Aptamer-guided acridine derivatives for cervical cancer.

Abstract

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.

• Authors: Josué Carvalho, Jéssica Lopes-Nunes, Ana Catarina Lopes, Maria Paula Cabral Campello, António Paulo, João A Queiroz, Carla Cruz
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 17 Issue 11 Pg. 2992-3002 (03 13 2019) ISSN: 1477-0539 [Electronic] England
• PMID: 30810582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acridines
• Antineoplastic Agents
• Aptamers, Nucleotide
• Drug Carriers
• Ligands

Topics

• Acridines (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Aptamers, Nucleotide (chemistry)
• Cell Proliferation (drug effects)
• Cell Survival
• Dose-Response Relationship, Drug
• Drug Carriers (chemistry)
• Drug Screening Assays, Antitumor
• Female
• HeLa Cells
• Humans
• Ligands
• Molecular Structure
• Structure-Activity Relationship
• Uterine Cervical Neoplasms (drug therapy, pathology)