(15a) Synergy of an HDAC Inhibitor and Chemotherapy Delivered Via Lipid Nanoemulsions for TNBC

Triple negative breast cancers (TNBCs) represent a heterogenous disease with high patient mortality relative to other breast cancers. Doxorubicin (Dox), a DNA intercalating drug, is widely used as a chemotherapy for TNBC. However, it often accompanies severe side effects that limits the effective therapeutic dose. We hypothesized that the combination of Dox with a histone deacetylase (HDAC) inhibitor, panobinostat (Pan), may improve therapeutic efficacy by attacking rapid cell proliferation and abnormal histone deacetylation. Herein, pH-responsive, lipid targeting nanoemulsions (pLNEs) were designed to direct both Dox and Pan to TNBC cells that overexpress lysophosphatidic acid receptor 1 (LPAR₁) via the ratio of lysophosphatidic acid to lysophosphatidylcholine (LPA/LPC) and trigger Dox release via complexation with docosahexanoic acid (DHA) at low pH. We demonstrated that PAN and Dox exhibited a synergistic effect on the cell viability of TNBC cells at a specific ratio. The pLNE with a 1:1 ratio LPC and LPA had significantly higher tumor uptake efficiency than pLNEs with either LPC or LPA alone. pLNEs were used to encapsulate Pan and Dox. We performed in vivo studies that demonstrated a significant reduction in tumor burden relative to controls (including a Doxil mimic, Dox-LP) (Fig.1A). Additionally, survival curves demonstrated that Dox/Pan pLNEs had significantly greater survival than controls (Fig. 1B). Molecular analysis revealed that TNBC growth inhibition was mediated by re-expression of thioredoxin-interacting protein (TXNIP) and suppression of PI3K/Akt. axis. Dox/Pan-pLNEs resulted in a significant reduction in tumor burden and enhanced survival using a synergistic combination of HDAC inhibitor and the chemotherapeutic Dox. The reduced Dox concentration may reduce side effects. This lipid targeting, Dox/Pan encapsulating pLNE represents a platform for treating TNBC with greater therapeutic efficacy.