Synthetically Lethal BMN 673 (Talazoparib) Loaded Solid Lipid Nanoparticles for BRCA1 Mutant Triple Negative Breast Cancer.

Abstract

The purpose of the study was to produce BMN 673 loaded solid lipid nanoparticles (SLNs) to improve its therapeutic index, to minimize toxicity and to overcome homologous recombination (HR)-mediated resistance. Firstly, BMN 673-SLNs were characterized using Nano Zeta Sizer. After treatment with different concentrations of BMN 673 and BMN 673-SLNs, cell viability of HCC1937(BRCA1-/-), HCC1937-R (BMN 673-resistant) TNBC and MCF-10A normal human mammary breast epithelial cell line was analyzed by WST-1 assay. In an attempt to assess the therapeutic synthetic lethality efficacy of SLNs formulation, cell cycle arrest, DNA damage, mRNA expression levels of PARP1, H2AFX, RAD51 and BRCA1 gene were investigated. Then, PARP, ɣH2AX, RAD51 and BRCA1 protein expression and nuclear localization were analyzed by western blot and immunofluorescence analysis. When compared with BMN 673, BMN 673-SLNs showed remarkably a decrease in HCC1937 and HCC1937-R cells with less damage to MCF-10A cells. BMN 673-SLNs significantly induced toxicity through double-stranded DNA breaks, G2/M cell cycle arrest and PARP cleavage in TNBC cells. Additionally, BMN 673-resistance was mediated by miR-107, miR-193b and miR-1255b targeting BRCA1 and RAD51 in HCC1937 and HCC1937-R cells. However, BMN 673-SLNs treatment could overcome HR-mediated resistance in TNBC cells. As a result, our findings suggest that SLNs formulation strongly provides a synthetic lethal therapeutic potential in BRCA1 mutated sensitive and resistant TNBC cells.