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Lipid-modified G4-decoy oligonucleotide anchored to nanoparticles: delivery and bioactivity in pancreatic cancer
S Cogoi1, U Jakobsen2,3, E B Pedersen2
1Department of Medical and Biological Sciences, P. le Kolbe 4, 33100 Udine, Italy.
Abstract:
KRAS is mutated in >90% of pancreatic ductal adenocarcinomas. As its inactivation leads to tumour regression, mutant KRAS is considered an attractive target for anticancer drugs. In this study we report a new delivery strategy for a G4-decoy oligonucleotide that sequesters MAZ, a transcription factor essential for KRAS transcription. It is based on the use of palmitoyl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with lipid-modified G4-decoy oligonucleotides and a lipid-modified cell penetrating TAT peptide. The potency of the strategy in pancreatic cancer cells is demonstrated by cell cytometry, confocal microscopy, clonogenic and qRT-PCR assays.
Insights
Researchers developed a novel liposome delivery system for G4-decoy oligonucleotides targeting MAZ, a key factor in KRAS transcription. This strategy shows promise for treating pancreatic cancer by inhibiting mutant KRAS.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery Systems
Background:
- Mutations in KRAS are prevalent in over 90% of pancreatic ductal adenocarcinomas.
- Inactivating mutant KRAS is a promising therapeutic strategy for pancreatic cancer due to its role in tumor regression.
Purpose of the Study:
- To develop and evaluate a novel liposome-based delivery system for G4-decoy oligonucleotides targeting the transcription factor MAZ.
- To assess the efficacy of this delivery strategy in inhibiting KRAS transcription in pancreatic cancer cells.
Main Methods:
- Utilized palmitoyl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with lipid-modified G4-decoy oligonucleotides.
- Incorporated a lipid-modified cell-penetrating TAT peptide for enhanced delivery.
- Evaluated cellular effects using cell cytometry, confocal microscopy, clonogenic assays, and qRT-PCR.
Main Results:
- Demonstrated successful delivery of G4-decoy oligonucleotides into pancreatic cancer cells via the liposome system.
- Confirmed the sequestration of MAZ, a transcription factor crucial for KRAS transcription.
- Observed significant anti-cancer effects in pancreatic cancer cells, indicating the strategy's potency.
Conclusions:
- The developed liposome-based delivery system offers a novel and effective strategy for targeting KRAS transcription in pancreatic cancer.
- This approach holds potential for developing new therapeutic interventions against KRAS-driven pancreatic ductal adenocarcinomas.
