Sensitizing Triple Negative Breast Cancer to Tamoxifen Chemotherapy via a Redox-Responsive Vorinostat-containing Polymeric Prodrug Nanocarrier

There is an urgent and unmet need to develop effective therapies for triple negative breast cancers (TNBCs) which are much more aggressive and have poor prognosis due to lack of receptor targets for Her2-targeted and endocrine therapy. In this study we systematically evaluated the effect of Vorinostat (SAHA, a pan-HDAC inhibitor) in reactivating the expression of functional estrogen receptor alpha (ER alpha) and synergizing with tamoxifen (TAM, a selective estrogen-receptor modulator) in antitumor activity. In addition, a SAHA prodrug-based dual functional nanocarrier was developed for codelivery of SAHA and TAM for effective combination therapy. Methods: A SAHA-containing polymeric nanocarrier, POEG-co-PVDSAHA was developed via reversible addition-fragmentation transfer (RAFT) polymerization with SAHA incorporated into the polymer through a redox-responsive disulfide linkage. The effect of both free SAHA and POEG-co-PVDSAHA on reactivating the expression of functional ER alpha was investigated in several human and murine TNBC cell lines via examining the mRNA and protein expression of ER alpha target genes. The cytotoxicity of free SAHA and TAM combination and TAM-loaded POEG-co-PVDSAHA micelles was examined via MTT assay. The in vivo antitumor activity of TAM-loaded POEG-co-PVDSAHA was investigated in a murine breast cancer model (4T1.2). Results: Both free SAHA and POEG-co-PVDSAHA were effective in inducing the reexpression of functional estrogen receptor alpha (ER alpha), which may have helped to sensitize TNBCs to TAM. More importantly, POEG-co-PVDSAHA self-assembled to form small-sized micellar carrier that is effective in formulating and codelivery of TAM. TAM-loaded POEG-co-PVDSAHA micelles exhibited enhanced and synergistic cytotoxicity against TNBC cell lines compared with free SAHA, free TAM and TAM loaded into a pharmacologically inert control carrier (POEG-co-PVMA). In addition, codelivery of TAM via POEG-co-PVDSAHA micelles led to significantly improved antitumor efficacy in 4T1.2 tumor model compared with other groups such as combination of free SAHA and TAM and TAM-loaded POEG-co-PVMA micelles. Conclusion: Our prodrug-based co-delivery system may provide an effective and simple strategy to re-sensitize TNBCs to TAM-based hormone therapy.