A Lipid Targeting, pH‐Responsive Nanoemulsion Encapsulating a DNA Intercalating Agent and HDAC Inhibitor Reduces TNBC Tumor Burden. Issue 3 (12th January 2021)

• Record Type: Journal Article
• Authors: Kim, Bumjun; Hebert, Jacob M.; Liu, Daxing; Auguste, Debra T.
• Is Part Of: Advanced therapeutics. Volume 4:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-12
• Subjects: drug combinations -- lipid nanoemulsion -- lysophosphatidic acid -- thioredoxin interacting protein -- triple‐negative breast cancers; Therapeutics -- Periodicals; Pharmaceutical technology -- Periodicals; Pharmacogenetics -- Periodicals; 615.5
• DOI: 10.1002/adtp.202000211
• Languages: English
• ISSNs: 2366-3987

Abstract

Abstract: 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 chemotherapy for TNBC. However, it often accompanies severe side effects that limit the effective therapeutic dose. It is hypothesized that the combination of Dox with a histone deacetylase inhibitor, panobinostat (Pan), may improve therapeutic efficacy by attacking rapid cell proliferation and abnormal histone deacetylation. Herein, pH‐responsive, lipid targeting nanoemulsions (pLNEs) are designed to direct both Dox and Pan to TNBC cells that overexpress lysophosphatidic acid (LPA) receptor 1 (LPAR1 ) via the ratio of LPA to lysophosphatidylcholine and trigger Dox release via disassociation from docosahexanoic acid. Dox/Pan‐pLNEs result in higher intranuclear Dox compared to free Dox, free Dox/Pan, and Dox‐pLNEs. Tumors treated with Dox/Pan‐pLNEs exhibit 2.4‐fold reduction in tumor burden relative to free Dox alone. Molecular analysis reveals that MDA‐MB‐231 tumor growth inhibition is mediated by re‐expression of thioredoxin‐interacting protein and suppression of cytoplasmic p27 kip1 and c‐Jun activation domain‐binding protein‐1. This lipid targeting, Dox/Pan encapsulating pLNE represents a platform for treating TNBC with greater therapeutic efficacy. Abstract : Delivery of a DNA intercalating agent and histone deacetylase inhibitor via a lipid targeting, pH‐responsive lipid nanoemulsion (Dox/Pan‐pLNEs) reduce triple negative breast cancers (TNBC) tumor burden more effectively. Dox/Pan‐pLNEs increase reactive oxygen species in TNBCs by regulating the thioredoxin (TRX)/TRX interacting protein pathway and the accompanied suppression of the phosphoinositide 3‐kinase/protein kinase B/mammalian rapamycin pathway.