NF-κB decoy polyplexes decrease P-glycoprotein-mediated multidrug resistance in colorectal cancer cells

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Nanotechnology

Background:

• Multidrug resistance (MDR) in cancer chemotherapy is often caused by efflux pumps like P-glycoprotein (P-gp).
• P-gp expression is regulated by the NF-κB signaling pathway in tumor cells.
• Targeting P-gp and NF-κB is a strategy to overcome MDR.

Purpose of the Study:

• To develop a nanoparticle-based system for delivering NF-κB decoy oligodeoxynucleotides (ODNs) into colorectal cancer cells.
• To modulate P-gp expression and activity in colon cancer cells.
• To assess the efficacy of this approach in overcoming P-gp-mediated multidrug resistance.

Main Methods:

• Fabrication of self-assembling nonviral nanoparticles using a novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethylmethacrylate) diblock copolymer (pHPMA-b-pDMAEMA).
• Evaluation of DNA condensation capacity and cellular safety of the nanoparticles.
• Transfection of Caco-2 cells with NF-κB decoy ODN-loaded nanoparticles.
• Quantification of P-gp protein levels and assessment of intracellular accumulation of Rhodamine123.

Main Results:

• pHPMA-b-pDMAEMA nanoparticles demonstrated high DNA condensation capacity and good cellular safety.
• Transfection efficiency in Caco-2 cells was comparable to commercial standards, achieving a 98% reduction in P-gp protein levels.
• Intracellular accumulation of Rhodamine123, a P-gp substrate, increased nearly twofold.

Conclusions:

• NF-κB ODN polyplexes formulated with pHPMA-b-pDMAEMA effectively reduce P-gp-mediated efflux activity in colon cancer cells.
• This approach successfully interferes with NF-κB binding sites in the ABCB1 gene promoter.
• The developed nanoparticle system shows promise for overcoming P-gp-mediated multidrug resistance in cancer therapy.