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

T. Santos, Patrícia Pereira, Maria Paula Cabral Campello, António Paulo, João A. Queiroz, Eurico Cabrita, C. Cruz

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)473-479
Number of pages7
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume142
DOIs
Publication statusPublished - 1 Sep 2019

Keywords

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

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