Liposomes decorated with G-Quadruplex Decoy Oligonucleotides: Their Nanoparticle Delivery and efficient Bioactivity in Pancreatic Cancer Cells

Here we demonstrate a possible solution to the delivery problem of oligonucleotides. Unsuccessful delivery of oligonucleotides is the main obstacle to their use as therapeutics although their potential is well documented. We... [ view full abstract ]

Here we demonstrate a possible solution to the delivery problem of oligonucleotides. Unsuccessful delivery of oligonucleotides is the main obstacle to their use as therapeutics although their potential is well documented. We now base delivery on the use of liposomes functionalized with lipid-modified oligonucleotides and a lipid-modified cell penetrating TAT peptides which are anchored non-covalently to the outside surface of the liposomes. In this way the oligonucleotide and the peptide are freely accessible to act as a therapeutic and a cell uptake helper, respectively. The potency of the strategy in pancreatic cancer cells is demonstrated by cell cytometry, confocal microscopy, clonogenic and qRT-PCR assays.

KRAS is mutated in >90% of pancreatic ductal adenocarcinomas (PDAC). As its inactivation leads to tumour regression, mutant KRAS is considered an attractive target for anticancer drugs. Decoy G4-quadruplexes show the strong affinity for MAZ (myc-associated zinc-finger) which activates the transcription of KRAS. A TINA-modified quadruplex (twisted intercalated nucleic acid) showed a strong bioactivity, as it suppressed KRAS, inhibited proliferation, activated apoptosis in Panc-1 cancer cells, inhibited tumour growth and increased the survival time of the mice by ~50%. To improve the delivery we used liposomes to which we anchored non-covalently the lipid modified G4-decoy oligonucleotide and cell penetrating TAT. The liposome-anchored G4-decoy efficiently internalize in pancreatic Panc-1 cancer cells where it reduces the metabolic activity, the clonogenicity as well as the level of KRAS transcript.