Nucleares

  IST > C2TN

  Centro de Ciências e Tecnologias Nucleares

  De: orcid

  ID: 57710077

  De: cienciavitae

  ID: 615113

AO - Versão original do autor

Royal Society of Chemistry

https://pubs.rsc.org/en/journals/journal/ob

Organic & Biomolecular Chemistry

3002

17

11

1477-0520

10.1039/c9ob00318e

WOS:000461223700017

chemical-sciences - Química

eng - Inglês

http://dx.doi.org/10.1039/c9ob00318e