Nano-targeted Delivery of Rad6/Translesion Synthesis Inhibitor for Triple Negative Breast Cancer Therapy

The triple negative breast cancer (TNBC) subtype regardless of their BRCA1 status has the poorest outcome compared to other breast cancer subtypes and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of Rad6-mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting Rad6 with a Rad6-selective small molecule inhibitor SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its in vitro cytotoxic activity towards TNBC cells. Here we characterized the in vivo pharmacokinetic and therapeutic properties of PEGylated GNP-conjugated SMI#9 in BRCA1 wild type and BRCA1 mutant TNBC xenograft models, and investigated the impact of Rad6 inhibition on TNBC metabolism by 1H-NMR spectroscopy. GNP conjugation allowed the released SMI#9 to achieve higher systemic exposure and longer retention as compared to the unconjugated drug. Systemically administered SMI#9-GNP inhibited TNBC growth as effectively as intratumorally injected unconjugated SMI#9. Inductively coupled mass spectrometry analysis showed highest GNP concentrations in tumors and liver of SMI#9-GNP and blank-GNP treated mice; however, tumor growth inhibition occurred only in the SMI#9-GNP treated group. SMI#9-GNP was tolerated without overt signs of toxicity. SMI#9-induced sensitization was associated with perturbation of a common set of glycolytic pathways in BRCA1 wild type and BRCA1 mutant TNBC cells. These data reveal novel SMI#9 sensitive markers of metabolic vulnerability for TNBC management and suggest that nanotherapy mediated Rad6 inhibition offers a promising strategy for TNBC treatment.