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Effectiveness of Small Interfering RNA Delivery via Arginine-Rich Polyethylenimine-Based Polyplex in Metastatic and

Shan Lu1, Viola B Morris1, Vinod Labhasetwar2

  • 1Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio (S.L., V.B.M., V.L.); University of Akron, Integrated Bioscience Program, Akron, Ohio (S.L.); and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (V.L.).

The Journal of Pharmacology and Experimental Therapeutics
|April 4, 2019
PubMed

Insights

This study developed a novel polymer-based nanoparticle for delivering small interfering RNA (siRNA), overcoming common delivery barriers. The new formulation effectively silenced target genes in cancer cells, showing promise for therapeutic applications.

Area of Science:

  • Biomaterials Science
  • Nanotechnology
  • Molecular Biology

Background:

  • Naked small interfering RNAs (siRNAs) face challenges like poor cellular uptake, serum degradation, and inefficient transfection, limiting their therapeutic use.
  • Developing effective delivery systems is crucial for siRNA-based therapies.

Purpose of the Study:

  • To evaluate a novel polyplex nanoparticle for siRNA delivery, formulated with PEG-modified l-arginine oligo(-alkylaminosiloxane) grafted with PEI.
  • To test the hypothesis that this polyplex overcomes siRNA delivery barriers by balancing PEI for condensation, PEG for stability and reduced toxicity, and arginine for cellular uptake.

Main Methods:

  • Synthesized a novel polymer for polyplex formulation.
  • Tested polyplex efficacy using antiluciferase siRNA in luciferase-expressing breast cancer cells (MDA-MB-231-Luc-D3H2LN).
  • Assessed anti-ABCB1 siRNA polyplex in doxorubicin-resistant breast cancer cells (MCF-7/Adr) to evaluate ABCB1 downregulation and drug sensitivity.

Main Results:

  • The polyplex demonstrated stability in serum, no cellular toxicity, and protected siRNA from degradation.
  • Effective knockdown of luciferase expression was achieved in MDA-MB-231-Luc-D3H2LN cells.
  • In MCF-7/Adr cells, anti-ABCB1 siRNA polyplex downregulated ABCB1, increased doxorubicin uptake, and enhanced its cytotoxic effect, though complete drug resistance reversal was not observed.

Conclusions:

  • The developed polyplex is an effective system for siRNA delivery, addressing key challenges in the field.
  • This formulation holds potential for various therapeutic applications, warranting further investigation and optimization.

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