Triple-negative breast cancer (TNBC) accounts for 15-25% of diagnosed breast cancers, and its lack of a clinically defined therapeutic target has caused patients to suffer from earlier relapse and higher mortality rates than patients with other breast cancer subtypes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of multiple genes through RNA interference to maintain normal tissue function. The tumor suppressor miR-34a is downregulated in TNBC, and its loss-of-expression correlates with worse disease outcomes. Therefore, delivering miR-34a mimics into TNBC cells is a promising strategy to combat disease progression. To achieve this goal, we synthesized layer-by-layer assembled nanoparticles (LbL NPs) comprised of spherical poly(lactic-co-glycolic acid) cores surrounded by alternating layers of poly-L-lysine (PLL) and miR-34a. TNBC cells internalized these LbL NPs to a greater extent than polyplexes comprised of PLL and miRNA, and confocal microscopy showed that LbL NPs delivered a substantial fraction of miR-34a cargo into the cytosol. This yielded robust suppression of the miR-34a target genes CCND-1, Notch-1, Bcl-2, Survivin, and MDR-1, which reduced TNBC cell proliferation and induced cell cycle arrest. These data validate that miR-34a delivery can impair TNBC cell function and support continued investigation of this platform for treatment of TNBC.
Keywords: gene regulation; intracellular trafficking; miRNA; nanocarrier; oncology.
© 2019 Wiley Periodicals, Inc.