Efficient Short Interference RNA Delivery to Tumor Cells Using a Combination of Octaarginine, GALA and Tumor-Specific, Cleavable Polyethylene Glycol System

Abstract

We recently developed a multifunctional envelope-type nano device (MEND) for efficient nucleic acid delivery. Here, we report on the development of an octaarigine (R8)-modified MEND encapsulating small interfering RNA (siRNA) with a tumor-specific, cleavable, polyethylene glycol (PEG)-lipid (PPD). We first determined the optimal concentration of R8 and pH-sensitive fusogenic peptide (GALA) on the lipid envelope of MEND (R8/GALA-MEND). Then, we examined the combination of optimized R8/GALA-MEND with a PEG-lipid. When a conventional PEG-lipid was used, the R8/GALA-MEND failed to knockdown expression of the target gene. On the other hand, PPD-modified R8/GALA-MEND exhibited efficient silencing activity to the level of the PEG-unmodified R8/GALA-MEND. In addition, we compared a R8/GALA-MEND with a MEND composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) that is a conventional cationic lipid used as a lipoplex component. The knockdown ability of the R8/GALA-MEND was much higher than that of the DOTAP-based MEND at the dose that is commonly employed in in vitro siRNA transfection. These results demonstrate that the R8/GALA-MEND is a promising delivery system for the transfer of siRNA to tumor cells.

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

“…The introduction of GALA to PEGylated MENd enhanced the silencing activity of siRNA after in vitro and in vivo intratumoral injection. 112,113) However, when injected into the blood circulation, the GALA-modified PEGylated MENd was eliminated rapidly. We hypothesized that this was caused by the recognition of GALA by serum proteins because GALA was not masked completely.…”

Octaarginine-modified liposomes enhance the anti-oxidant effect of Lecithinized superoxide dismutase by increasing its cellular uptake

“…It is assumed that endosomal escape would not be sufficient for achieving effective PC-SOD delivery. We recently reported that a liposome surface modification with the pH-sensitive fusogenic peptide, GALA, enhanced endosomal escape and permitted cytosolic delivery to be efficiently achieved [25,26,27]. Accordingly, it would be expected that the modification of GALA with R8-LP (PC-SOD) would show stronger anti-oxidant effects.…”

Recent Advances in Endogenous and Exogenous Stimuli-Responsive Nanocarriers for Drug Delivery and Therapeutics

“…GALA undergoes structural change to the α-helix under acidic conditions, similarly to endosomes/lysosomes, which could induce membrane fusion. The introduction of GALA and its derivative 22 amino acid short version GALA (WEAALAEALAEALAEHLAEALA: shGALA) to liposomes enhanced the silencing activity of their cargos [25][26][27][28][29] (Fig. 1b).…”