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

Weina Ma; Jingjing Sun; Jieni Xu; Zhangyi Luo; Dingwei Diao; Ziqian Zhang; Patrick J Oberly; Margaret Beth Minnigh; Wen Xie; Samuel M Poloyac; Yi Huang; Song Li

doi:10.7150/thno.38973

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

Journal article

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Peer reviewed

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

Weina Ma, Jingjing Sun, Jieni Xu, Zhangyi Luo, Dingwei Diao, Ziqian Zhang, Patrick J Oberly, Margaret Beth Minnigh, Wen Xie, Samuel M Poloyac, …

Theranostics, Vol.10(6), pp.2463-2478

01/01/2020

DOI: 10.7150/thno.38973

PMCID: PMC7052901

PMID: 32194813

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Abstract

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 α (ERα) 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. : A SAHA-containing polymeric nanocarrier, POEG- -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- -PVDSAHA on reactivating the expression of functional ERα was investigated in several human and murine TNBC cell lines via examining the mRNA and protein expression of ERα target genes. The cytotoxicity of free SAHA and TAM combination and TAM-loaded POEG- -PVDSAHA micelles was examined via MTT assay. The antitumor activity of TAM-loaded POEG- -PVDSAHA was investigated in a murine breast cancer model (4T1.2). : Both free SAHA and POEG- -PVDSAHA were effective in inducing the reexpression of functional estrogen receptor α (ERα), which may have helped to sensitize TNBCs to TAM. More importantly, POEG- -PVDSAHA self-assembled to form small-sized micellar carrier that is effective in formulating and codelivery of TAM. TAM-loaded POEG- -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- -PVMA). In addition, codelivery of TAM via POEG- -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- -PVMA micelles. : Our prodrug-based co-delivery system may provide an effective and simple strategy to re-sensitize TNBCs to TAM-based hormone therapy.

Animals

Antineoplastic Combined Chemotherapy Protocols - administration & dosage

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Cell Line, Tumor

Drug Carriers - administration & dosage

Drug Carriers - pharmacology

Drug Combinations

Drug Synergism

Estrogen Receptor alpha - metabolism

Female

Glutathione - metabolism

Histone Deacetylase Inhibitors - administration & dosage

Histone Deacetylase Inhibitors - pharmacology

Humans

Mice

Mice, Inbred BALB C

Micelles

Nanoparticles - administration & dosage

Oxidation-Reduction - drug effects

Polymers - chemistry

Polymers - pharmacology

Prodrugs - administration & dosage

Prodrugs - pharmacology

Tamoxifen - administration & dosage

Tamoxifen - pharmacology

Triple Negative Breast Neoplasms - drug therapy

Triple Negative Breast Neoplasms - pathology

Vorinostat - administration & dosage

Vorinostat - pharmacology

Details

Title: Subtitle: Sensitizing Triple Negative Breast Cancer to Tamoxifen Chemotherapy via a Redox-Responsive Vorinostat-containing Polymeric Prodrug Nanocarrier
Creators: Weina Ma - PharmacoGenetics (China)
Jingjing Sun - University of Pittsburgh
Jieni Xu - University of Pittsburgh
Zhangyi Luo - University of Pittsburgh
Dingwei Diao - University of Pittsburgh
Ziqian Zhang - University of Pittsburgh
Patrick J Oberly - University of Pittsburgh
Margaret Beth Minnigh - University of Pittsburgh
Wen Xie - University of Pittsburgh
Samuel M Poloyac - University of Pittsburgh
Yi Huang - University of Pittsburgh
Song Li - University of Pittsburgh
Resource Type: Journal article
Publication Details: Theranostics, Vol.10(6), pp.2463-2478
DOI: 10.7150/thno.38973
PMID: 32194813
PMCID: PMC7052901
NLM abbreviation: Theranostics
ISSN: 1838-7640
eISSN: 1838-7640
Grant note: R01 CA219399 / NCI NIH HHS R01 CA174305 / NCI NIH HHS R01 CA223788 / NCI NIH HHS
Language: English
Date published: 01/01/2020
Academic Unit: Internal Medicine
Record Identifier: 9984383284802771

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