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Published on: January 15, 2015
Fatty acid modified octa-arginine for delivery of siRNA
Yuhuan Li1, Yujing Li1, Xinmei Wang2
1School of Life Sciences, Jilin University, Changchun 130012, China.
Abstract:
Therapeutic delivery of small interfering RNA (siRNA) is a major challenge that limits its potential clinical application. Four fatty acids derivatives of octa-arginine (R8) were synthesized and evaluated for the delivery of siRNA into hepatocellular carcinoma Hep G2 and human lung adenocarcinoma A549 cells. The results showed that the long chain acid oleic acid or stearic acid derivatives of R8, OA-R8 and StA-R8, were more efficient in siRNA complexation and form nanoparticles with greater stability compared to the native R8. Cellular uptake of fluorescence-labeled siRNA delivered by OA-R8 and StA-R8 in Hep G2 and A549 cells was substantially 40-50 times higher than unmodified R8. A significant reduction in siRNA cellular uptake was observed in the presence of sucrose and cytochalasin D, indicating endocytosis as a primary mechanism of cellular entry. A survivin siRNA was used to prepare nanoparticles with OA-R8 or StA-R8 and evaluated for silencing of survivin mRNA and protein in A549 cells, and the inhibition efficiencies of survivin protein reached to 50.3% and 54.6%, respectively. The results showed greater effectiveness with the derivatized R8. Taken together, these findings showed that long chain fatty acid derivatives of R8 are efficient delivery agents for siRNA and may facilitate its therapeutic application.
Insights
Modified octa-arginine (R8) peptides with fatty acids demonstrate enhanced delivery of small interfering RNA (siRNA) into cancer cells. These novel carriers significantly improve siRNA uptake and therapeutic silencing, overcoming key delivery challenges.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Molecular Biology
Background:
- Therapeutic delivery of small interfering RNA (siRNA) faces significant challenges, hindering its clinical potential.
- Octa-arginine (R8) is a peptide known for its cell-penetrating properties, but its efficiency in siRNA delivery requires optimization.
Purpose of the Study:
- To synthesize and evaluate fatty acid derivatives of octa-arginine (R8) as novel carriers for siRNA delivery.
- To assess the efficiency of these modified R8 peptides in complexing siRNA, forming stable nanoparticles, and facilitating cellular uptake in cancer cell lines.
- To investigate the therapeutic potential of these delivery systems by evaluating gene silencing efficacy.
Main Methods:
- Synthesis of four fatty acid derivatives of octa-arginine (R8).
- Evaluation of siRNA complexation and nanoparticle stability with native R8 and its derivatives (OA-R8, StA-R8).
- Assessment of cellular uptake of fluorescently labeled siRNA in Hep G2 and A549 cells using flow cytometry.
- Investigation of cellular entry mechanisms via endocytosis inhibitors (sucrose, cytochalasin D).
- Preparation of survivin siRNA nanoparticles and evaluation of survivin mRNA and protein silencing in A549 cells.
Main Results:
- Oleic acid and stearic acid derivatives of R8 (OA-R8, StA-R8) showed superior siRNA complexation and nanoparticle stability compared to native R8.
- Cellular uptake of siRNA delivered by OA-R8 and StA-R8 was 40-50 times higher than with unmodified R8 in Hep G2 and A549 cells.
- Endocytosis was confirmed as the primary mechanism for cellular entry of siRNA delivered by these peptides.
- Survivin siRNA delivered by OA-R8 and StA-R8 achieved significant inhibition of survivin protein expression (50.3% and 54.6%, respectively) in A549 cells.
Conclusions:
- Long-chain fatty acid derivatives of R8 are effective agents for enhancing siRNA delivery into cancer cells.
- These modified R8 peptides improve siRNA complexation, nanoparticle stability, and cellular uptake.
- The developed siRNA delivery systems demonstrate significant gene silencing efficacy, suggesting potential for therapeutic applications in cancer treatment.
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