RNA G-quadruplex as supramolecular carrier for cancer-selective delivery

Setembro 2019

Nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands; their high chemical flexibility; as well as tissue penetration capability. RNA G-quadruplex (rG4) sequences have been described as structures with high stability and selectivity towards cancer cells. Recently, precursor microRNAs (pre-miRNAs) have been described as new G4 forming molecules. Surface nucleolin (NCL) is a known target of aptamer G4 AS1411 and is overexpressed on prostate cancer cells when compared with normal cells. We have shown that the sequence 5′ GGGAGGGAGGGACGGG 3′ found in pre-miR-149 forms a rG4 parallel structure, which can bind NCL. Also, another rG4 sequence with a longer loop was evaluated in terms of G4 formation, stabilization and binding affinity to NCL. Both rG4s sequences were studied as supramolecular carriers for the cancer-selective delivery of acridine ligand C8. The rG4s-C8 complexes showed high affinity (KD = 10−6 M) and stabilization (Tm > 30 °C). The affinity of the rG4s-C8 complexes against NCL was in the low nanomolar range, indicating that C8 did not affect NCL binding. Noteworthy, the short loop rG4-C8 complex showed selective antiproliferative effects in prostate cancer cells when compared with normal prostatic cells. The stability and nuclease resistance of rG4 and rG4-C8 complex were evaluated in biological conditions and revealed the maintenance of G4 structure and complex stability. Furthermore, confocal microscopy studies confirmed the potential of rG4s-C8 complexes in the targeting of prostate cancer cells. Overall, it is here demonstrated that the rG4 found in pre-miR-149 can be used as a cancer-selective delivery carrier of C8 to prostate cancer cells.

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: 60350767

  De: cienciavitae

  ID: 701463

• 

  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: 65298451

  De: cienciavitae

  ID: 819756

Elsevier

https://www.sciencedirect.com/journal/european-journal-of-pharmaceutics-and-biopharmaceutics

European Journal of Pharmaceutics and Biopharmaceutics

473

479

142

0939-6411

10.1016/j.ejpb.2019.07.017

WOS:000488654000048

basic-medicine - Medicina Básica

Palavras-chave

• Precursor microRNA 149
• G-quadruplex
• Nucleolin
• Drug delivery
• Prostate cancer,

eng - Inglês

http://dx.doi.org/10.1016/j.ejpb.2019.07.017