Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 142, Issue -, Pages 473-479Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2019.07.017
Keywords
Precursor microRNA 149; G-quadruplex; Nucleolin; Drug delivery; Prostate cancer
Categories
Funding
- Fundacao para a Ciencia e Tecnologia (FCT), Portugal [PD/BD/142851/2018, PD/00065/2013]
- FCT [IF/00959/2015, UID/Multi/04349/2019]
- FLAD-Healthcare 2020, Portugal [45/2018, MIT-XPL/BIO/0008/2017, UTAP-EXPL/NTec/0015/2017]
- POCI COMPETE 2020 - Operational Programme Competitiveness and Internationalisation in Axis I - Strengthening research, technological development and innovation [POCI-01-0145-FEDER-007491]
- Fundação para a Ciência e a Tecnologia [PD/BD/142851/2018] Funding Source: FCT
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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 C-8. The rG4s-C-8 complexes showed high affinity (K-D = 10(-6) M) and stabilization (T-m > 30 degrees C). The affinity of the rG4s-C-8 complexes against NCL was in the low nanomolar range, indicating that C-8 did not affect NCL binding. Noteworthy, the short loop rG4-C-8 complex showed selective antiproliferative effects in prostate cancer cells when compared with normal prostatic cells. The stability and nuclease resistance of rG4 and rG4-C-8 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-C-8 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 C-8 to prostate cancer cells.
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