Peptide nanoparticle-mediated combinatorial delivery of cancer-related siRNAs for synergistic anti-proliferative activity in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is one of the deadliest types of cancer for women of different age groups. Frequently this cancer does not respond to conservative treatment. Combinatorial RNAi can be suggested as an advanced approach to TNBC therapy. Due to the fact that TNBC cells overexpress chemokine receptor 4, we used modular L1 peptide nanoparticles modified with CXCR4 ligand for combinatorial delivery of siRNAs suppressing major transduction pathways.

TNBC cell line MDA-MB-231 was used as a cellular model. Genes encoding the AQP3, CDC20, and COL4A2 proteins responsible for proliferative activity in TNBC cells were selected as RNAi targets. The siRNA binding ability of the carrier was studied at different charge ratios. The silencing specificity was demonstrated for all siRNAs studied.

AlamarBlue exclusion assay has shown a significant reduction in the anti-proliferative activity after combinatorial siRNA transfection compared to single siRNA delivery. The most significant synergistic effects have been demonstrated after combinatorial transfection with anti-CDC20 siRNA.

Based on our findings, we have concluded that combinatorial treatment by L1-polyplexes formed with AQP3, CDC20, and COL4A2 siRNAs effectively inhibits proliferation of TNBC cells and can be suggested as useful tool for RNAi-mediated cancer therapy.